A Phase 2, Single-Arm, Open-Label, Multicenter Study of the Bruton Tyrosine Kinase Inhibitor Zanubrutinib in Patients With CD79B Mutant Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Phase: PHASE2
Conditions: Relapsed Diffuse Large B-cell Lymphoma, Refractory Diffuse Large B-cell Lymphoma
Sponsor: BeiGene

BGB-3111-218 
BeiGene 
Protocol Amendment 3.0 
 
 
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CLINICAL STUDY PROTOCOL TITLE PAGE  
A Phase 2, Single-Arm, Open-Label, Multicenter Study of the Bruton 
Tyrosine Kinase Inhibitor Zanubrutinib in Patients With CD79B Mutant 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma  
Brief Title: 
A Study of Zanubrutinib in Patients With CD79B Mutant Relapsed/Refractory Diffuse Large B-Cell 
Lymphoma 
Protocol Number: 
BGB-3111-218 
Amendment Number: 
Amendment 3.0 
Investigational Medicinal 
Product: 
Zanubrutinib (BGB-3111) 
Regulatory Agency 
Identification Number(s): 
Not applicable 
Sponsor: 
BeiGene (Suzhou) Co., Ltd. 
Building 9, Biological Industrial Park  
No. 218 Sangtian Street, Suzhou Industrial Park  
China (Jiangsu) Pilot Free Trade Zone Suzhou Area 
Approval Date: 
See electronic signature 
Contact Information: 
BeiGene Medical Officer 
Phone: 1.877.828.5568 
Email: clinicaltrials@beigene.com 
 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is confidential and the proprietary property of BeiGene, Ltd. and its 
affiliates.  Any unauthorized use or disclosure of such information without the prior written 
authorization of BeiGene, Ltd. or any of its affiliates, or outside the cases and forms provided for by 
applicable legal provisions, is expressly prohibited. 
 
 
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INVESTIGATOR SIGNATURE PAGE  
I have read the protocol, appendices, and accessory materials related to study BGB-3111-218 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials. 
• To protect the rights, safety, and welfare of the patients under my care. 
• To provide oversight to all personnel to whom study activities have been delegated.  
This includes personnel at my site as well as personnel working in any facility where 
study activities are my responsibility. 
• To control all investigational products provided by the sponsor and maintain records 
of the disposition of those products. 
• To conduct the study in accordance with all applicable laws and regulations, the 
requirements of the ethics committee of record for my clinical site, and current GCP 
as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to patients 
before initiating the study at my site. 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all patients enrolled at my study site before initiating any 
study-specific procedures or administering investigational products to those patients. 
• To maintain records of each patient’s participation and all data required by the 
protocol in an accurate and timely manner. 
Acceptance of this protocol constitutes my agreement that no confidential information contained 
herein will be published or disclosed without prior written approval from BeiGene, Ltd. or one of 
its affiliates, unless and only to the extent required by applicable laws and regulations. 
Name:  Last name, First name 
Title:  Title at Institution 
Institution:  Address 
  
  
  
Signature:   
Date:  DD Month YYYY 
  
  
 
 
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DOCUMENT HISTORY  
Amendment Version Number 
Approval Date 
Type of Protocol Amendment 
BGB-3111-218 Amendment 2.0 
07 September 2022 
Non-substantial 
BGB-3111-218 Amendment 1.0 
15 February 2022 
Substantial 
Original protocol 
18 November 2020 
Not applicable 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
This Protocol Amendment 3.0 replaces the previous Protocol Amendment 2.0. The primary 
purpose of Amendment 3.0 is to: 
• Remove IRC-dependent assessments; 
• Remove CDx development; 
• Clarify that there would be options for patients to continue treatment after study closeout; 
• Update data of zanubrutinib and contraception language to align with the current 
investigator’s brochure. 
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 Study Objectives 
Section 3.1 Summary of Study 
Design 
Section 3.2 Figure 1 Study Schema 
Section 5.7 Efficacy Assessments 
Section 5.7.1 Radiographic Imaging 
Section 5.14 Long-Term Follow-up 
Section 9.1 Study Endpoints 
Section 9.1.2 Secondary Endpoints 
Section 9.2.5.2 Secondary Efficacy 
Endpoint Analyses 
Section 10.2 Independent Review 
Committee (deleted section) 
Appendix 1 Schedule of Assessments 
Footnotes c, s, t 
Removed IRC-dependent 
assessments and the definition of 
IRC. 
To convert the study from 
a potential pivotal study to 
a proof-of-concept study. 
Section 5.4.1 Prescreening 
Section 5.10 Biomarker Assessments 
Appendix 1 Schedule of Assessments 
Footnote h 
Removed CDx development and 
updated to allow residual samples 
for exploratory biomarker testing. 
To convert the study from 
a potential pivotal study to 
a proof-of-concept study. 
Section 5.15 End of Study 
Updated the language to state 
that patients who may benefit 
from zanubrutinib could be 
offered the option to continue 
treatment after the end of the 
study. 
To clarify that there would 
be options for patients to 
continue treatment after 
study closeout.  
Section 3.1 Summary of Study 
Design 
Section 5.7.1 Radiographic Imaging 
MRI and a non-contrast chest 
CT scan may be used instead of 
contrast CT for patients with 
serious contrast allergy. 
For clarity and feasibility. 
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Section Number and Title 
Summary of Change 
Brief Rationale for 
Change 
Appendix 1 Schedule of Assessments 
Footnote t 
Section 4.1 Inclusion Criteria 
Section 5.3 Females of Childbearing 
Potential and Contraception 
Section 5.8.6 Pregnancy Test 
Section 8.7 Pregnancy Reporting 
Appendix 1 Schedule of Assessments 
Footnote aa 
Updated the requirements for 
contraception and pregnancy 
testing/reporting to align with the 
current investigator’s brochure. 
For consistency. 
Section 1.4 Background Information 
on Zanubrutinib (BGB-3111) 
Section 1.4.1 Nonclinical Data for 
Zanubrutinib 
Section 1.4.3.3 Phase 2 Study 
BGB-3111-213 
Section 1.6 Benefit-Risk Assessment 
Updated to align with the current 
investigator’s brochure. 
To provide the most 
current data of 
zanubrutinib. 
Section 8.1.1.3 Following Adverse 
Events and Serious Adverse Events 
Section 8.4.1 Adverse Event 
Reporting Period 
Appendix 1 Schedule of Assessments 
Footnote r 
Added the endpoint of initiation 
of any alternative anticancer 
therapy for initial/follow-up 
reporting period of all AEs and 
SAEs. 
For clarity and consistency 
throughout this protocol. 
Clinical Study Protocol Title Page, 
Investigator Signature Page 
Appendix 6 Signature of Investigator 
(deleted appendix) 
Updated the current study 
information per the current 
guidance and template. 
To update for 
administrative purposes 
and consistency with the 
protocol template. 
Document History 
Added Document History page. 
For consistency with the 
protocol template. 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL TITLE PAGE ...........................................................................1 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS  ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background Information on DLBCL ..........................................................................21 
1.2. 
Current Treatment of DLBCL and Unmet Clinical Needs .........................................23 
1.3. 
Bruton Tyrosine Kinase Therapy With DLBCL ........................................................24 
1.4. 
Background Information on Zanubrutinib (BGB-3111) .............................................26 
1.4.1. 
Nonclinical Data for Zanubrutinib ..............................................................................26 
1.4.2. 
Clinical Pharmacology ................................................................................................27 
1.4.3. 
Preliminary Efficacy and Safety Data with Zanubrutinib in DLBCL Patients ..........28 
1.4.3.1. 
Phase 1/2 Study BGB-3111-AU-003 ..........................................................................28 
1.4.3.2. 
Phase 2 Study BGB-3111-207 ....................................................................................29 
1.4.3.3. 
Phase 2 Study BGB-3111-213 ....................................................................................29 
1.4.3.4. 
Phase 1 Study BGB-3111-GA101-Study-001 ............................................................30 
1.5. 
Study Rationales .........................................................................................................31 
1.5.1. 
Rationale for Selection of Dose ..................................................................................31 
1.5.2. 
Rationale for the Therapy ...........................................................................................31 
1.6. 
Benefit-Risk Assessment ............................................................................................33 
2. 
STUDY OBJECTIVES ..............................................................................................34 
3. 
STUDY DESIGN .......................................................................................................35 
3.1. 
Summary of Study Design ..........................................................................................35 
3.2. 
Study Schema .............................................................................................................37 
3.3. 
Blinding ......................................................................................................................38 
4. 
SELECTION OF STUDY POPULATION ................................................................39 
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4.1. 
Inclusion Criteria ........................................................................................................39 
4.2. 
Exclusion Criteria .......................................................................................................40 
5. 
ENROLLMENT AND STUDY PROCEDURES ......................................................43 
5.1. 
Visit Windows ............................................................................................................43 
5.2. 
Informed Consent .......................................................................................................43 
5.3. 
Females of Childbearing Potential and Contraception ...............................................43 
5.4. 
Enrollment ..................................................................................................................44 
5.4.1. 
Prescreening ................................................................................................................44 
5.4.2. 
Screening ....................................................................................................................45 
5.4.3. 
Patient Numbering ......................................................................................................45 
5.4.4. 
Medical and Cancer History .......................................................................................45 
5.4.5. 
Confirmation of Eligibility .........................................................................................46 
5.5. 
Zanubrutinib Dispensation ..........................................................................................46 
5.6. 
Safety Assessments .....................................................................................................46 
5.6.1. 
Physical Examination and Vital Signs ........................................................................46 
5.6.2. 
ECOG Performance Status .........................................................................................47 
5.6.3. 
Electrocardiogram .......................................................................................................47 
5.6.4. 
Echocardiogram/Multiple Gated Acquisition Scan ....................................................47 
5.6.5. 
Pulmonary Function Test ............................................................................................47 
5.6.6. 
Concomitant Medications Review ..............................................................................47 
5.6.7. 
Adverse Events Review ..............................................................................................47 
5.7. 
Efficacy Assessments .................................................................................................47 
5.7.1. 
Radiographic Imaging ................................................................................................48 
5.7.2. 
Bone Marrow Examination .........................................................................................48 
5.8. 
Laboratory Assessments .............................................................................................48 
5.8.1. 
Hematology .................................................................................................................49 
5.8.2. 
Serum Chemistry ........................................................................................................49 
5.8.3. 
Coagulation .................................................................................................................49 
5.8.4. 
Urinalysis ....................................................................................................................49 
5.8.5. 
Hepatitis B and C Testing ...........................................................................................49 
5.8.6. 
Pregnancy Test ............................................................................................................51 
5.9. 
Pharmacokinetics ........................................................................................................51 
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5.10. 
Biomarker Assessments ..............................................................................................51 
5.11. 
Unscheduled Visits .....................................................................................................52 
5.12. 
End of Treatment ........................................................................................................52 
5.13. 
Safety Follow-Up Visit ...............................................................................................53 
5.14. 
Long-Term Follow-Up ...............................................................................................53 
5.15. 
End of Study ...............................................................................................................53 
5.16. 
Loss to Follow-Up ......................................................................................................54 
6. 
STUDY TREATMENT ..............................................................................................55 
6.1. 
Zanubrutinib ...............................................................................................................55 
6.1.1. 
Packaging and Labeling of Zanubrutinib ...................................................................55 
6.1.2. 
Handling and Storage of Zanubrutinib .......................................................................55 
6.1.3. 
Compliance and Accountability of Zanubrutinib .......................................................55 
6.1.4. 
Disposal and Destruction of Zanubrutinib ..................................................................56 
6.1.5. 
Dosage and Administration of Zanubrutinib ..............................................................56 
6.1.6. 
Precautions of Zanubrutinib .......................................................................................56 
6.1.6.1. 
Overdose .....................................................................................................................56 
6.1.6.2. 
Surgery and Procedures ..............................................................................................56 
6.1.7. 
Dose Interruption and Modification of Zanubrutinib .................................................56 
6.1.7.1. 
Zanubrutinib Dose Reductions for Hematologic Toxicity .........................................57 
6.1.7.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity ...................................57 
7. 
PRIOR AND CONCOMITANT THERAPY .............................................................59 
7.1. 
Prior Therapy ..............................................................................................................59 
7.2. 
Concomitant Therapy .................................................................................................59 
7.2.1. 
Permitted Medications ................................................................................................59 
7.2.2. 
Prohibited Medications ...............................................................................................60 
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................60 
8. 
SAFETY MONITORING AND REPORTING .........................................................62 
8.1. 
Adverse Events ...........................................................................................................62 
8.1.1. 
Definitions and Reporting of an Adverse Event .........................................................62 
8.1.1.1. 
Assessment of Severity ...............................................................................................62 
8.1.1.2. 
Assessment of Causality .............................................................................................63 
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8.1.1.3. 
Following Adverse Events and Serious Adverse Events ............................................64 
8.1.2. 
Laboratory Test Abnormalities ...................................................................................64 
8.2. 
Definition of a Serious Adverse Event .......................................................................65 
8.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................65 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................66 
8.4.1. 
Adverse Event Reporting Period ................................................................................66 
8.4.2. 
Eliciting Adverse Events ............................................................................................66 
8.5. 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events .........................................................................................................................66 
8.5.1. 
Disease Progression ....................................................................................................66 
8.5.2. 
Death ...........................................................................................................................66 
8.6. 
Reporting of Serious Adverse Events .........................................................................67 
8.6.1. 
Prompt Reporting of Serious Adverse Events ............................................................67 
8.6.2. 
Completion and Transmission of the Serious Adverse Event Report ........................67 
8.6.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................67 
8.7. 
Pregnancy Reporting ..................................................................................................68 
8.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees .....................................................................68 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................69 
9.1. 
Study Endpoints ..........................................................................................................69 
9.1.1. 
Primary Endpoint ........................................................................................................69 
9.1.2. 
Secondary Endpoints ..................................................................................................69 
9.1.3. 
Exploratory Endpoints ................................................................................................69 
9.2. 
Statistical Analysis ......................................................................................................69 
9.2.1. 
Analysis Sets ...............................................................................................................69 
9.2.2. 
Patient Disposition ......................................................................................................70 
9.2.3. 
Demographics and Other Baseline Characteristics .....................................................70 
9.2.4. 
Prior and Concomitant Therapy ..................................................................................70 
9.2.5. 
Efficacy Analyses .......................................................................................................70 
9.2.5.1. 
Primary Efficacy Endpoint Analysis ..........................................................................70 
9.2.5.2. 
Secondary Efficacy Endpoint Analyses ......................................................................71 
9.2.6. 
Biomarker Analyses ....................................................................................................72 
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9.2.7. 
Pharmacokinetic Analyses ..........................................................................................72 
9.2.8. 
Subgroup Analyses .....................................................................................................72 
9.3. 
Safety Analyses ..........................................................................................................73 
9.3.1. 
Extent of Exposure .....................................................................................................73 
9.3.2. 
Adverse Events ...........................................................................................................73 
9.3.3. 
Laboratory Analyses ...................................................................................................74 
9.3.4. 
Vital Signs ..................................................................................................................74 
9.3.5. 
Electrocardiogram .......................................................................................................74 
9.3.6. 
Echocardiogram/Multiple Gated Acquisition Scan ....................................................74 
9.3.7. 
Pulmonary Function Test ............................................................................................74 
9.4. 
Sample Size Consideration .........................................................................................74 
9.5. 
Interim Analysis ..........................................................................................................75 
9.6. 
Primary Analysis ........................................................................................................75 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................76 
10.1. 
Safety Monitoring Committee ....................................................................................76 
10.2. 
Provision of Study Results and Information to Investigators .....................................76 
11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ..........................77 
11.1. 
Regulatory Authority Approval ..................................................................................77 
11.2. 
Investigator Responsibilities .......................................................................................77 
11.2.1. 
Good Clinical Practice ................................................................................................77 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................77 
11.2.3. 
Informed Consent .......................................................................................................78 
11.2.4. 
Investigator Reporting Requirements .........................................................................78 
11.2.5. 
Confidentiality ............................................................................................................78 
11.2.6. 
Data Collection ...........................................................................................................80 
11.2.7. 
Data Management/Coding ..........................................................................................80 
11.2.8. 
Drug Integrity and In-house Blinding .........................................................................81 
11.2.9. 
Drug Accountability ...................................................................................................81 
11.2.10. 
Inspections, Audits, and Monitoring Visits ................................................................81 
11.2.11. 
Protocol Adherence ....................................................................................................81 
11.2.12. 
Financial Disclosure ...................................................................................................81 
11.3. 
Protocol Modifications ...............................................................................................82 
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11.4. 
Study Report and Publications....................................................................................82 
11.5. 
Study and Study Center Closure .................................................................................83 
11.6. 
Records Retention and Study Files .............................................................................83 
11.7. 
Information Disclosure and Inventions ......................................................................84 
11.8. 
Joint Investigator/Sponsor Responsibilities ................................................................85 
11.8.1. 
Access to Information for Monitoring ........................................................................85 
11.8.2. 
Access to Information for Auditing or Inspections ....................................................85 
12. 
REFERENCES ...........................................................................................................86 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................91 
APPENDIX 2. LUGANO CLASSIFICATION FOR NON-HODGKIN LYMPHOMA ...........96 
APPENDIX 3. NEW YORK HEART ASSOCIATION CLASSIFICATION .........................100 
APPENDIX 4. CYP3A INHIBITORS AND INDUCERS .......................................................101 
APPENDIX 5. ECOG PERFORMANCE STATUS.................................................................102 
 
LIST OF TABLES  
Table 1: 
Overall Response Rates of BTK Inhibitors in CD79B Mutant/Wild-type 
ABC/Non-GCB DLBCL Patients ...............................................................................32 
Table 2: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection .......................................50 
Table 3: 
Zanubrutinib Dose Reduction Levels .........................................................................57 
Table 4: 
Dose Modification for Zanubrutinib When Coadministered With 
Strong/Moderate CYP3A Inhibitors or Inducers ........................................................61 
Table 5: 
Time Frame for Reporting Serious Adverse Events to the Sponsor or 
Designee .....................................................................................................................67 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................38 
 
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SYNOPSIS   
Name of Sponsor/Company:  BeiGene (Suzhou) Co., Ltd. 
Investigational Product:  Zanubrutinib (BGB-3111) 
Title of Study:  A Phase 2, Single-Arm, Open-Label, Multicenter Study of the Bruton Tyrosine Kinase 
Inhibitor Zanubrutinib in Patients With CD79B Mutant Relapsed/Refractory Diffuse Large B-Cell 
Lymphoma 
Protocol Identifier:  BGB-3111-218 
Phase of Development:  2 
Number of Patients:  Approximately 66 patients will be enrolled. 
Objectives of Study 
Primary Objective 
• 
To evaluate the efficacy of zanubrutinib in patients with CD79B mutant relapsed/refractory 
diffuse large B-cell lymphoma (R/R DLBCL), as measured by overall response rate determined 
by the investigator assessment in accordance with the 2014 modification of the International 
Working Group on non-Hodgkin lymphoma (NHL) Criteria (hereafter referred to as the 
Lugano classification) (Cheson et al 2014). 
Secondary Objectives 
• 
To evaluate the efficacy of zanubrutinib in patients with CD79B mutant R/R DLBCL, as 
measured by the following: 
− Complete response rate determined by investigator assessment 
− Duration of response determined by investigator assessment 
− Progression-free survival determined by investigator assessment 
− Time to response determined by investigator assessment 
− Overall survival 
• 
To evaluate the safety and tolerability of zanubrutinib in patients with CD79B mutant R/R 
DLBCL when given as monotherapy 
Exploratory Objectives 
• 
To evaluate the pharmacokinetics (PK) of zanubrutinib in patients with CD79B mutant R/R 
DLBCL 
− 
Summary of plasma concentrations of zanubrutinib 
• 
To evaluate the correlation of clinical/genetic risk factors and clinical outcomes 
• 
To explore mechanisms of disease resistance 
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Study Design 
This single-arm, open-label, multicenter Phase 2 study is designed to assess the efficacy and safety of 
zanubrutinib in patients with CD79B mutant R/R DLBCL.  The primary efficacy endpoint is the 
overall response rate determined by the investigator assessment.  Disease response will be assessed per 
the Lugano classification (Cheson et al 2014).  The primary analysis will take place approximately 6 
months after the first dose of the last patient. 
Prescreening evaluations of CD79B mutation status by central laboratory will be performed for patients 
who have histologically confirmed DLBCL and show a trend of lack of efficacy in their current 
systemic anti-DLBCL treatments, or the trend of disease progression.  Only DLBCL patients with 
centrally confirmed CD79B mutation (except for patients with CD79B mutation locally confirmed and 
approved by the sponsor) and refractory or relapsed disease as confirmed by investigators are eligible 
for screening evaluations.  Screening evaluations will be performed within 21 days before the first 
administration of study drug unless noted otherwise.   
The treatment period starts with the first day of zanubrutinib administration and continues until the last 
dose of zanubrutinib has been administered.  Zanubrutinib will be administered orally as two 80-mg 
capsules twice a day (160 mg twice a day) continuously.  Each cycle is 28 days in length.  Patients will 
receive zanubrutinib until disease progression, unacceptable toxicity, loss to follow-up, or the end of 
the study, whichever occurs first.   
All patients who permanently discontinue study drug will remain in the study, have a Safety Follow-up 
Visit, and subsequently commence long-term follow-up. 
Safety Follow-up Visit occurs approximately 30 days (± 7 days) after the last dose of zanubrutinib to 
perform the planned safety assessments and laboratory assessments, and to collect information on 
alternative anticancer therapy given after the last dose of study drug.   
Long-term follow-up includes monitoring survival status, second primary malignances, subsequent 
therapies for DLBCL, and may also include imaging and tumor response assessments for patients who 
have not yet had confirmed radiographic progression, which will continue until disease progression, 
start of alternative anticancer therapy, loss to follow-up, or the end of the study, whichever occurs first. 
Study Assessments: 
Assessments of DLBCL status during the study include disease-related constitutional symptoms, 
physical examination of lymph nodes, liver, and spleen; bone marrow examination; positron emission 
tomography (PET)-computed tomography (CT) and/or CT scan with contrast of the chest, abdomen, 
pelvis, and neck if clinically indicated. 
Response will be evaluated on the basis of clinical and radiologic evaluations using the Lugano 
classification.  All patients must have a baseline PET-CT and CT scan with contrast of the chest, 
abdomen, pelvis, and neck if clinically indicated within 21 days before the first dose of study drug.  
PET-CT scans are required at screening, at Week 12 and Week 24 after treatment, and at the time when 
complete response (CR) or progressive disease (PD) is suspected.  For fluorodeoxyglucose (FDG) 
non-avid disease, only CT scans will be required for post-baseline visit.  Contrast CT will be performed 
at screening, every 12 weeks for 24 months, and every 24 weeks thereafter until disease progression, 
start of alternative anticancer therapy, loss to follow-up, or the end of the study, whichever occurs first.  
PET-CT may be used in lieu of a CT with contrast only if the CT of the PET-CT has been performed 
with diagnostic quality and contrast is administered.  When both PET-CT and CT evaluations are 
available for the same tumor assessment visit, the results of PET-CT shall prevail.  Bone marrow 
biopsy and aspirate are required to assess bone marrow involvement of lymphoma for all patients 
during the screening period, unless they have been performed within 60 days before the first dose of 
study drug as part of the standard care and there has been no intervening therapy from the time of the 
biopsy/aspirate until the start of study drug.  For patients with bone marrow involvement of lymphoma 
at baseline, repeated bone marrow biopsy and aspirate are required if CR is suspected.  Clinical 
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suspicion of disease progression at any time will require radiologic confirmation to be performed 
promptly, rather than waiting for the next scheduled radiologic assessment.  Magnetic resonance 
imaging (MRI) and a non-contrast chest CT scan may be used instead of contrast CT for patients with 
serious contrast allergy; whichever method is used should be used consistently. 
Safety assessments will include adverse events, serious adverse events, clinical laboratory tests, 
physical examinations, and vital signs.  Adverse events will be graded for severity per the National 
Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE).  
Laboratory assessments, including serum chemistry, complete blood count (CBC), coagulation, 
urinalysis, and pregnancy tests, should be performed at a local certified laboratory.  Details for hepatitis 
B and hepatitis C are listed in Section 5.8.5.   
Blood samples will be collected sparsely at predose and 2 hours (± 30 minutes) postdose on Day 1 of 
Cycle 1 and Cycle 2 to evaluate the exposure of zanubrutinib. 
Tumor tissue must be sent to the central laboratory for CD79B mutation status analysis at the 
Prescreening Visit.  For those patients enrolled, other predictive biomarkers will also be determined 
during screening and correlated with response, resistance, and prognosis.  CD79B mutation status in 
the blood will be assessed.  Blood-based biomarker analysis will also be performed to explore their 
association with response, resistance, and prognosis. 
Key Eligibility Criteria 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Men and women ≥ 18 years of age at the time of informed consent. 
2. Histologically confirmed DLBCL based on the World Health Organization (WHO) 2008 
classification of tumors of hematopoietic and lymphoid tissue.  
3. Positive CD79B mutation confirmed by the central laboratory. 
4. Previously received at least 1 line of adequate systemic anti-DLBCL therapy, defined as an 
anti-CD20 antibody-based chemoimmunotherapy for at least 2 consecutive cycles, unless 
patients had disease progression before Cycle 2.  
5. Relapsed or refractory (R/R) disease before study entry, defined as either:  
a. Recurrent disease after having achieved disease remission (CR or partial response 
[PR]) at the completion of the latest treatment regimen. 
b. Stable disease or PD at the completion of the latest treatment regimen. 
6. Ineligible for high dose therapy/stem cell transplantation, which is defined as meeting any of 
the following criteria: 
a. Significant organ dysfunction (eg, left ventricular ejection fraction < 50% by 
echocardiogram or multiple gated acquisition scan [MUGA], diffuse lung capacity for 
carbon monoxide < 60% predicted by pulmonary function test, creatinine clearance 
< 70 mL/min shown by nuclear medicine scan or 24-hour urine collection) or 
comorbidities precluding the use of high dose therapy/stem cell transplantation on the 
basis of unacceptable risk of treatment-related morbidity. 
b. Failure to achieve CR or PR with salvage therapy. 
c. Failure to collect stem cells or unable to perform stem cell collection as assessed by the 
investigator. 
7. Patients who have completed autologous stem cell transplantation ≥ 100 days before the first 
dose of zanubrutinib may be enrolled. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  
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9. Measurable disease as defined by at least 1 lymph node > 1.5 cm in longest diameter, or at 
least 1 extranodal lesion that is > 1.0 cm in longest diameter.  
10. Adequate hematologic function, defined as: 
a. Absolute neutrophil count (ANC) ≥ 1 x 109/L, except for patients with bone marrow 
involvement in which ANC must be ≥ 0.75 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 (or ≥ 50 x 109/L for patients with bone marrow 
involvement of lymphoma), independent of growth factor support or transfusion within 
7 days before the first dose of study drug. 
c. Hemoglobin > 80 g/L, independent of growth factor support or transfusion within 
7 days before the first dose of study drug. 
11. Adequate hepatic function, defined as: 
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper 
limit of normal (ULN). 
b. Total bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome, in which case ≤ 5 x 
ULN is allowed). 
12. Adequate renal function, defined as creatinine clearance of ≥ 30 mL/min (as estimated by the 
Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the modification 
of diet in renal disease [MDRD]). 
13. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time 
(aPTT) ≤ 1.5 x ULN. 
14. Female patients of childbearing potential must practice highly effective methods of 
contraception (Section 5.3) starting from before the first dose of study drug, throughout the 
study treatment, and for up to 1 month after the last dose of zanubrutinib. 
15. Male patients are eligible if abstinent or vasectomized or if they agree to use highly effective 
contraception (as described in Section 5.3) during the study treatment period and for up to 1 
week after the last dose of zanubrutinib. 
16. Life expectancy of > 3 months. 
17. Able to provide written informed consent and can understand and comply with the 
requirements of the study. 
Exclusion Criteria 
Each patient eligible to participate in this study must not meet any of the following exclusion criteria: 
1. Patients who have NHL other than classical histology DLBCL (DLBCL, not otherwise 
specified), eg, patients with DLBCL transformed from indolent lymphomas, primary 
mediastinal (thymic) large B-cell lymphoma,  primary cutaneous DLBCL, primary effusion 
lymphoma, and central nervous system (CNS) lymphoma.  
2. History of allogeneic stem cell transplantation or chimeric antigen receptor (CAR) T-cell 
therapy. 
3. Prior exposure to a Bruton tyrosine kinase (BTK) inhibitor. 
4. Receipt of the following treatment at the time indicated before the first dose of study drug: 
a. Corticosteroid given with antineoplastic intent within 2 weeks, but a short course 
(≤ 7 days) of systemic corticosteroid treatment at doses ≤ 20 mg/day prednisone 
equivalent for control of lymphoma-related symptoms is allowed prior to enrollment 
provided that it is tapered off within 5 days after initiation of study treatment. 
b. Chemotherapy or radiotherapy within 2 weeks. 
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c. Monoclonal antibody within 2 weeks. 
d. Investigational therapy within 2 weeks. 
e. Chinese patent medicine with antineoplastic intent within 2 weeks. 
5. Toxicity of Grade ≥ 2 from prior anticancer therapy (except for alopecia, ANC, hemoglobin 
and platelets.  For ANC, hemoglobin and platelets, please follow inclusion criterion #10). 
6. History of other active malignancies within 2 years before study entry, with the exception of 
(1) adequately treated in-situ carcinoma of the cervix; (2) localized basal cell or squamous cell 
carcinoma of the skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
7. 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 arrhythmia (eg, sustained ventricular tachycardia, ventricular 
fibrillation, torsade de pointes). 
d. QTcF (Fridericia’s correction) > 480 msec. 
e. History of second-degree atrioventricular (AV) block Type II or third-degree AV 
block. 
f. New York Heart Association class 3 or 4 congestive heart failure (see Appendix 3). 
g. Uncontrolled hypertension as indicated by at least 2 consecutive blood pressure 
measurements showing systolic blood pressure > 170 mm Hg and diastolic blood 
pressure > 105 mm Hg at screening. 
8. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand 
disease, or history of spontaneous bleeding requiring blood transfusion or other medical 
intervention. 
9. History of stroke or intracranial hemorrhage within 6 months before the first dose of study 
drug. 
10. Inability to swallow capsules or presence of a disease that significantly affects gastrointestinal 
function such as malabsorption syndrome, resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
11. Active fungal, bacterial and/or viral infection that requires systemic therapy. 
12. Known HIV, or serologic status reflecting active hepatitis B virus (HBV) or hepatitis C virus 
(HCV) infection as follows:  
a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb).  Patients with presence of HBcAb, but without HBsAg, are eligible if HBV 
DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monthly 
monitoring for HBV reactivation.  
b. Presence of HCV antibody.  Patients with presence of HCV antibody are eligible if 
HCV RNA is undetectable (< 15 IU/mL). 
13. Requires ongoing treatment with strong and moderate cytochrome P450 3A (CYP3A) 
inhibitors or inducers (see Appendix 4).  If patients have been on strong or moderate CYP3A 
inhibitors or inducers in the past, they will not be eligible if the administration was within 
7 days (or 5 half-lives of these drugs) before the first dose of study drug. 
14. Major surgery within 4 weeks before the first dose of study drug. 
15. Live vaccination within 4 weeks before the first dose of study drug. 
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16. Any medical condition or organ system dysfunction that, in the investigator’s opinion, could 
compromise the patient’s safety or put the study at risk. 
17. Pregnant or lactating women. 
Test Product, Dose, and Mode of Administration 
Zanubrutinib will be administered orally as two 80-mg capsules twice a day (160 mg twice a day) 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.  Each cycle is 28 days in length. 
Statistical Methods 
Analysis Sets: 
Safety Analysis Set: includes all patients who receive at least one dose of zanubrutinib.  The Safety 
Analysis Set will be used for both safety and efficacy analyses. 
PK Analysis Set: includes all patients for whom there is at least one available postdose zanubrutinib 
PK concentration measurement. 
Efficacy Analyses: 
Efficacy assessments will use the Lugano classification to assess overall disease response. 
Primary Efficacy Analysis: 
The primary efficacy endpoint is the overall response rate determined by the investigator assessment, 
where the overall response rate is defined as the proportion of patients in the Safety Analysis Set whose 
best overall response is either CR or PR.  The best overall response is defined as the best response 
recorded from the start of zanubrutinib until the data cutoff date or the start of alternative anticancer 
treatment.  Patients who drop out earlier with no post-baseline response assessment (for any reason) 
will be considered nonresponders for best overall response. 
The overall response rate of historical control in this study is 30% (Section 9.2.5.1).  A binomial exact 
test will be performed for hypothesis testing H0: overall response rate of zanubrutinib = 30% versus Ha: 
overall response rate of zanubrutinib > 30% in the Safety Analysis Set.  If the null hypothesis can be 
rejected at one-sided significance level of 0.025, it will be concluded that the historical control of 30% 
can be ruled out.  A 2-sided Clopper-Pearson 95% confidence interval (CI) of overall response rate will 
also be calculated to assess the precision of the estimation. 
The primary analysis will take place approximately 6 months after the first dose of the last patient.  
Secondary Efficacy Analyses: 
The complete response rate determined by investigator assessment will be summarized along with the 
2-sided Clopper-Pearson 95% CI. 
Duration of response is defined as the time from the date that the response criteria are first met to the 
date that PD is objectively documented or death, whichever occurs first.  The duration of response will 
be only summarized for responders.  The Kaplan-Meier method will be used to estimate duration of 
response curves and corresponding quantiles (including the median) (Schemper and Smith 1996).  A 
2-sided 95% CI of median, if estimable, will be constructed with a generalized Brookmeyer and 
Crowley method (Brookmeyer and Crowley 1982).  The duration of response event-free rates at 
selected timepoints will be estimated along with the corresponding 95% CI. 
Progression-free survival is defined as the time from the starting date of the therapy to the date of first 
documentation of disease progression or death, whichever occurs first.  The Kaplan-Meier method will 
be used to estimate progression event-free curves and corresponding quantiles (including the median) 
(Schemper and Smith 1996).  A 2-sided 95% CI of median, if estimable, will be constructed with a 
generalized Brookmeyer and Crowley method (Brookmeyer and Crowley 1982).  The progression-free 
survival probability at selected timepoints will be estimated along with the corresponding 95% CI. 
Time to response, defined as time from the starting date of therapy to the date the response criteria are 
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first met, will be summarized with descriptive statistics only for responders. 
Overall survival, defined as the time from the starting date of the therapy to the date of death due to any 
reason, will be analyzed similarly as progression-free survival. 
Primary and selected secondary endpoints will also be summarized descriptively in specified subgroups 
and the within group values will be presented in forest plots. 
Safety Analyses: 
Drug exposure will be summarized descriptively, including duration, dosage, and dose intensity. 
Verbatim description of adverse events will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA) terms and graded according to the NCI-CTCAE Version 5.0.   
A treatment-emergent adverse event is defined as an adverse event that had an onset date or worsening 
in severity from baseline (pretreatment) on or after the first dose of study drug and up to 30 days after 
the last dose of zanubrutinib, or the initiation of any alternative anticancer therapy, whichever comes 
first.  Worsening of an event to Grade 5 beyond day 30 after last dose of study drug of a treatment-
emergent adverse event is also considered a treatment-emergent adverse event.  The patient incidence 
of all treatment-emergent adverse events, serious treatment-emergent adverse events, treatment-
emergent adverse events of Grade 3 or higher, treatment-emergent adverse events leading to death, and 
treatment-emergent adverse events leading to treatment discontinuation and dose modification (dose 
reduction or dose interruption) will be summarized.  Multiple occurrences of the same event will be 
counted once at the maximum severity within a system organ class (SOC) and preferred term (PT).  
Deaths and cause of deaths will be summarized. 
Laboratory test results, vital signs, and their changes from baseline were summarized using descriptive 
statistics (eg, n, mean, standard deviation, median, minimum, and maximum for continuous variables; 
n [%] for categorical variables). 
PK Analyses: 
Plasma zanubrutinib concentration data will be tabulated and summarized by cycle.  Descriptive 
statistics including means, standard deviations, medians, and ranges as appropriate, will be used for the 
analysis of plasma zanubrutinib concentrations. 
Sample Size: 
The sample size of the study is planned based on the level of precision of overall response rate estimate 
as well as the power of a hypothesis testing against a historical rate.  The targeted overall response rate 
in this study is 50% (Section 1.5.2), which is deemed a clinically meaningful improvement based on a 
historical control of 30%.  Assuming a true overall response rate of 50% in the study population, 
66 patients will provide 90% power to reject the null hypothesis of 30% ORR at the one-sided 
significance level of 0.025.  The 95% Clopper-Pearson CI will be (37.4%, 62.6%) with a sample size of 
66 patients, when the observed overall response rate is 50%. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ABC DLBCL 
activated B cell-like diffuse large B-cell lymphoma 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under plasma concentration-time curve 
BGB-3111 
zanubrutinib 
BTK 
Bruton tyrosine kinase 
CBC  
complete blood count 
CDx 
companion diagnostics 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum plasma concentration 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FL 
follicular lymphoma 
GCB DLBCL 
germinal center B cell-like diffuse large B-cell lymphoma 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IPI 
International Prognostic Index 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MUGA 
multiple gated acquisition scan 
MZL 
marginal zone lymphoma 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
ULN 
upper limit of normal 
WBC 
white blood cell 
WM 
Waldenström macroglobulinemia 
 
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1. 
INTRODUCTION  
1.1. 
Background Information on DLBCL  
Diffuse large B-cell lymphoma (DLBCL) is an aggressive (fast‑growing) and high‑grade 
lymphoma that can arise in nodal or extranodal sites, such as the gastrointestinal tract, testes, 
thyroid, skin, breast, bone, or brain.  DLBCL arises from a mature B cell and is usually 
composed of cells resembling centroblasts or immunoblasts, which are 2 distinct types of 
activated B cells.  DLBCL is the most common type of non-Hodgkin lymphoma (NHL) and 
accounts for 30% to 40% of new diagnoses (Al-Hamadani et al 2015; Teras et al 2016).  There 
were 509,590 new cases of NHL and 248,724 deaths resulting from this disease worldwide in 
2018 (Bray et al 2018).  The incidence of NHL is increasing in many regions.  The 
age-standardized incidence has increased by 35% in 30 years (1988 to 2007) in England, and a 
similar trend has been recorded in the United States (US), with an annual percentage increase of 
3.7% in the incidence of NHL between 1975 and 1991, and a 0.3% annual increase from 1992 to 
2007 (Shankland et al 2012).  Based on the data in the registration database of the Chinese 
Center for Disease Control and Prevention, in 2015, approximately 88,200 new cases of 
lymphoma and 52,100 death cases occurred in China, and lymphoma ranks 12th in terms of 
incidence and 11th in terms of mortality among all cancers, respectively (Chen et al 2016).  
According to one retrospective analysis for lymphoma subtype distribution conducted by the 
China Lymphoma Study Group, DLBCL makes up about 40.8% of NHL cases and 35.8% of all 
lymphoma cases (Li et al. 2012).  According to current Surveillance Epidemiology and End 
Results (SEER) data, the median age at diagnosis is 67 years (SEER 2010).  DLBCL is usually 
aggressive, marked by rapidly growing tumors in lymph nodes, spleen, liver, bone marrow, or 
other organs (Coiffier 2001).  A very aggressive malignancy in its untreated natural history, 
DLBCL is a potentially curable disease, with a significant proportion of patients cured with 
modern chemoimmunotherapy.  Nonetheless, for those patients not cured by standard initial 
therapy, the prognosis remains generally poor (Gisselbrecht 2010) and DLBCL still accounts for 
the highest number of deaths per year of all the NHL histologies. 
DLBCL is staged according to the Ann Arbor classification (Carbone et al 1971); less than 
one-third patients have Stage 1 or 2 disease at diagnosis, one-third present with bulky disease 
(> 7.5 cm), about 40% have extra-nodal involvement, and 20% have marrow involvement 
(Moller et al 2004).  The International Prognostic Index (IPI), proposed in 1993, predicts the 
survival of patients with NHL.  The IPI consists of 5 factors: patient age > 60 years, lactate 
dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) performance status 
> 2, > 2 extranodal sites, and Stage 3 or 4 disease.  Patients are stratified into 4 risk groups: low 
risk (1 factor), low-intermediate risk (2 factors), high-intermediate risk (3 factors), and high risk 
(4-5 factors).  Five-year survival rates are 73%, 51%, 43%, and 26% for the 4 groups, 
respectively.  Regarding applicability of the IPI in the era of modern chemoimmunotherapy 
(eg, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone]), a recent 
report of a large series of patients treated with rituximab-based regimens found that the IPI 
remains predictive for disease-free and overall survival (Shipp et al 1993). 
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DLBCL has distinct morphological and clinicopathological subtypes.  The common 
morphological subtypes are centroblastic, immunoblastic, and anaplastic.  Centroblasts are large 
noncleaved cells with round or oval nuclei associated with good prognosis, whereas 
immunoblasts are large cells with prominent nucleoli and plasmacytoid features.  Plasmablastic 
lymphoma is a morphological variant that is immunophenotypically distinct from other variants. 
Biological studies have shown that DLBCL is not a single disease but a group of disorders with 
specific signaling programs from the perspective of clinicopathology.  In 2000, gene expression 
profiling (GEP) of 96 normal and DLBCL lymphocytes was used to identify 3 different subtypes 
of disease based on cell of origin (COO) (Alizadeh et al 2000).  The 3 subtypes are: the germinal 
center B cell-like (GCB) subtype (which resembles the GEP of normal GCBs), the activated B 
cell-like (ABC) subtype (which resembles normal ABCs), and unclassifiable disease.  In recent 
years, according to the Hans algorithm, DLBCL can be categorized into GCB and non-GCB 
phenotypes by the immunohistochemical expression pattern of CD10, B-cell lymphoma 6 
(BCL6), and multiple myeloma oncogene 1 (MUM1) (Xie et al 2015; Meyer et al 2011).  
In parallel to the COO studies, the subtypes of DLBCL based on molecular features have also 
been found to have prognostic impacts.  DLBCL is a highly heterogeneous lymphoid neoplasm 
with variations in gene expression profiles and genetic alterations, which lead to substantial 
variations in clinical course and response to therapy.  The advent of high-throughput genome 
sequencing platforms, and especially whole-exome sequencing, has helped to define the genetic 
landscape of DLBCL.  In the past 10 years, numerous studies have identified many genetic 
alterations in DLBCL, some of which are specific to B-cell lymphomas, whereas others can also 
be observed in other types of cancer.  These aberrations result in the altered activation of a wide 
range of signalling pathways and other cellular processes, including those involved in B-cell 
differentiation, B-cell receptor signalling, activation of the nuclear factor 
kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, apoptosis and epigenetic 
regulation.  Among these mutations, some potential therapeutic targets have been identified, such 
as MYD88, CD79A, CD79B, EZH2, and BCL2.  Patients with relapsed/refractory (R/R) DLBCL 
contains a CD79B mutation are the selected biomarker-driven population for this Phase 2 study. 
CD79B Mutant DLBCL 
Signaling via an aberrantly activated B-cell receptor is known to play a critical role in the 
pathogenesis of B-cell malignancies by promoting survival and clonal expansion of malignant 
B-cells.  Antigen specificity of the B-cell receptor is provided by surface immunoglobulin, but 
signaling is mediated by 2 associated proteins,CD79A (Ig-a) and CD79B (Ig-b) 
(Dal Porto et al 2004).  The CD79A-CD79B heterodimer is a scaffold for the assembly and 
membrane expression of the B-cell receptor and also initiates downstream signaling to the 
NF-κB, phosphatidylinositol-3-OH kinase, extracellular signal-regulated kinase (ERK) 
mitogen-activated protein (MAP) kinase and nuclear factor of activated T cells (NF-AT) 
pathways.  Engagement of the B-cell receptor by antigen induces Src-family kinases to 
phosphorylate tyrosines in the intracellular immunotyrosine-based activation motif (ITAM) of 
CD79A and CD79B (Davis et al 2010).  
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In mouse B cells, mutations in the CD79A or CD79B ITAM tyrosine residues elevate surface 
B-cell receptor expression by inhibiting receptor internalization (Gazumyan et al 2006).  
Interruption of chronic active B-cell receptor signaling with dasatinib, a kinase inhibitor 
approved for the treatment of chronic myelogenous leukemia, inhibits Src-family kinases and 
Bruton tyrosine kinase (BTK) increased surface B-cell receptor expression in ABC DLBCL cells 
with wild-type but not mutant CD79B.  Hence, one function of the CD79 mutations is to 
maintain surface B-cell receptor expression in the face of chronic active B-cell receptor signaling 
(Davis et al 2010). 
Studies that examined the association between specific mutations and survival among all 
DLBCLs found that CD79B mutations were strongly associated with poorer survival 
(Reddy et al 2017).  In one study, 574 DLBCL biopsy samples were analyzed using exome and 
transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon 
resequencing of 372 genes to identify genes with recurrent aberrations.  CD79B mutations were 
found in 15.5% of all DLBCL samples, of which 26.8% were found in the ABC subtype, 1.9% in 
the GCB subtype, and 6.1% in the unclassified subtype (Schmitz et al 2018).  In a Phase 1/2 
study of ibrutinib, 9/38 (23.7%) patients with ABC DLBCL were found to have CD79B mutation 
(Wilson et al 2015).  And in zanubrutinib studies, 21/77 (27.3%) patients with non-GCB DLBCL 
were found to have CD79B mutation.  Thus, it is estimated that a CD79B mutation is present in 
approximately 25% of patients with non-GCB/ABC DLBCL, and the percentage of CD79B 
mutation in all patients with DLBCL is estimated to be approximately 15%.  Based on the fact 
that SEER and GLOBOCAN 2018 data suggest a NHL incidence of 88,090 cases per year in 
China and 74,680 cases in the USA, and that the percentage of DLBCL in NHL is approximately 
33%, it can be estimated that the incidence of CD79B mutant DLBCL is about 4000 per year in 
China and the USA each. 
1.2. 
Current Treatment of DLBCL and Unmet Clinical Needs  
DLBCL is a heterogeneous clinicopathologic entity accounting for 30% to 40% of NHL cases.  
Despite recent advances, there is still an unmet need for better therapies, especially R/R DLBCL 
(Witzig et al 2015). 
In clinical practice, the treatment decision is based on various factors such as the age of the 
patient, disease stage, presence of bulky disease, and IPI.  After rituximab was introduced to treat 
DLBCL, the current first-line treatment is R-CHOP regimen.  Due to the complex pathogenesis 
of DLBCL, 30% to 40% patients develop R/R disease and have poor outcomes despite recent 
progress in improving prognosis.  Patients might fail first-line chemoimmunotherapy or salvage 
therapy followed by high dose therapy and bone marrow transplantation; only 10% to 20% of 
patients have long-term disease-free survival (Crump et al 2017).  Patients with primary 
refractory disease or those who relapse within 12 months have a dismal outcome with the current 
standard of care; the median overall survival is about 5 to 6 months (Friedberg 2011).  CD79B 
mutation is detected mainly in ABC DLBCL, and it is reported that, in patients with newly 
diagnosed and R/R DLBCL, ABC DLBCL and non-GCB DLBCL were associated with worse 
outcomes than GCB DLBCL, with shorter progression-free survival and overall survival 
(Batlle-López et al 2016; Hernandez-Ilizaliturri et al 2011; Thieblemont et al 2011). 
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Moreover, patients may be ineligible for bone marrow transplantation because of age or 
comorbidities.  Patients who relapse following autologous bone marrow transplantation also have 
poor outcomes with limited treatment options.  Both the US National Comprehensive Cancer 
Network (NCCN) (NCCN 2020) and the European Society for Medical Oncology (ESMO) 
recommend inclusion in a clinical study whenever possible (Tilly et al 2015). 
Multiple drugs are currently under clinical investigation for DLBCL, including alternative kinase 
inhibitors (targeting BTK, mammalian target of rapamycin, and phosphatidylinositol-3 kinase 
[PI3K]), immunotherapies (including lenalidomide and chimeric antigen receptor T cells), and 
other targeted agents (such as venetoclax, a BCL 2 inhibitor).  Chimeric antigen receptor (CAR) 
T-cell therapy shows promise in these patients (Brudno and Kochenderfer 2018); however, this 
therapy is limited to certain treatment centers and may have significant toxicity which may be 
intolerable for some patients.  Lenalidomide and avadomide, two immunomodulatory agents 
with pleiotropic antitumor activity, showed an overall response rate of 27.5% and 29%, 
respectively, in the patients with R/R DLBCL (Czuczman et al 2017, Carpio et al 2020).  
Immune checkpoint blockade with the anti-programmed death-1 (anti-PD1) monoclonal 
antibody nivolumab demonstrated a low overall response rate in patients with R/R DLBCL who 
were ineligible for autologous hematopoietic cell transplantation (auto-HCT) or who experienced 
treatment failure with auto-HCT in a Phase 2 study (overall response rate of 3% and 10%, 
respectively) (Ansell et al 2019).  Panobinostat, a pan histone deacetylase inhibitor, exhibited an 
overall response rate of 29% in R/R DLBCL patients, and combination of rituximab did not 
increase the overall response rate (26%) (Assouline et al 2016).  Selinexor, an exportin 1 (XPO1) 
inhibitor, exhibited an overall response rate of 29% in patients with R/R DLBCL; however, 
toxicities were difficult to tolerate and necessitated close monitoring and supportive care 
(Kasamon et al 2021, Maerevoet et al 2021).  For antibody-drug conjugates, coltuximab 
ravtansine showed an overall response rate of 31.1% in R/R DLBCL patients 
(Coiffier et al 2016), and pinatuzumab vedotin exhibited objective responses in 9/25 DLBCL 
patients (Advani et al 2017).  Tafasitamab (MOR208), an anti-CD19 antibody, showed an overall 
response of 26% in 35 R/R DLBCL patients, with a duration of response of 20.1 months and 
median progression-free survival of 2.7 months after a median follow-up of 21 months 
(Jurczak et al 2018).  Mosunetuzumab and RG6026 are bi-specific CD20/CD3 antibodies that 
redirect cytotoxicity of endogenous T cells against malignant B cells by simultaneously binding 
to CD3 on T cells and to CD20 on B cells.  A Phase 1 study examining mosunetuzumab in 
patients with R/R transformed follicular lymphoma (FL) or DLBCL is ongoing 
(Budde et al 2018).  Preliminary results of 55 evaluated patients reported overall response and 
complete response rates of 33% and 21% respectively.  The Phase 1 study of RG6026 also 
demonstrated an overall response rate of 33% in 64 evaluable R/R aggressive NHL patients 
(47 with DLBCL) (Hutchings et al 2018).  These chemo-free therapies showed only modest 
efficacy results, therefore, there is a substantial unmet need for novel treatments for relapsed or 
refractory DLBCL. 
1.3. 
Bruton Tyrosine Kinase Therapy With DLBCL  
The B-cell receptor consists of an antigen-specific immunoglobulin that recognizes a specific 
antigen and CD79 heterodimers that are responsible for the initiation of B-cell receptor signal 
transduction.  B-cell receptor signaling is essential for normal B-cell development, 
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differentiation, function, and survival (Dal Porto et al 2004; Niiro and Clark 2002).  The aberrant 
B-cell receptor pathway is implicated in the pathogenesis of several B-cell malignancies, 
including DLBCL, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), FL, and 
Waldenström macroglobulinemia (WM) (Rickert 2013). 
Bruton tyrosine kinase (BTK), an intermediary in the B-cell receptor signaling pathway, has 
been validated as a therapeutic target based on clinical data from BTK inhibitor-treated patients 
with a variety of B-cell malignancies characterized by constitutive B-cell receptor activation 
(Cameron and Sanford 2014).  As a member of the family of cytoplasmic tyrosine kinases 
expressed in hepatocellular carcinoma (TEC), BTK is a critical component of the B-cell receptor 
signaling cascade.  BTK is predominantly expressed in B lymphocytes at various stages of 
development.  BTK activation in B cells initiates a series of signaling events, including 
recruitment of BTK to the plasma membrane, autophosphorylation at Tyr223, activation of 
phospholipase Cγ2 (PLCγ2), subsequent NF-κB activation, and expression of genes involved in 
proliferation and survival (Humphries et al 2004; Advani et al 2013; Petro and Khan 2001). 
Inhibition of BTK has emerged as a promising strategy for targeting B-cell malignancies.  
Efficacy of BTK inhibitors has been primarily demonstrated in a proof-of-concept study in 
patients with B-cell malignancies, with a well-tolerated toxicity profile and quality of life.   
Ibrutinib, the first-in-class BTK inhibitor has demonstrated promising activity in B-cell 
receptor-driven B-cell malignancies and is approved by the US Food and Drug Administration 
(FDA).  Ibrutinib is an orally administered selective and covalent inhibitor of BTK that reduces 
NF-κB pathway signaling and might therefore be effective for patients with the ABC subtype of 
DCBCL.  A Phase 1/2 study examined the efficacy and safety of ibrutinib in 80 patients with 
R/R DLBCL, including 38 patients with ABC DLBCL and 20 patients with GCB DLBCL 
(Wilson et al 2015).  Two thirds of the patients were refractory to chemotherapy and had 
received a median of 3 (ABC DLBCL group) or 3.5 (GCB DLBCL group) prior regimens.  An 
autologous stem cell transplantation had been performed in 13% of patients in the ABC DLBCL 
group and in 30% of patients in the GCB DLBCL group.  The overall response rate was 25%, 
with a higher overall response rate in the ABC DLBCL group than in the GCB DLBCL group 
(37% versus 5%, p = 0.0106).  The duration of response in patients with the ABC DLBCL 
subtype was 4.8 months.  After a median follow-up of 11.5 months, median progression-free 
survival and overall survival were 1.6 and 6.4 months in all patients, respectively.  The most 
frequent adverse events were fatigue (40%), diarrhea (38%), and nausea (30%). 
Acalabrutinib (ACP-196) is a second-generation BTK inhibitor with increased target selectivity 
and potency compared to ibrutinib.  It was reported that overall response rate for R/R de novo 
DLBCL patients of acalabrutinib was 24% (5/21; 19% complete response [CR]).  NanoString 
subtyping conducted on 15 patients revealed 5 GCB, 9 ABC, and 1 unclassified DLBCL.  
Common adverse events (any grade) were diarrhea (43%), fatigue (43%), anemia (29%), cough 
(29%) and dizziness (29%); common Grade 3/4 adverse events were anemia (24%), fatigue 
(10%) and abdominal pain (10%).  Three patients experienced Grade 5 adverse events 
(respiratory failure, meningeal progression, and sepsis); none were drug related (Dyer et al 
2018). 
From the preliminary efficacy results previously noted, recent BTK-inhibitor monotherapy 
demonstrated modest efficacy results in R/R DLBCL patients.  However, given the important 
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role of BTK inhibitors with B-cell malignancies and activation of the B-cell receptor pathway 
and downstream NK-κB pathway, the structure optimization of BTK inhibitors or combined 
therapy with other treatment agents will bring more benefits in the control of treatment outcome 
for DLBCL. 
1.4. 
Background Information on Zanubrutinib (BGB-3111)  
Zanubrutinib is a potent, specific, and irreversible BTK inhibitor with a favorable pharmacologic 
and pharmacokinetic (PK) profile.  Zanubrutinib is different from ibrutinib in the following 
ways:  
1. Zanubrutinib is more selective in the relative inhibition of BTK versus off-target tyrosine 
kinases, including EGFR, FGR, FRK, HER2, HER4, ITK, JAK 3, LCK, and TEC, which 
may reduce toxicities possibly due to off-target inhibition such as diarrhea, 
thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue.  
2. Zanubrutinib has improved oral bioavailability.  
3. Zanubrutinib displays significantly less inhibitory effect on rituximab-induced 
antibody-dependent cell-mediated cytotoxicity, and so it is unlikely to adversely impact 
the antitumor effects of rituximab. 
1.4.1. 
Nonclinical Data for Zanubrutinib  
Summaries of nonclinical studies are provided below.  For more detailed information please refer 
to the zanubrutinib Investigator’s Brochure. 
Zanubrutinib is a potent, specific and irreversible BTK kinase inhibitor with a 50% maximum 
inhibitory concentration (IC50) of 0.3 nanomole per liter (nM).  Cellular assays confirm that 
zanubrutinib inhibits B-cell receptor aggregation-triggered BTK autophosphorylation, and blocks 
downstream PLCγ2 signaling in mantle cell lymphoma cell lines.  Zanubrutinib had an IC50 of 
1.8 nM in a homogeneous time resolved fluorescent-based BTKpY223 assay; it potently and 
selectively inhibited cellular growth of several mantle cell lymphoma cell lines (REC-1, Mino 
and JeKo-1) and the activated B-cell type diffuse large B-cell lymphoma cell line transmembrane 
domain 8 (TMD-8), with IC50 values from 0.36 nM to 20 nM, while it was inactive in many 
other hematologic cancer cell lines.  
In vivo studies have demonstrated that zanubrutinib induces dose-dependent antitumor effects 
against REC-1 mantle cell lymphoma xenografts engrafted either subcutaneously or systemically 
in mice, which are significantly more effective than ibrutinib.  Zanubrutinib also demonstrated 
better antitumor activity than ibrutinib in the TMD-8 DLBCL subcutaneous xenograft model.  In 
a PK/pharmacodynamic study, oral administration of zanubrutinib resulted in time-dependent 
occupancy of BTK in mice blood and in spleen, and was approximately 3-fold more potent than 
ibrutinib in mouse pharmacodynamic assays.  
In a panel of 342 human kinases, 1 µM zanubrutinib inhibited only 12 other kinases by > 70%.  
Zanubrutinib was more selective than ibrutinib for inhibition of kinase activity of BTK versus 
EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC.  Cellular assays also confirmed 
that zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR 
(> 6-fold).  Inhibition of ITK has been reported to reduce rituximab-induced antibody-dependent 
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cell-mediated cytotoxicity.  Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib 
in inhibiting rituximab-induced antibody-dependent cell-mediated cytotoxicity, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity 
than ibrutinib in both biochemical and cellular assays. 
Cytochrome P450 (CYP) phenotyping in human liver microsomes suggests that CYP3A was the 
major CYP isoform responsible for zanubrutinib metabolism.  Zanubrutinib is not a 
time-dependent CYP inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
or CYP3A.  Zanubrutinib is not an inducer of CYP1A2 but shows induction potential for 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A.  Zanubrutinib is not a substrate of breast 
cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, 
OATP1B3, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, and OAT3, 
but is likely to be a substrate of P-glycoprotein (P-gp).  Additionally, zanubrutinib is predicted 
not to cause clinically relevant inhibition of transporters, OATP1B1, OATP1B3, OAT1, OAT3, 
and OCT2.  
The toxicity profiles of zanubrutinib have been well characterized in rats and dogs.  No specific 
safety concerns were identified in vital organs/systems including cardiovascular system, 
respiratory system, and central nervous systems.  No corrected QT interval (QTc) changes were 
noted in the conscious, telemetry implanted dogs over 24 hours after dosing up to 100 mg/kg, or 
in the repeat-dose toxicity studies in dogs over 91 days at doses up to 100 mg/kg/day.  No 
mortality or severe toxicity was noted in 91-day repeat-dose toxicity studies in both rats and dogs 
at doses up to 300 mg/kg and 100 mg/kg, respectively.  Test article-related reversible 
histopathology changes were mainly noted in rats, including pancreas, spleen, prostate gland, 
cecum, colon, rectum, skin (lip and/or nose), and uterus.  None of the above findings were 
considered to be adverse in the 91-day repeated dosing studies.  No genotoxicity was noted in the 
genotoxicity core battery studies. 
1.4.2. 
Clinical Pharmacology  
In the first-in-human, Phase 1/2 study, BGB-3111-AU-003, the PK of zanubrutinib was linear 
between 40 mg and 320 mg once a day administered orally.  The absorption of zanubrutinib is 
rapid with median time to maximum plasma concentration of 2 hours.  The terminal elimination 
half-life is approximately 2 to 4 hours, with minimal accumulation observed after repeated 
dosing.  Results from a food effect study (BGB-3111-103) showed that dosing with food 
(high-fat or low-fat meal) did not cause any significantly meaningful effects on the area under 
plasma concentration-time curve (AUC) of zanubrutinib; therefore, zanubrutinib can be 
administered with or without food. 
The QT interval prolongation potential of zanubrutinib was evaluated in healthy subjects in a 
thorough QT study (BGB-3111-106).  Results from this study demonstrated that single oral 
doses of zanubrutinib at a therapeutic dose of 160 mg and a supratherapeutic dose of 480 mg did 
not have a clinically relevant effect on electrocardiogram (ECG) parameters, including QTc 
intervals and other ECG intervals.  Because of the short half-life and no accumulation seen upon 
multiple dosing, these results are also applicable for steady-state conditions. 
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicate that 
coadministration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg once a day 
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for 8 days) decreased exposure of zanubrutinib by 13.5‑fold for AUC0-∞ and 12.6-fold for 
maximum plasma concentration (Cmax) in healthy subjects.  Co-administration of zanubrutinib 
with strong CYP3A inhibitor itraconazole (200 mg once a day for 4 days) increased exposure of 
zanubrutinib by 3.8-fold for AUC0-∞ and by 2.6-fold for Cmax.  Additionally, physiologically 
based pharmacokinetic (PBPK) simulations suggest that coadministration of multiple doses of a 
moderate CYP3A inhibitor (eg, fluconazole, diltiazem, and erythromycin) may increase the Cmax 
and AUC of zanubrutinib by approximately 2-fold.  PBPK simulations suggest that a moderate 
CYP3A inducer (eg, efavirenz) may decrease the Cmax and AUC of zanubrutinib by 
approximately 2- to 3-fold.  These results are consistent with the role for CYP3A isoenzymes as 
the principal metabolic pathway for zanubrutinib.   
A clinical drug-drug interaction study (BGB-3111-108) was conducted to assess the effect of 
zanubrutinib on the PK of substrates of CYP3A (midazolam), CYP2C9 (warfarin), CYP2C19 
(omeprazole), P-glycoprotein (P-gp [digoxin]), BCRP (rosuvastatin) using a cocktail approach.  
The results showed that zanubrutinib does not affect drugs metabolized by CYP2C9 (warfarin) 
or transported by BCRP (rosuvastatin).  Zanubrutinib had a weak induction effect on CYP3A 
and CYP2C19 enzymes.  AUC0-t and Cmax values were approximately 47% and 30% lower, 
respectively, when midazolam was coadministered with zanubrutinib.  AUC0-t and Cmax values 
were approximately 36% and 20% lower, respectively, when omeprazole was coadministered 
with zanubrutinib.  Repeated dosing of zanubrutinib increased exposure of digoxin (P-gp 
substrate) with a mean increase of 11% for AUC0-t and 34% for Cmax. 
For more detailed information on the clinical experience for zanubrutinib, please refer to the 
zanubrutinib Investigator’s Brochure. 
1.4.3. 
Preliminary Efficacy and Safety Data with Zanubrutinib in DLBCL Patients  
1.4.3.1. 
Phase 1/2 Study BGB-3111-AU-003  
Study BGB-3111-AU-003 was a global, first-in-human, Phase 1/2, open-label, multiple-dose, 
dose-escalation and dose-expansion study of zanubrutinib that was initiated in Australia in 
August 2014.  The study consisted of 2 parts.  In Part 1, the primary objectives were to determine 
the safety and tolerability of zanubrutinib in patients with various B-cell malignancies 
(CLL/small lymphocytic lymphoma [SLL], NHL, and WM) and to determine the recommended 
Phase 2 dose.  In Part 2, the primary objective was to further assess the safety and tolerability of 
zanubrutinib in patients with B-cell malignancies, while a secondary objective was to assess the 
antitumor activity of zanubrutinib at the recommended Phase 2 dose.   
As of the data cutoff date (31 March 2021), 385 patients had been dosed in this clinical study.  
Dosing of the first patient occurred on 16 September 2014.  A total of 45 DLBCL patients were 
enrolled in the BGB-3111-AU-003 study, 66.7% of which were male, with 55.6% of these 
patients ≥ 65 years old; 86.7% of DLBCL patients had an ECOG score of 0 to 1. 
As of 31 March 2021, 43/45 (95.6%) DLBCL patients had experienced ≥ 1 treatment-emergent 
adverse event while on study, 23 (51.1%) of which were considered as related to zanubrutinib, 
and 29/45 (64.4%) had reported ≥ 1 serious adverse event.  The most frequent treatment-
emergent adverse events of the DLBCL cohort were pyrexia (26.7%), cough (24.4%), 
constipation (22.2%), upper respiratory tract infection (20.0%), nausea (20.0%), fatigue (17.8%), 
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back pain (15.6%), diarrhea (13.3%), pneumonia (13.3%), anemia (11.1%), contusion (11.1%), 
pruritus (11.1%), and hypertension (11.1%).  As reported by Tam et al 2019 with a data cutoff of 
15 September 2017, 99 patients with NHL had been enrolled, including 27 DLBCL patients, and 
of which 26 patients were evaluable for efficacy.  After a median follow-up of 5.6 months 
(range: 0.1 to 31.9 months) for the aggressive lymphoma group (DLBCL and MCL), the overall 
response rate was 62% (36/58), with a complete response rate of 21% (12/58). 
1.4.3.2. 
Phase 2 Study BGB-3111-207  
Study BGB-3111-207 was a single-arm, open-label, multicenter Phase 2 study being conducted 
in China in patients with histologically documented non-GCB-type DLBCL who had no 
response or relapsed after ≥ 1 prior treatment regimens including rituximab and anthracycline-
based chemotherapy.  Patients must also have been ineligible for intensive chemotherapy and 
hematopoietic stem cell transplantation.   
The primary objective was to evaluate the efficacy of zanubrutinib administered orally at a dose 
of 160 mg twice a day in patients with R/R non-GCB DLBCL.  Secondary objectives included 
the evaluation of the safety and tolerability of zanubrutinib administered orally at a dose of 
160 mg twice a day and evaluation of the efficacy of zanubrutinib as measured by duration of 
response, progression free survival, and time to response.   
Dosing of the first patient in this study occurred on 30 June 2017.  As of the 03 September 2020 
data cutoff date, a total of 41 patients had been dosed.  The median age of patients was 62.0 
years (range: 28 to 75 years).  Most patients were male (61.0%) and had a baseline ECOG score 
of 0 or 1 (24.4% patients and 65.9% patients, respectively).  
An overall response rate of 29.3% (95% confidence interval [CI]: 16.13% to 45.54%) was 
observed, with a complete response rate of 17.1% (95% CI: 7.15% to 32.06%).  Median 
progression-free survival for this study was 2.8 months (95% CI: 2.56 to 5.45 months), with 
estimated progression-free survival event-free rates of 45.9%, 21.6%, and 10.1% at 3, 6, and 
12 months, respectively.  Median overall survival for this study was 8.4 months (95% CI: 
4.8 months to not estimable [NE]), with estimated overall survival event-free rates at 3, 6, and 
12 months of 89.8%, 58.1%, and 35.6%, respectively. 
As of the 03 September 2020 data cutoff date, 36/41 patients (87.8%) had experienced at least 
1 treatment-emergent adverse event while on study.  The most frequent treatment-emergent 
adverse events were neutrophil count decreased (22.0%), hypokalaemia (17.1%), pneumonia 
(12.2%), and platelet count decreased (12.2%).  As of the data cutoff date, 12/41 patients 
(29.3%) had experienced a serious adverse event.  The most frequently reported serious adverse 
event was pneumonia (3 patients, 7.3%). 
1.4.3.3. 
Phase 2 Study BGB-3111-213  
Study BGB-3111-213 was an open-label, multicenter study evaluating the safety and efficacy of 
zanubrutinib in combination with rituximab in patients with either R/R non-GCB DLBCL or R/R 
FL or R/R marginal zone lymphoma (MZL).  Zanubrutinib was administered orally at 160 mg 
twice a day.  Rituximab was administered at 375 mg/m2 intravenously on Days 1, 8, 15, and 22 
of Cycle 1, and on Day 1 of Cycles 4, 6, 8, and 10.  Zanubrutinib was administered ≥ 30 minutes 
prior to the initiation of the rituximab infusion.  All patients were to receive zanubrutinib in 
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combination with rituximab for Cycles 1 to 10, followed by zanubrutinib monotherapy starting at 
Cycle 11 until disease progression, unacceptable toxicity or death, withdrawal of consent, or the 
study was terminated by the sponsor for final analysis. 
The primary objective was to evaluate efficacy in these patient populations, as measured by 
overall response rate assessed by the investigator.  The secondary objectives were to evaluate 
other efficacy measures as well as the safety and tolerability of the study drug combination. 
Dosing of the first patient in this study occurred on 04 January 2018.  As of the 23 September 
2020 data cutoff, a total of 41 patients had been dosed, including 20 non-GCB DLBCL patients.  
In the non-GCB DLBCL cohort, 65% of patients were male, 30% of patients were ≥ 65 years 
old, and 35% of patients had a baseline ECOG score of 1 to 2. 
The median follow-up duration was 9.5 months for the non-GCB DLBCL cohort at the efficacy 
data cutoff date.  The overall response rate was 35.0% in the non-GCB DLBCL cohort.  Two 
(10.0%) non-GCB DLBCL patients achieved CR.  In the non-GCB DLBCL cohort, the median 
duration of response was 8.79 months, and the median progression-free survival was 3.38 
months.  The estimated progression-free survival event-free rate at 12 months was 17.4% for the 
non-GCB DLBCL cohort. 
As of the safety data cutoff date of 23 September 2020, all of the patients in the non-GCB 
DLBCL cohort had experienced at least 1 treatment-emergent adverse event while on study.  The 
most frequent treatment-emergent adverse events reported in the non-GCB DLBCL cohort were 
white blood cell count decreased (25.0%), abdominal pain upper (25.0%), anemia (20.0%), 
neutrophil count decreased (20.0%), alanine aminotransferase increased (15.0%), platelet count 
decreased (15.0%), aspartate aminotransferase increased (10.0%), and pneumonia (10.0%).  
Three fatal treatment-emergent adverse events were reported in the non-GCB DLBCL cohort 
(dyspnea, death in setting of disease progression, and suicide).  Treatment-emergent adverse 
events led to treatment discontinuation in 5 non-GCB DLBCL patients. 
1.4.3.4. 
Phase 1 Study BGB-3111-GA101-Study-001  
Study BGB-3111-GA101-Study-001 was a global Phase 1b, open-label, multicenter study with a 
combined zanubrutinib and obinutuzumab treatment in patients with B-cell malignancies, 
specifically, CLL/SLL, WM, FL, MCL, MZL, and DLBCL.  This was a 2-part study; Part 1 was 
focused on safety evaluation, and Part 2 included indication-specific expansion cohorts.  Dosing 
of the first patient in this study occurred on 13 January 2016.  As of the 02 September 2020 data 
cutoff, a total of 119 patients had been dosed, including 23 patients with DLBCL.  About half of 
these DLBCL patients were male (56.5%), and the median age was 74 years old, with most 
having an ECOG score of 0 or 1 (78.2%).  
All patients with DLBCL had experienced ≥ 1 treatment-emergent adverse event.  The most 
frequent treatment-emergent adverse events reported among the DLBCL patients were fatigue 
(43.5%), pyrexia (34.8%), diarrhea (30.4%), upper respiratory tract infection (26.1%), 
neutropenia (26.1%), cough (17.4%), contusion (17.4%), oedema peripheral (17.4%), 
constipation (17.4%), urinary tract infection (17.4%), hematuria (17.4%), nausea (13.0%), rash 
(13.0%), dizziness (13.0%), and cellulitis (13.0%).  Among the DLBCL patients, 15/23 (65.2%) 
had experienced ≥ 1 treatment-emergent serious adverse event. 
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Please refer to the zanubrutinib Investigator’s Brochure for more preliminary efficacy and safety 
data. 
1.5. 
Study Rationales  
1.5.1. 
Rationale for Selection of Dose  
Dose selection of zanubrutinib was based on results from the Phase 1/2 dose-finding 
Study BGB-3111-AU-003, which evaluated the pharmacokinetics/pharmacodynamics, safety, 
and preliminary efficacy of zanubrutinib at doses from 40 mg to 320 mg once a day and 
160 mg twice a day.  A maximum tolerated dose was not reached in Study BGB-3111-AU-003, 
and no dose-limiting toxicity was observed during the dose escalation part of the study. 
Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all patients in the 
BGB-3111-AU-003 study, while occupancy in lymph node tissue was assessed only at 160 mg 
twice a day and 320 mg once a day (Tam et al 2015).  At the 160 mg twice a day dose, full BTK 
occupancy was observed at trough, suggesting that sustained target occupancy could be achieved 
in disease-originating tissues, thus more efficiently inhibiting BTK on a continuous basis, further 
preventing breakthrough signaling despite cycles of new BTK synthesis.  Activity has been 
observed across various B-cell malignancies (including CLL, MCL, WM, and FL) at all tested 
dose levels; thus, a minimum effective dose cannot be established at this time.  Conversely, there 
is now extensive experience at doses of 160 mg twice a day and 320 mg once a day, with both 
schedules showing a high level of activity without compromising the tolerability profile as 
compared to lower doses of zanubrutinib.  Therefore, 160 mg administered orally twice a day has 
been selected as the recommended Phase 2 dose based on sustained target occupancy, high rates 
of objective response in multiple types of B-cell malignancies, and a favorable safety and 
tolerability profile. 
Since zanubrutinib has been studied at the dose of 160 mg twice a day on a continuous daily 
dosing schedule and is well tolerated, it will be administered daily until disease progression or 
unacceptable toxicity.   
1.5.2. 
Rationale for the Therapy  
DLBCLs are neoplasms of medium or large B-lymphoid cells with a diffuse growth pattern.  
DLBCL encompasses many different disease entities with distinct clinical, pathological and 
biological features.  Further elaboration of the genetics of DLBCL will not only improve our 
understanding of disease pathogenesis but also provide further insight into disease classification, 
prognostication and therapeutic targets.  Patients in whom R/R DLBCL contains a CD79B 
mutation are the selected biomarker-driven population for this study. 
Treatment with BTK inhibitors such as ibrutinib has demonstrated responses in patients with 
various B-cell malignancies including CLL/SLL, MCL, DLBCL, FL, MZL, and WM.  The 
CD79B mutation may be predictive of BTK inhibitor sensitivity in the DLBCL.  It has been 
reported that CD79B mutant DLBCL cell lines are sensitive to ibrutinib.  It was observed that 
gain-of-function mutations targeting the B-cell receptor subunit CD79B were in 23% of ABC 
DLBCL biopsy samples.  Among patients with CD79B mutations, the response rate to ibrutinib 
was 55.6% (5/9).  Tumors with CD79B mutations responded frequently to ibrutinib, albeit to 
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varying degrees and durations (Wilson et al 2015).  The compared efficacy data of ibrutinib and 
zanubrutinib for patients with ABC/non-GCB DLBCL and CD79B mutant/wild-type 
ABC/non-GCB DLBCL are listed in Table 1.  In general, approximately 50% of the overall 
response rate is observed in CD79B mutant ABC/non-GCB DLBCL patients by BTK inhibitors 
monotherapy, while the overall response rate for ABC/non-GCB DLBCL patients is 
approximately 30%. 
Table 1: 
Overall Response Rates of BTK Inhibitors in CD79B Mutant/Wild-type 
ABC/Non-GCB DLBCL Patients  
Response/Patients 
Overall response rate (%) 
Zanubrutinib a (Non-GCB) 
Ibrutinib b 
(ABC) 
Mono 
Combo 
Total 
Mono 
All Non-GCB DLBCL 
24/79    30.4% 
12/42    28.6% 
36/121   29.8% 
14/38  36.8% 
NGS Available Non-GCB 
DLBCL 
18/44    40.9% 
11/33    33.3% 
29/77    37.7% 
14/38  36.8% 
   CD79B Mutant 
9/17     52.9% 
6/8      75.0% 
15/25    60.0% 
5/9   55.6% 
     CD79B Wild-type 
9/27     33.3% 
5/25     20.0% 
14/52    26.9% 
9/29   31.0% 
P Value (CD79B Mutant 
versus Wild-type) 
0.1977 
0.0041 
0.0050 
NA 
Difference in overall 
response rate (95% CI) 
19.6% 
(-10.20%, 46.87%) 
55.0% 
(15.75%,78.76%) 
33.1% 
(9.60%,53.57%) 
NA 
Abbreviations: ABC, activated B cell-like; CI, confidence interval; DLBCL, diffuse large B cell lymphoma; GCB, 
germinal center B cell-like; NA, not applicable; NGS, next-generation sequencing. 
Note:  
a. BeiGene internal results from studies of BGB-3111-207 (data cutoff date: 31 August 2019), BGB-3111-213 (data 
cutoff date: 31 May 2019), BGB-3111-AU-003 (data cutoff date: 09 September 2019), and BGB-3111-GA101-
Study-001 (data cutoff date: 31 August 2019). 
b. Wilson et al 2015. 
Ibrutinib and acalabrutinib exhibit significant clinical activity in several B-cell malignancies, 
while both demonstrate modest efficacy in relapsed DLBCL as a single treatment agent.  Clinical 
efficacy of ibrutinib as a single agent in patients with relapsed DLBCL was modest (overall 
response rate of 23%) (Younes et al 2017).  Acalabrutinib (ACP-196) is a second-generation 
BTK inhibitor with increased target selectivity and potency compared to ibrutinib.  Clinical 
efficacy of acalabrutinib monotherapy in patients with R/R DLBCL was also modest (overall 
response rate of 24%) (Dyer et al 2018).   
Zanubrutinib, compared to ibrutinib, is a more potent, more specific new-generation BTK 
inhibitor that has demonstrated a well-tolerated and acceptable safety profile.  Furthermore, 
compared to ibrutinib, zanubrutinib is more selective against off-target kinases including ITK. 
In light of the preliminary efficacy and safety data of the ongoing global and China studies of 
zanubrutinib in B-cell malignancies, the preliminary efficacy as well as safety, tolerability, and 
PK of zanubrutinib in CD79B mutant DLBCL patients will be explored in this study. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, the Declaration of Helsinki and any applicable regulatory requirements. 
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1.6. 
Benefit-Risk Assessment  
As of the data cutoff date of 13 November 2023, approximately 3030 patients have been enrolled 
worldwide in completed and ongoing clinical studies evaluating zanubrutinib in B-cell 
malignancies and received at least 1 dose of zanubrutinib either as monotherapy or in 
combination with another agent.  As demonstrated by clinical data obtained to date, zanubrutinib 
is a highly selective and orally bioavailable BTK inhibitor that not only achieves high systemic 
exposure for complete BTK occupancy in the blood and lymph nodes but also remains highly 
tolerable, despite its exposure and occupancy advantages.  When examined in sum, safety and 
efficacy findings in patients with B-cell malignancies demonstrate that zanubrutinib is well 
tolerated and has substantial activity against B-cell malignancies, suggesting that studies of 
zanubrutinib are warranted for patients with lymphoma.  BTK inhibitor ibrutinib have been 
approved by a number of countries for the treatment of CLL/SLL, MCL, WM, and MZL.  
Zanubrutinib, a new generation BTK inhibitor, has a higher selectivity and stronger inhibitory 
abilities compared to ibrutinib, and is likely to inhibit tumor growth more effectively in clinical 
practice.   
Available data for zanubrutinib in patients with B-cell malignancies support a positive 
benefit-risk profile for the use of zanubrutinib as investigational agents to develop new treatment 
options for patients with CD79B mutant R/R DLBCL. 
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2. 
STUDY OBJECTIVES  
Primary Objective 
• To evaluate the efficacy of zanubrutinib in patients with CD79B mutant R/R DLBCL, 
as measured by overall response rate determined by the investigator assessment in 
accordance with the 2014 modification of the International Working Group on 
non-Hodgkin lymphoma (NHL) Criteria (hereafter referred to as the Lugano 
classification) (Cheson et al 2014). 
Secondary Objectives 
• To evaluate the efficacy of zanubrutinib in patients with CD79B mutant R/R DLBCL, 
as measured by the following: 
− Complete response rate determined by investigator assessment 
− Duration of response determined by investigator assessment 
− Progression-free survival determined by investigator assessment 
− Time to response determined by investigator assessment 
− Overall survival 
• To evaluate the safety and tolerability of zanubrutinib in patients with CD79B mutant 
R/R DLBCL when given as monotherapy 
Exploratory Objectives 
• To evaluate the PK of zanubrutinib in patients with CD79B mutant R/R DLBCL 
− Summary of plasma concentrations of zanubrutinib 
• To evaluate the correlation of clinical/genetic risk factors and clinical outcomes 
• To explore mechanisms of disease resistance 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This single-arm, open-label, multicenter Phase 2 study is designed to assess the efficacy and 
safety of zanubrutinib in patients with CD79B mutant R/R DLBCL.  Patients enrolled in this 
study should have histologically confirmed DLBCL and central laboratory confirmed positive 
CD79B mutation.  The patients need to have received at least 1 line of adequate systemic 
anti-DLBCL therapy (ie, anti-CD20 antibody-based chemoimmunotherapy) for at least 
2 consecutive cycles, unless who had disease progression before Cycle 2.  The patients should be 
also ineligible for high dose therapy/stem cell transplantation due to comorbidities or failure for 
salvage therapy and stem cell collection (or unable to perform stem cell collection as assessed by 
the investigator). 
The primary efficacy endpoint is the overall response rate determined by the investigator 
assessment.  Disease response will be assessed per the Lugano classification (Cheson et al 2014, 
Appendix 2).  The primary analysis will take place approximately 6 months after the first dose of 
the last patient. 
Prescreening evaluations of CD79B mutation status by central laboratory will be performed for 
the patients who have histologically confirmed DLBCL and show the trend of lack of efficacy in 
their current systemic anti-DLBCL treatments, or the trend of disease progression.  Tumor tissue 
will be collected and sent to the central laboratory for CD79B mutation confirmation.  A separate 
prescreening informed consent form must be signed.  Only DLBCL patients with centrally 
confirmed CD79B mutation (except for patients with CD79B mutation locally confirmed and 
approved by the sponsor) and refractory or relapsed disease as confirmed by investigators are 
eligible for screening evaluations.  For the DLBCL patients who were tested as CD79B mutant 
by local laboratories should provide the reports to the sponsor for review, and the tumor tissue 
are still required to send to the central laboratory.  Once the local report results on CD79B 
mutation are accepted by the sponsor, these patients are eligible for screening evaluations with 
no need to wait for the central laboratory results.  Refer to Section 5.4.1 for detailed information.  
Screening evaluations will be performed within 21 days before the first administration of study 
drug unless noted otherwise.  Patients who agree to participate will sign the informed consent 
form (ICF) before any study-specific screening evaluations.  The schema and Schedule of 
Assessments for this study are presented in Figure 1 and Appendix 1, respectively.   
The treatment period starts with the first day of zanubrutinib administration and continues until 
the last dose of zanubrutinib has been administered.  Zanubrutinib will be administered orally as 
two 80-mg capsules twice a day (160 mg twice a day) continuously.  Each cycle is 28 days in 
length.  Patients will receive zanubrutinib until disease progression, unacceptable toxicity, loss to 
follow-up, or the end of the study, whichever occurs first.   
All patients who permanently discontinue study drug will remain in the study, have a Safety 
Follow-up Visit, and subsequently commence long-term follow-up. 
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Safety Follow-up Visit occurs approximately 30 days (± 7 days) after the last dose of 
zanubrutinib to perform the planned safety assessments and laboratory assessments, and to 
collect information on alternative anticancer therapy given after the last dose of study drug. 
Long-term follow-up includes monitoring survival status, second primary malignances, 
subsequent therapies for DLBCL, and may also include imaging and tumor response assessments 
for patients who have not yet had confirmed radiographic progression, which will continue until 
disease progression, start of alternative anticancer therapy, loss to follow-up, or the end of the 
study, whichever occurs first. 
Study Assessments 
Assessments of DLBCL status during the study include disease-related constitutional symptoms, 
physical examination of lymph nodes, liver, and spleen; bone marrow examination; positron 
emission tomography (PET)-computed tomography (CT) and/or CT scan with contrast of the 
chest, abdomen, pelvis, and neck if clinically indicated.  For details about study procedures, see 
Section 5 and Appendix 1. 
Response will be evaluated on the basis of clinical and radiologic evaluations using the Lugano 
classification.  All patients must have a baseline PET-CT and CT scan with contrast of the chest, 
abdomen, pelvis, and neck if clinically indicated within 21 days before the first dose of study 
drug.  PET-CT scans are required at screening, at Week 12 and Week 24 after treatment, and at 
the time when CR or progressive disease (PD) is suspected.  For fluorodeoxyglucose (FDG) 
non-avid disease, only CT scans will be required for post-baseline visit.  Contrast CT will be 
performed at screening, every 12 weeks for 24 months, and every 24 weeks thereafter until 
disease progression, start of alternative anticancer therapy, loss to follow-up, or the end of the 
study, whichever occurs first.  PET-CT may be used in lieu of a CT with contrast only if the CT 
of the PET-CT has been performed with diagnostic quality and contrast is administered.  When 
both PET-CT and CT evaluations are available for the same tumor assessment visit, the results of 
PET-CT shall prevail.  Bone marrow biopsy and aspirate are required to assess bone marrow 
involvement of lymphoma for all patients during the screening period, unless they have been 
performed within 60 days before the first dose of study drug as part of the standard care and 
there has been no intervening therapy from the time of the biopsy/aspirate until the start of study 
drug.  For patients with bone marrow involvement of lymphoma at baseline, repeated bone 
marrow biopsy and aspirate are required if CR is suspected. Clinical suspicion of disease 
progression at any time will require radiologic confirmation to be performed promptly, rather 
than waiting for the next scheduled radiologic assessment.  Magnetic resonance imaging (MRI) 
and a non-contrast chest CT scan may be used instead of contrast CT for patients with serious 
contrast allergy; whichever method is used should be used consistently. 
Safety assessments will include adverse events, serious adverse events, clinical laboratory tests, 
physical examinations, and vital signs.  Adverse events will be graded for severity per the 
National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0 
(NCI-CTCAE).  Laboratory assessments, including serum chemistry, complete blood count 
(CBC), coagulation, urinalysis, and pregnancy tests, should be performed at a local certified 
laboratory.  Details for hepatitis B and hepatitis C are listed in Section 5.8.5.   
In addition, blood samples will be collected sparsely at predose and 2 hours (± 30 minutes) 
postdose on Day 1 of Cycle 1 and Cycle 2 to evaluate the exposure of zanubrutinib.   
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Tumor tissue must be sent to the central laboratory for CD79B mutation status analysis at the 
Prescreening Visit.  For those patients enrolled, other predictive biomarkers will also be 
determined during screening and correlated with response, resistance, and prognosis.  CD79B 
mutation status in the blood will be assessed.  Blood-based biomarker analysis will also be 
performed to explore their association with response, resistance, and prognosis. 
3.2. 
Study Schema  
The study schematic is provided in Figure 1. 
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Figure 1: 
Study Schema  
Abbreviations: CR, complete response; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; PD, 
progressive disease; PET, positron emission tomography. 
3.3. 
Blinding  
Treatment with zanubrutinib will be open label. 
Treatment  
Zanubrutinib 160 mg twice a day, 
orally, continuously 
 
Safety Follow-up Visit (30 ± 7 days after End of Treatment) 
Screening (Day -21 to Day -1) 
Tumor assessment 
PET-CT will be performed at screening, at 
Week 12 and Week 24 after treatment, and the 
time when CR or PD is suspected; For FDG 
non-avid disease, only CT scans will be required 
for post-baseline visit; Contrast CT will be 
performed at screening, every 12 weeks for 24 
months, and every 24 weeks thereafter (until 
disease progression, start of alternative 
anticancer therapy, loss to follow-up, or the end 
of the study, whichever occurs first) 
End of Treatment 
Long-term Follow-up: 
Continue tumor assessments per schedule (for patients who discontinue the treatment for 
non-PD reasons only); 
Monitor survival status, secondary primary malignances, and subsequent therapies for 
DLBCL 
Prescreening 
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4. 
SELECTION OF STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  No eligibility waivers will be granted. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Men and women ≥ 18 years of age at the time of informed consent. 
2. Histologically confirmed DLBCL based on the World Health Organization (WHO) 2008 
classification of tumors of hematopoietic and lymphoid tissue. 
3. Positive CD79B mutation confirmed by the central laboratory. 
4. Previously received at least 1 line of adequate systemic anti-DLBCL therapy, defined as 
an anti-CD20 antibody-based chemoimmunotherapy for at least 2 consecutive cycles, 
unless patients had disease progression before Cycle 2.  
5. Relapsed or refractory (R/R) disease before study entry, defined as either: 
a. Recurrent disease after having achieved disease remission (CR or partial response 
[PR]) at the completion of the latest treatment regimen. 
b. Stable disease or PD at the completion of the latest treatment regimen. 
6. Ineligible for high dose therapy/stem cell transplantation, which is defined as meeting 
any of the following criteria: 
a. Significant organ dysfunction (eg, left ventricular ejection fraction < 50% by 
echocardiogram or multiple gated acquisition scan [MUGA], diffuse lung capacity for 
carbon monoxide < 60% predicted by pulmonary function test, creatinine clearance 
< 70 mL/min shown by nuclear medicine scan or 24-hour urine collection) or 
comorbidities precluding the use of high dose therapy/stem cell transplantation on the 
basis of unacceptable risk of treatment-related morbidity. 
b. Failure to achieve CR or PR with salvage therapy. 
c. Failure to collect stem cells or unable to perform stem cell collection as assessed by 
the investigator. 
7. Patients who have completed autologous stem cell transplantation ≥ 100 days before the 
first dose of zanubrutinib may be enrolled. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
9. Measurable disease as defined by at least 1 lymph node > 1.5 cm in longest diameter, or 
at least 1 extranodal lesion that is > 1.0 cm in longest diameter. 
10. Adequate hematologic function, defined as: 
a. Absolute neutrophil count (ANC) ≥ 1 x 109/L, except for patients with bone marrow 
involvement in which ANC must be ≥ 0.75 x 109/L, independent of growth factor 
support within 7 days before the first dose of study drug. 
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b. Platelet count ≥ 75 x 109/L (or ≥ 50 x 109/L for patients with bone marrow 
involvement of lymphoma), independent of growth factor support or transfusion 
within 7 days before the first dose of study drug. 
c. Hemoglobin > 80 g/L, independent of growth factor support or transfusion within 
7 days before the first dose of study drug. 
11. Adequate hepatic function, defined as: 
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper 
limit of normal (ULN). 
b. Total bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome, in which case 
≤ 5 x ULN is allowed). 
12. Adequate renal function, defined as creatinine clearance of ≥ 30 mL/min (as estimated by 
the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the 
modification of diet in renal disease [MDRD]). 
13. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin 
time (aPTT) ≤ 1.5 x ULN. 
14. Female patients of childbearing potential must practice highly effective methods of 
contraception (Section 5.3) starting from before the first dose of study drug, throughout 
the study treatment, and for up to 1 month after the last dose of zanubrutinib. 
15. Male patients are eligible if abstinent or vasectomized or if they agree to use highly 
effective contraception (as described in Section 5.3) during the study treatment period 
and for up to 1 week after the last dose of zanubrutinib. 
16. Life expectancy of > 3 months. 
17. Able to provide written informed consent and can understand and comply with the 
requirements of the study. 
4.2. 
Exclusion Criteria  
Each patient eligible to participate in this study must NOT meet any of the following exclusion 
criteria: 
1. Patients who have NHL other than classical histology DLBCL (DLBCL, not otherwise 
specified), eg, patients with DLBCL transformed from indolent lymphomas, primary 
mediastinal (thymic) large B-cell lymphoma,  primary cutaneous DLBCL, primary 
effusion lymphoma, and central nervous system (CNS) lymphoma. 
2. History of allogeneic stem cell transplantation or chimeric antigen receptor (CAR) T-cell 
therapy. 
3. Prior exposure to a BTK inhibitor. 
4. Receipt of the following treatment at the time indicated before the first dose of study 
drug: 
a. Corticosteroid given with antineoplastic intent within 2 weeks, but a short course 
(≤ 7 days) of systemic corticosteroid treatment at doses ≤ 20 mg/day prednisone 
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equivalent for control of lymphoma-related symptoms is allowed prior to enrollment 
provided that it is tapered off within 5 days after initiation of study treatment. 
b. Chemotherapy or radiotherapy within 2 weeks. 
c. Monoclonal antibody within 2 weeks. 
d. Investigational therapy within 2 weeks. 
e. Chinese patent medicine with antineoplastic intent within 2 weeks. 
5. Toxicity of Grade ≥ 2 from prior anticancer therapy (except for alopecia, ANC, 
hemoglobin and platelets.  For ANC, hemoglobin and platelets, please follow inclusion 
criterion #10). 
6. History of other active malignancies within 2 years before study entry, with the exception 
of (1) adequately treated in-situ carcinoma of the cervix; (2) localized basal cell or 
squamous cell carcinoma of the skin; (3) previous malignancy confined and treated 
locally (surgery or other modality) with curative intent. 
7. 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 arrhythmia (eg, sustained ventricular tachycardia, ventricular 
fibrillation, torsade de pointes). 
d. QTcF (Fridericia’s correction) > 480 msec. 
e. History of second-degree atrioventricular (AV) block Type II or third-degree AV 
block. 
f. New York Heart Association class 3 or 4 congestive heart failure (see Appendix 3). 
g. Uncontrolled hypertension as indicated by at least 2 consecutive blood pressure 
measurements showing systolic blood pressure > 170 mm Hg and diastolic blood 
pressure > 105 mm Hg at screening. 
8. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand 
disease, or history of spontaneous bleeding requiring blood transfusion or other medical 
intervention. 
9. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
study drug. 
10. Inability to swallow capsules or presence of a disease that significantly affects 
gastrointestinal function such as malabsorption syndrome, resection of the stomach or 
small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction. 
11. Active fungal, bacterial and/or viral infection that requires systemic therapy. 
12. Known HIV, or serologic status reflecting active hepatitis B virus (HBV) or hepatitis C 
virus (HCV) infection as follows: 
a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb).  Patients with presence of HBcAb, but without HBsAg, are eligible if HBV 
DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monthly 
monitoring for HBV reactivation. 
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b. Presence of HCV antibody.  Patients with presence of HCV antibody are eligible if 
HCV RNA is undetectable (< 15 IU/mL). 
13. Requires ongoing treatment with strong and moderate CYP3A inhibitors or inducers (see 
Appendix 4).  If patients have been on strong or moderate CYP3A inhibitors or inducers 
in the past, they will not be eligible if the administration was within 7 days (or 
5 half-lives of these drugs) before the first dose of study drug. 
14. Major surgery within 4 weeks before the first dose of study drug. 
15. Live vaccination within 4 weeks before the first dose of study drug. 
16. Any medical condition or organ system dysfunction that, in the investigator’s opinion, 
could compromise the patient’s safety or put the study at risk. 
17. Pregnant or lactating women. 
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5. 
ENROLLMENT AND STUDY PROCEDURES  
Study enrollment and procedures are summarized in the following subsections.  The timing of all 
study procedures is provided in the Schedule of Assessments (Appendix 1). 
5.1. 
Visit Windows  
The schedule of visits and assessments will be fixed from Cycle 1 Day 1 in this study.  The study 
visit schedule is based around 28-day cycles.  Acceptable windows around these visits are 
indicated in Appendix 1.  Procedures for a given visit may be split across the window to allow 
for drug resupply and completion of study procedures.   
5.2. 
Informed Consent  
A separate prescreening informed consent form must be signed before prescreening evaluation to 
obtain tissues for CD79B mutation test.  At the Prescreening and Screening Visit, study site 
personnel must explain to potential study participants all aspects of the study, including all 
scheduled visits and activities.  A copy of the ICF will be given to the patient to read, and the 
patient must have adequate time to understand the content and ask questions.  
Study site personnel must obtain signed informed consent before any study-specific procedures 
are conducted, unless the procedures are part of routine standard of care.  Personnel must 
document the informed consent process in the patient’s clinical record.  Informed consent may 
be obtained before the 21-day screening period.  Consent must be obtained using the most 
current version of the form approved by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC).  
Repeating screening procedures or tests are allowed if the patient did not previously meet the 
inclusion and exclusion criteria, or if needed to have a documented result within the 
protocol-specified screening window.  
For patients who provide informed consent and subsequently do not meet eligibility criteria or 
withdraw consent before enrollment, study site personnel should document the screen failure in 
the patient’s source documents.  The documentation should include demographics, medical 
history, the reason for screen failure, the eligibility criteria reviewed, procedures performed, etc. 
5.3. 
Females of Childbearing Potential and Contraception  
Female patients of childbearing potential must practice highly effective methods of contraception 
starting from before the first dose of study drug, throughout the study treatment, and for up to 1 
month after the last dose of zanubrutinib.  A woman is considered to be of childbearing potential 
(WOCBP), ie, fertile, following menarche and until becoming post-menopausal unless 
permanently sterile.  Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy.  Highly effective contraceptive methods include the 
following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
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• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day before the 
first dose of study drug, throughout the study treatment, and for up to 1 month after 
the last dose of zanubrutinib for female patients and up to 1 week after the last dose 
of zanubrutinib for male patients).  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, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to investigational medicinal 
product, 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 another acceptable method listed above.   
For patients using hormonal contraceptives such as birth control pills or devices, a second barrier 
method of contraception (eg, condoms) must be used. 
A post-menopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle-stimulating hormone level in the post-menopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  However, in the absence of 12 months of amenorrhea, a single 
follicle-stimulating hormone measurement is insufficient. 
Male patients are eligible if abstinent (as defined above) or vasectomized or if they agree to use 
of barrier contraception in combination with other methods described above during the study 
treatment period and for up to 1 week after the last dose of zanubrutinib. 
5.4. 
Enrollment  
5.4.1. 
Prescreening  
Prescreening evaluations of CD79B mutation status will be performed for the patients who have 
histologically confirmed DLBCL and show the trend of lack of efficacy in their current systemic 
anti-DLBCL treatments, or the trend of disease progression.  Definitions of the trend of lack of 
efficacy, or the trend of disease progression are as followed: 
• Patients failed to achieve PR or better after at least 2 consecutive cycles of the current 
systemic anti-DLBCL therapy, or 
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• Patients whose disease lesions enlarged, or new lesions appeared, which were 
suspected of disease progression by investigators.  
Tumor tissue will be collected and sent to the central laboratory for CD79B mutation 
confirmation.  A separate prescreening informed consent form must be signed to obtain tissue. 
Any AE or SAE evaluated by the investigators as related to the procedures for study-relevant 
tumor tissue collection (eg, biopsy) after signing the prescreening informed consent form should 
be recorded in the electronic case report form (eCRF).  
For DLBCL patients who were CD79B mutant tested by local laboratories, they should provide 
the reports to the sponsor for review and approval to start the screening evaluations, without 
waiting for the central laboratory confirmation result.  Meanwhile, tumor tissues are still required 
for confirmation of CD79B mutation status at central laboratory.   
Only DLBCL patients with centrally confirmed CD79B mutation (except for patients with 
CD79B mutation locally confirmed and approved by the sponsor) and refractory or relapsed 
disease as confirmed by investigators are eligible for screening evaluations.   
5.4.2. 
Screening  
All screening procedures must be performed within 21 days before the first dose of study drug, 
unless noted otherwise; assessments not completed within this interval must be repeated.  The 
investigator is responsible for maintaining a record of all patients screened and those who are 
enrolled in the study. 
5.4.3. 
Patient Numbering  
Patients will be identified by a patient number.  Each patient enrolled in this study will receive a 
unique patient number which will be assigned when the patient is screened or enrolled in the 
study.  Patient numbers will be assigned in chronological order starting with the lowest number.  
Once a patient number has been assigned to a patient, it cannot be reassigned to any other 
patient. 
5.4.4. 
Medical and Cancer History  
Medical and cancer history, including presence or absence of disease-related constitutional 
symptoms, will be reviewed any time after informed consent has been obtained.  Clinically 
significant medical history findings (eg, previous diagnoses, diseases, or surgeries) that do not 
pertain to the study indication, that started before signing of the informed consent, and that are 
considered relevant for the patient’s study eligibility will be collected and captured in the eCRF.  
“Clinically significant” is defined as any event, diagnosis or laboratory value that requires 
treatment or follow-up or if there if in the presence of signs or symptoms that require medical 
intervention.  Concurrent medical signs and symptoms must be documented to establish baseline 
severities. 
Other background information including history of disease (including date of initial diagnosis 
and current disease status), staging, and sites of disease, will also be collected.  Prior 
medications/significant nondrug therapies and demographic data (gender, year of birth [or age] 
and race/ethnicity) will also be collected.  The investigator will obtain the patient’s medical 
history at the Screening Visit.  Medical history will include all active conditions, and any 
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conditions diagnosed within the previous 10 years that are considered clinically significant by 
the investigator.  Significant findings that were present before signing of the informed consent 
must be included in the relevant medical history/current medical conditions page on the patient’s 
eCRF. 
5.4.5. 
Confirmation of Eligibility  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined.  No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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. 
The archival tissue sample used for DLBCL diagnosis or the associated pathology report from 
diagnosis will be sent to the central pathology laboratory for confirmation of tissue diagnosis 
retrospectively.  The status of CD79B should be confirmed by the central laboratory.  Refer to 
Section 5.10 for more details. 
5.5. 
Zanubrutinib Dispensation  
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.  Instructions for dosing, storage, and the return of all bottles 
(used and unused) are to be provided at future visits. 
5.6. 
Safety Assessments  
5.6.1. 
Physical Examination and Vital Signs  
Physical examination, vital signs (sitting blood pressure, pulse rate, body temperature, and 
respiratory rate), and weight will be performed at the Screening Visit, each visit during study 
treatment, and the Safety Follow-up Visit.  Height (cm) is determined at screening only. 
Assessment of vital signs and physical examination on the first day of Cycle 1 may be skipped if 
performed within previous 7 days.   
A complete physical examination is performed at the study site and includes an assessment of 
systems per standard of care and as clinically indicated by symptoms.  Physical examination will 
include an examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, and a basic nervous system 
evaluation.  To the extent feasible, blood pressure will be measured using the same arm 
throughout the study.  Patients must be resting in a sitting position for 10 minutes before vital 
signs are obtained.  If blood pressure is > 150/100 mm Hg in a patient without a history of 
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hypertension or is increased by > 20 mm Hg (diastolic) from baseline measurement in a patient 
with a previous history of hypertension, the assessment should be repeated in 10 minutes for 
confirmation.  Height in centimeters and body weight (to the nearest 0.1 kg in indoor clothing, 
but without shoes) will be measured. 
5.6.2. 
ECOG Performance Status  
ECOG performance status will be assessed at the Screening Visit, each visit during study 
treatment, and the Safety Follow-up Visit. 
5.6.3. 
Electrocardiogram  
A 12-lead ECG will be performed locally in triplicate (≥ 1 minute apart) at screening for all 
patients and as clinically indicated at other timepoints.  The calculated QTcF average of 3 ECGs 
must be ≤ 480 msec for eligibility.  Patients should in a supine position and resting for at least 
10 minutes before the ECG is obtained. 
5.6.4. 
Echocardiogram/Multiple Gated Acquisition Scan  
An echocardiogram or MUGA is to be performed at screening unless one has been performed 
within 30 days before the first dose of study drug. 
5.6.5. 
Pulmonary Function Test  
Pulmonary function will be assessed at screening and as clinically indicated during the study. 
5.6.6. 
Concomitant Medications Review  
Record any new medications, changes in ongoing medications or procedures, and medications 
discontinued within 21 days before the first dose of study drug, and on study thereafter until 
30 days after the last dose of zanubrutinib. 
5.6.7. 
Adverse Events Review  
Adverse events that occurred during prescreening or screening will be recorded on the medical 
history case report form and in the patient’s source document.  For prescreening, only AEs or 
SAEs evaluated by the investigator as related to the procedures for study-relevant tumor tissue 
collection (eg, biopsy) after signing the prescreening informed consent form should be recorded. 
The adverse event reporting period is defined in Section 8.4.1.  
The accepted regulatory definition for an adverse event is provided in Section 8.1.1 and the 
definition of an serious adverse event is provided in Section 8.2.  Important additional 
requirements for reporting serious adverse events are explained in Section 8. 
5.7. 
Efficacy Assessments  
Treatment response will be assessed by the investigator according to the Lugano classification 
for NHL (Cheson et al 2014).  The primary endpoint will be the overall response rate based on 
the investigator assessment.  Response parameters will include assessment of lymphadenopathy, 
hepatomegaly and splenomegaly, and bone marrow aspirate and biopsy.  In the event of a 
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treatment delay, disease assessments are to continue per the Schedule of Assessments 
(Appendix 1). 
5.7.1. 
Radiographic Imaging  
All patients must have a baseline PET-CT and CT scan with contrast of the chest, abdomen, 
pelvis, and neck if clinically indicated (within 21days before the first dose of study drug). 
PET-CT scans are required at screening, at Week 12 and Week 24 after treatment, and at the 
time when CR or PD is suspected.  For FDG non-avid disease, only CT scans will be required for 
post-baseline visit.  Contrast CT will be performed at screening, every 12 weeks for 24 months, 
and every 24 weeks thereafter until disease progression, start of alternative anticancer therapy, 
loss to follow-up, or the end of the study, whichever occurs first.  PET-CT may be used in lieu of 
a CT with contrast only if the CT of the PET-CT has been performed with diagnostic quality and 
contrast is administered.  When both PET-CT and CT evaluations are available for the same 
tumor assessment visit, the results of PET-CT shall prevail. 
MRI and a non-contrast chest CT scan may be used instead of contrast CT for patients with 
serious contrast allergy; whichever method is used should be used consistently.  All efforts will 
be made to ensure that the imaging equipment, contrast agent, and person (investigator or 
radiologist) performing the evaluation is constant throughout a patient’s course on study. 
Clinical suspicion of disease progression at any time will require radiologic confirmation to be 
performed promptly, rather than waiting for the next scheduled radiologic assessment. 
5.7.2. 
Bone Marrow Examination  
Bone marrow biopsy and aspirate are required to assess bone marrow involvement of lymphoma 
for all patients during the screening period, unless they have been performed within 60 days 
before the first dose of study drug as part of the standard care and there has been no intervening 
therapy from the time of the biopsy/aspirate until the start of study drug.  For patients with bone 
marrow involvement of lymphoma at baseline, repeated bone marrow biopsy and aspirate are 
required if CR is suspected. 
Bone marrow aspirates will be reviewed by local laboratory and results will be entered into the 
eCRF.  In addition, all the bone marrow biopsies from screening to end of study will be collected 
to be reviewed by a pathologist from central pathology laboratory. 
5.8. 
Laboratory Assessments  
Laboratory assessments should be performed at a local certified laboratory, except for hepatitis B 
and hepatitis C testing of some cases; please refer to Section 5.8.5.   
Serum chemistry, CBC, coagulation, urinalysis, and hepatitis serologies testing will be 
performed at the timepoints specified in the Schedule of Assessments (Appendix 1) and may also 
be performed as medically necessary.  In Cycle 1, laboratory assessments should be done before 
the first dose of study drug. 
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Abnormal laboratory values will constitute adverse events only if they are associated with 
clinical signs or symptoms that are clinically significant and/or require therapy, and should be 
recorded in the adverse events eCRF.  In addition, isolated abnormal laboratory values that are 
considered clinically significant (eg, the value causes study discontinuation or constitutes in and 
of itself a serious adverse event) should be recorded in the adverse events eCRF. 
5.8.1. 
Hematology  
CBC with differential is required to be performed at screening (a repeated CBC test is required if 
not done within 7 days before the first dose of study drug), and at every visit during the treatment 
phase and the Safety Follow-up Visit.  CBC includes hemoglobin, hematocrit, platelet count, red 
blood cell count, white blood cell (WBC) count with differential including neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils. 
5.8.2. 
Serum Chemistry  
Serum chemistry testing includes sodium, potassium, chloride, uric acid, bicarbonate/total carbon 
dioxide, glucose, urea or blood urea nitrogen (BUN), creatinine, calcium, phosphate/phosphorus, 
magnesium, total bilirubin, total protein, albumin, ALT, AST, LDH, and alkaline phosphatase 
and is required to be performed at screening, every visit during the treatment phase, and at the 
Safety Follow-up Visit. 
5.8.3. 
Coagulation  
The coagulation profile includes prothrombin time (which will also be reported as international 
normalized ratio [INR]) and activated partial thromboplastin time (aPTT).  The coagulation 
profile will be performed at screening, on Day 1 of subsequent cycles, and at the Safety 
Follow-up Visit. 
5.8.4. 
Urinalysis  
Urinalysis (which includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose) 
will be performed at screening. 
5.8.5. 
Hepatitis B and C Testing  
Hepatitis B/C serologic markers and/or viral load will be tested at screening.  Viral hepatitis B 
and C testing may be performed by a local laboratory if the laboratory is able to perform the test 
to the required sensitivity (< 20 IU/mL and < 15 IU/mL for hepatitis B and C, respectively); 
otherwise the results must be confirmed by the central laboratory.  The hepatitis B testing 
includes HBsAg, HBcAb, and HBsAb as well as HBV DNA by polymerase chain reaction 
(PCR) if the patient is negative for HBsAg but is HBcAb positive (regardless of HBsAb status).  
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.  
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Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo at 
least monthly (± 7 days) HBV DNA screening by PCR.  These patients should be considered for 
prophylactic antiviral treatment in consultation with a local HBV expert.  If a patient is being 
treated prophylactically with antiviral therapy, HBV DNA screening by PCR must be done at 
least every 90 days (± 7 days). 
During monthly monitoring of HBV DNA by PCR, if the value is between 20 IU/mL and 
100 IU/mL, then the HBV DNA level should be rechecked within 2 weeks.  Study drug should 
be stopped 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 stopped and 
antiviral therapy initiated or continued.  Resumption of study drug in patients whose HBV 
reactivation resolves should be discussed with and approved by the medical monitor and 
physicians with expertise in managing hepatitis B. 
Patients who are positive for HCV antibody but negative for HCV RNA must undergo monthly 
(± 7 days) HCV RNA screening.  Patients with HCV RNA of 15 IU/mL or greater should stop 
study drug, and antiviral therapy should be initiated.  The question of whether to resume study 
drug in patients whose HCV reactivation resolves 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 2 describes how the results for HBV and HCV testing at screening relate to study 
eligibility. 
Table 2: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection  
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA “Not detected” 
 
Perform monthly (± 7 days) monitoring of HBV DNA  
(or at least every 90 ± 7 days for patients receiving 
prophylactic antiviral therapy) 
HBsAg (-) and 
HBcAb (+) 
HBV DNA detected 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not detected” 
 
Perform monthly (± 7 days) monitoring of HCV RNA 
Antibody (+) 
HCV RNA Detected 
Abbreviations: DNA, deoxyribonucleic acid; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; 
HBV, hepatitis B virus; HCV, hepatitis C virus; RNA, ribonucleic acid. 
Note: All samples will be detected by polymerase chain reaction (PCR).  For HBV DNA, detected means HBV 
DNA ≥ 20 IU/mL, and undetected means HBV DNA < 20 IU/mL; for HCV RNA, detected means HCV RNA 
≥ 15 IU/mL, and undetected means HCV RNA < 15 IU/mL. 
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5.8.6. 
Pregnancy Test  
For women of childbearing potential, a serum pregnancy test will be performed at screening and 
at the end of treatment.  Patients must have a negative serum pregnancy test at screening.  
Pregnancy tests must be performed at each visit during the treatment period and at the Safety 
Follow-up Visit.  Any patient who is pregnant will not be eligible for the study.  Subsequent tests  
at each visit may be urine tests, and 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 
initiation of study treatment will be immediately withdrawn from participation in the study. 
5.9. 
Pharmacokinetics  
Blood samples will be collected sparsely at predose and 2 hours (± 30 minutes) postdose on 
Day 1 of Cycle 1 and Cycle 2 to evaluate the exposure of zanubrutinib.  The actual collection 
date and time of each blood sample will be recorded in the eCRF.  In addition, patients will be 
instructed to record the dosing time of the evening dose at home (and be recorded on the eCRF) 
prior to coming in for the predose sample on Day 1 of Cycle 2.  Additional PK samples may be 
taken if needed. 
Blood samples for PK analysis will be collected into ethylenediaminetetraacetic acid (EDTA) 
collection tubes.  Shipping, storage, and handling of samples will be managed through a central 
laboratory.  Full details on sample collection, processing, storage, and shipment will be provided 
in the laboratory manual.  Samples will be shipped to the designated bioanalytical laboratory for 
quantification of plasma zanubrutinib concentrations using a validated method. 
5.10. 
Biomarker Assessments  
Samples for biomarker assessment will be collected as specified in the Schedule of Assessments 
(Appendix 1).  Shipping, storage, and handling of the samples for biomarker assessments will be 
managed through a central laboratory.  Refer to the laboratory manual for details about sample 
handling. 
Approximately 10 unstained slides must be sent to the central laboratory for detection of CD79B 
mutation status at the Prescreening Visit.  A fresh tumor biopsy is preferred at prescreening.  If 
fresh tumor biopsies are not available, then an archival tumor tissue taken within 2 years before 
prescreening will be requested.  Prescreening 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. 
For patients who proceed to screening stage, 5 more unstained slides should be sent to the central 
laboratory for analysis of other potential predictors of response including assessment of 
subtypes, MYD88L265P mutation, and BCL2/MYC/TCL1A expression.  DLBCL characteristic 
markers may also be assessed.  Residual samples from prescreening may be allowed to be used 
for the related exploratory biomarker testing.  Enrollment of a patient who cannot provide 
sufficient tumor tissue may be permitted on a case-by-case basis after discussion with the 
medical monitor and in consultation with the sponsor.  
Optional biopsy will also be taken during the study from accessible tumor sites in patients who 
have confirmed disease progression; these biopsies are done to explore genetic alterations 
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associated with drug resistance, including DNA alterations and analyses of the subtype (based on 
the gene expression profile).  Written patient consent is required for fresh tumor biopsies.   
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.  Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable.  
Blood samples will be collected at screening, time of first response, and time of disease 
progression.  CD79B mutation status in blood will be assessed.  Blood-based biomarker analysis 
such as DNA/ctDNA alterations will be performed to explore their association with response, 
resistance, and prognosis. 
5.11. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and 
may include vital signs and/or focused physical examination; ECOG performance status; adverse 
event review; concomitant medications and procedures review; radiographic assessments; 
physical examination of liver, spleen, and lymph nodes; 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 investigator assessment as appropriate, and the 
results of these tests should be entered in the unscheduled visit eCRF. 
5.12. 
End of Treatment  
The treatment period starts with the first day of assigned study treatment and continues until the 
last dose of study drug has been administered. 
Study drug will be discontinued for any of the following reasons: 
• Disease progression 
• Any intolerable adverse event that cannot be improved with standard medical 
intervention or that would lead to undue risk to the patient 
• Consent withdrawal by the patient 
• Patient pregnancy 
• The investigator or sponsor determines it is in the best interest of the patient 
• Other 
Patients may voluntarily withdraw consent for the study at any time. 
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5.13. 
Safety Follow-Up Visit  
All patients who permanently discontinue study drug will have a Safety Follow-up Visit 
approximately 30 days (± 7 days) after the last dose of zanubrutinib.  Refer to the Schedule of 
Assessments (Appendix 1) for the assessments to be performed at the Safety Follow-up Visit. 
Adverse events need to be collected at the Safety Follow-up Visit, including those that may have 
occurred or have been ongoing after the patient discontinued study treatment.  All adverse 
events, including serious adverse events, will be collected as described in Section 8.  The adverse 
event reporting period is defined in Section 8.4.1. 
The investigator or his/her designee will also continue to collect information on alternative 
anticancer therapy given after the last dose of study drug.  A laboratory assessment is required 
only if at the previous visit the patient had an ongoing laboratory abnormality 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 this information.   
5.14. 
Long-Term Follow-Up  
All patients who discontinue study drug treatment will remain in the study, complete the Safety 
Follow-up Visit, and subsequently commence long-term follow-up, which includes monitoring 
for survival status, second primary malignances, subsequent therapies for DLBCL, and may also 
include imaging and tumor response assessments for patients who have not yet had confirmed 
radiographic progression.  Visits repeat every 12 weeks (± 14 days) until the end of the study.  
For patients who permanently discontinue study drug treatment before radiographic progression 
is documented and confirmed by the investigator, tumor assessments will continue until disease 
progression, start of alternative anticancer therapy, loss to follow-up, or the end of the study, 
whichever occurs first. 
If the patient refuses to return for these visits or is unable to do so, every effort should be made 
to contact them or the patient’s guardian by telephone to determine the patient’s disease status 
and survival. 
5.15. 
End of Study  
Reasons for complete withdrawal from the study (including treatment and all follow-up visits) 
will occur under the following circumstances:  
• Consent withdrawal by the patient 
• Death  
• Study termination by sponsor  
• Other  
Patients may voluntarily withdraw consent for the study at any time.  The overall study ends 
when the primary analysis takes place. 
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At the end of the study as determined by the sponsor, any patient who is still on treatment and 
continues to benefit from study drug, in the opinion of the investigator, may be offered the option 
of continued access. 
5.16. 
Loss to Follow-Up  
Every reasonable effort should be made to contact any patient lost to follow-up during the study 
to complete study-related assessments, record outstanding data, and retrieve study drug.  
If telephone contact is unsuccessful, an effort should be made to contact the patient by mail using 
a method that provides proof of receipt.  Attempts to reach alternative contacts (eg, primary care 
providers, referring physician, or relatives) is permissible if the patient is not reachable.  Such 
efforts should be documented in the patient’s source documents.  
If all efforts to establish contact fail, the patient will be considered lost to follow-up. 
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6. 
STUDY TREATMENT  
6.1. 
Zanubrutinib  
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.  Instructions for dosing, storage, and the return of all bottles 
(used and unused) are to be provided at scheduled study visits. 
6.1.1. 
Packaging and Labeling of Zanubrutinib  
Zanubrutinib capsules will be provided in a child-resistant, high-density, polyethylene bottle 
with induction seal and bottle label.  Labels will be prepared in accordance with local regulatory 
guidelines of each country participating in the study.  Label text will be translated into local 
language as required.  The contents of the study treatment labels will be in accordance with all 
applicable local regulatory requirements. 
6.1.2. 
Handling and Storage of Zanubrutinib  
The Interactive Response Technology (IRT) system will be used for drug supply management.  
The study drugs will be dispatched to a study center only after receipt of the required documents 
in accordance with applicable regulatory requirements and the sponsor’s procedures.  The 
investigator or pharmacist/designated personnel is responsible for maintaining the drug supply 
inventory and acknowledging receipt of all study drug shipments.  All study drugs must be stored 
in a secure area, with access limited to the investigator and authorized study center personnel and 
kept under physical conditions that are consistent with study drug-specific requirements.  
Zanubrutinib bottles must be stored at room temperature 15ºC to 30ºC (59°F to 86°F).  Do not 
use beyond the expiration date stamped on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
Study drugs must be dispensed or administered according to procedures described herein.  Only 
patients enrolled in the study may receive study drug(s), in accordance with all applicable 
regulatory requirements.  Only authorized study center personnel may supply or administer study 
drug(s). 
6.1.3. 
Compliance and Accountability of Zanubrutinib  
Compliance will be assessed by the investigator and/or study personnel at each patient visit, 
based on information provided by the patient and/or guardian.  
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 the amount administered to and returned 
by patients, if applicable. 
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6.1.4. 
Disposal and Destruction of Zanubrutinib  
After the completion of the study, and following final drug inventory reconciliation by the 
monitor, the study site will destroy or return all unused study drug supplies.  The inventoried 
supplies can be destroyed on site or at the depot according to institutional policies, after 
receiving written sponsor approval. 
6.1.5. 
Dosage and Administration of Zanubrutinib  
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 approximately the same time each day of dosing.  Patients will 
be asked to complete a patient diary that records dates and times of dosing between clinic visits.  
Patients will be requested to bring their diaries, 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 in the appropriate eCRF. 
Zanubrutinib will be administered orally as two 80-mg capsules twice a day (160 mg twice a 
day) 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.   
If a dose of the study drug is not taken at the scheduled time, the patient should skip the study 
drug if the time to next dose is 8 hours or less and return to normal dosing with next dose.  If a 
patient vomits after taking the zanubrutinib capsules, that dose should not be repeated. 
6.1.6. 
Precautions of Zanubrutinib  
6.1.6.1. 
Overdose  
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Adverse events associated with an overdose or incorrect administration of study drug 
will be recorded in the adverse event eCRF.  Any serious adverse events associated with an 
overdose or incorrect administration are required to be reported within 24 hours of awareness via 
the serious adverse event reporting process as described in Section 8.6.1.  There is no specific 
antidote for zanubrutinib.  In the event of an overdose, patients should be closely monitored and 
given appropriate supportive treatment. 
6.1.6.2. 
Surgery and Procedures  
Susceptibility to bleeding has been observed with BTK inhibitors.  Study treatment with 
zanubrutinib should be held for 3 to 7 days before and after surgery, depending on the type of 
surgery and the risk of hemorrhage. 
6.1.7. 
Dose Interruption and Modification of Zanubrutinib  
The guidelines shown in Table 3 should be followed for dose interruption or modification of 
zanubrutinib for hematologic toxicities (Section 6.1.7.1) or nonhematologic toxicities (other than 
hypertension adequately controlled with oral medication or asymptomatic laboratory events; 
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laboratory events indicating liver or renal dysfunction will not be considered asymptomatic 
laboratory events) (Section 6.1.7.2). 
Table 3: 
Zanubrutinib Dose Reduction Levels  
Toxicity Occurrence 
Dose Level 
Zanubrutinib Dose  
First 
0 = starting dose 
Restart at 160 mg twice daily 
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 
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. 
6.1.7.1. 
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 be restarted at full dose upon 
recovery of the toxicity to ≤ Grade 1 or baseline. 
If the same event reoccurs, treatment will be restarted at 1 dose level lower (level -1) after the 
toxicity has recovered 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. 
Asymptomatic treatment-related lymphocytosis should not be considered an adverse event.  
Patients with asymptomatic treatment-related lymphocytosis should remain on study treatment 
and continue with all study-related procedures. 
Any hematologic toxicities beyond the above-mentioned conditions determined by investigators 
as requiring Zanubrutinib dose interruptions or reductions need to be discussed with the medical 
monitor. 
6.1.7.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity  
Zanubrutinib should be withheld for any ≥ Grade 3 hemorrhage.  The drug should be 
permanently discontinued for any treatment-related ≥ Grade 3 hemorrhage unless the underlying 
condition can be fully treated (eg, gastric ulcer resulting in gastrointestinal bleed) and the risk of 
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rebleeding 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 suspected to be related to study drug 
treatment, study drug will be held until recovery to ≤ Grade 1 or baseline, and then restarted at 
the original dose level.  Note that laboratory events indicating liver or renal dysfunction will not 
be considered asymptomatic laboratory events.  If the event recurs at ≥ Grade 3, study drug will 
be held until recovery to ≤ Grade 1 or baseline and restarted at dose level -1.  If the event recurs 
at ≥ Grade 3 at dose level -1, study drug will be held until recovery to ≤ Grade 1 and restarted at 
dose level -2.  If the event recurs at ≥ Grade 3 at dose 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, study drug may be 
restarted at either the original dose or dose level -1, per discretion of the treating investigator.  
Any nonhematologic toxicities beyond the above-mentioned conditions determined by the 
investigators as requiring Zanubrutinib dose interruptions or reductions need to be discussed with 
the medical monitor. 
For information about withholding study drug based on the results of hepatitis B or hepatitis C 
testing, see Section 5.8.5. 
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7. 
PRIOR AND CONCOMITANT THERAPY  
7.1. 
Prior Therapy  
Medications taken within 4 weeks before the first dose and any medications prescribed for 
chronic or intermittent use during the study, or dose adjustments of these medications, will be 
recorded in the eCRF and in the patient’s source documents.  If any AE or SAE is reported 
during the prescreening phase, related medications should also be recorded in the eCRF. 
All prior therapies for DLBCL, including immunochemotherapy, chemotherapy, transplant, 
targeted therapy, radiation therapy, etc, will be recorded in the eCRF with the start and end dates 
of administration.  
Per the study eligibility criteria, patients who received certain prior medications and therapies for 
DLBCL (including prior allogeneic hematopoietic stem cell transplantation and prior exposure to 
a BTK inhibitor) are excluded from study participation. 
7.2. 
Concomitant Therapy  
All concomitant medications taken during the study (from enrollment until 30 days after the last 
dose of zanubrutinib) will be recorded in the eCRF with indication, dose information, 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, may be used per institutional 
standards. 
7.2.1. 
Permitted Medications  
The following treatments are allowed:  
• Blood product transfusion and growth factor support per standard of care and 
institutional guidelines. 
• Corticosteroids for non-NHL indication(s). 
− Patients should not receive treatment with systemic corticosteroid other than 
intermittently to control or prevent infusion reactions or for short durations 
(< 2 weeks) to treat non-NHL-related condition(s) (eg, to treat a flare of chronic 
obstructive pulmonary disease). 
− A short course (≤ 7 days) of systemic corticosteroid treatment at doses 
≤ 20 mg/day prednisone equivalent for control of lymphoma-related symptoms is 
allowed prior to enrollment provided it is tapered off within 5 days after initiation 
of study treatment. 
− Chronic systemic corticosteroid use is not permitted, except for adrenal 
replacement, which requires consultation with the medical monitor. 
• Therapy to reduce symptoms per standard of care and institutional guidelines. 
Tumor lysis syndrome has been infrequently reported with zanubrutinib treatment.  Patients with 
high tumor burden should be monitored closely and prophylactic measures, including 
allopurinol, may be instituted per institutional standards.  
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Patients with hematologic malignancies, particularly patients 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, including Pneumocystis jirovecii pneumonia (PJP), 
prophylaxis should be considered as per institutional standards. 
7.2.2. 
Prohibited Medications  
Patients should not receive other anticancer therapy (eg, chemotherapy, radiotherapy, biologics, 
or immunotherapy) while on treatment in this study.  Vaccination with live virus vaccines is not 
allowed within 4 weeks before the first dose of study drug or during treatment. 
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers 
(refer to Appendix 4 for a list of these medications), grapefruit juice, and Seville oranges should 
be done with caution, as these may affect the metabolism of zanubrutinib.  If at all possible, 
patients are encouraged not to use strong/moderate CYP3A inhibitors and inducers and consider 
using alternative agents.  If these agents will be used, follow the dose modification guidance in 
Table 4.  The medical monitor and clinical pharmacologist should be consulted in these 
situations.  Please refer to the FDA Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers List (FDA 2019) for a more complete list.  
Clinical drug-drug interaction studies indicated that 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, because 
zanubrutinib may decrease the plasma exposures of these drugs.  
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, use of a second barrier method of 
contraception (eg, condoms) is recommended.  The coadministration of oral P-gp substrates with 
a narrow therapeutic index (eg, digoxin) should be used with caution because zanubrutinib may 
increase their concentrations. 
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Table 4: 
Dose Modification for Zanubrutinib When Coadministered With 
Strong/Moderate CYP3A Inhibitors or Inducers  
Coadministered Drug 
Recommended Zanubrutinib Dose 
Strong CYP3A inhibitor 
80 mg once daily 
Interrupt dose as recommended for adverse reactions (Section 6.1.7) 
Moderate CYP3A inhibitor 
80 mg twice daily 
Modify dose as recommended for adverse reactions (Section 6.1.7) 
Moderate or strong CYP3A 
inducer 
Avoid concomitant use 
Abbreviation: CYP, cytochrome P450.  
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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 adverse event or serious adverse event as provided in this protocol.   
8.1. 
Adverse Events  
8.1.1. 
Definitions and Reporting of an Adverse Event  
An adverse event 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 an adverse event include: 
• Worsening of a chronic or intermittent preexisting condition including an increase in 
severity, frequency, or duration, and/or that is associated with a significantly worse 
outcome. 
• New condition(s) detected or diagnosed after study drug administration even if 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 (an overdose itself should not be reported as an adverse 
event or serious adverse event). 
When an adverse event or a serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory results, and 
diagnostics reports) relative to the adverse event or serious adverse event.  The investigator will 
then record all relevant information regarding an adverse event or serious adverse event in the 
eCRF.  However, there may be instances when copies of medical records for certain cases are 
requested by the sponsor.  In these instances, all patient identifiers will be blinded on the copies 
of the medical records prior to submission to the sponsor. 
8.1.1.1. 
Assessment of Severity  
The investigator will assess the severity for each adverse event and serious adverse event 
reported during the study.  When applicable, adverse events and serious adverse events should be 
assessed and graded based upon the NCI-CTCAE Version 5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
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• 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 adverse event  
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(for example, grade of a specific adverse event, 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 8.2. 
8.1.1.2. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each adverse event or serious adverse event using their best clinical judgment.  Alternative 
causes, such as the natural history of the underlying diseases, concomitant therapy, other risk 
factors, and the temporal relationship of the adverse event or serious adverse event to the study 
drug should be considered and investigated.  The investigator should also consult the 
Investigator’s Brochure and/or Product Information for marketed products, in the determination 
of his/her assessment. 
There may be situations when a serious adverse event 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 makes an assessment of causality for every serious adverse event 
prior to transmission of the serious adverse event report to the sponsor, because the causality 
assessment is one of the criteria used when determining regulatory reporting requirements.  The 
investigator may change his/her opinion of causality after considering follow-up information, 
amending the serious adverse event report/eCRF accordingly.  
The causality of each adverse event should be assessed and classified by the investigator as 
“related” or “not related.”  An adverse event is considered related if there is “a reasonable 
possibility” that the adverse event 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 adverse event 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 adverse event should be considered “related” to study drug if any of the following are met; 
otherwise, the event should be assessed as “not related”: 
• There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
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• 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 adverse event 
occurred within a reasonable time after administration of the study drug).  However, 
the influence of other factors may have contributed to the adverse event (eg, the 
patient’s clinical condition or other concomitant adverse events). 
8.1.1.3. 
Following Adverse Events and Serious Adverse Events  
After the initial adverse event or serious adverse event report, the investigator is required to 
proactively follow each patient and provide further information to the sponsor on the patient’s 
condition. 
All adverse events and serious adverse events documented at a previous visit/contact and 
designated as ongoing will be reviewed at subsequent visits/contacts. 
All adverse events and serious adverse events will be followed until resolution, the condition 
stabilizes or is considered chronic, the adverse event or serious adverse event is otherwise 
explained, the patient is lost to follow-up, the patient withdraws consent, or the initiation of any 
alternative anticancer therapy, whichever comes first.  The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the adverse event or serious adverse event.  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 adverse event or serious adverse event.  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 serious adverse 
event instructions provided to the site within the time frames outlined in Section 8.6.1. 
8.1.2. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, chemistry, CBC, coagulation, or urinalysis) or other abnormal 
assessments (eg, ECGs, echocardiogram/MUGA, pulmonary function test, or vital signs) that are 
judged by the investigator as clinically significant will be recorded as adverse events or serious 
adverse events.  This includes clinically significant abnormal laboratory findings or other 
abnormal assessments that are present at baseline and significantly worsen during the study.  
However, clinically significant abnormal laboratory findings or other abnormal assessments that 
are present at the start of the study and do not worsen will not be reported as adverse events or 
serious adverse events.  The definition of clinically significant is left to the judgment of the 
investigator.  In general, these are laboratory test abnormalities that are associated with clinical 
signs or symptoms, or require active medical intervention, or lead to dose interruption or 
discontinuation, require close observation, more frequent follow-up assessments, or further 
diagnostic investigation. 
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Asymptomatic treatment-related lymphocytosis should not be considered an adverse event. 
8.2. 
Definition of a Serious Adverse Event  
A serious adverse event 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 adverse 
event in which the patient was at risk of death at the time of the adverse event; it does 
not refer to an adverse event which hypothetically might have caused death if it were 
more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, “hospitalization” signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.  
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions, but do not constitute a substantial 
disruption.  
• Results in a congenital anomaly/birth defect 
• Is considered a significant medical adverse event 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 serious adverse events: 
• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admission for 
transfusion support or convenience 
8.3. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
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8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.4.1. 
Adverse Event Reporting Period  
After signing the prescreening informed consent form, any AE or SAE evaluated by the 
investigators as related to the procedures for study-relevant tumor tissue collection (eg, biopsy) 
should be reported. 
After screening informed consent has been signed but before the administration of the study 
drug, only serious adverse events should be reported.  If, after signing the informed consent but 
before the first dose of study drug, the patient experiences a new or worsening condition that 
does not meet the definition of serious, that condition should be reported only as medical history. 
After initiation of study drug, all adverse events and serious adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of zanubrutinib or the 
initiation of any alternative anticancer therapy, whichever comes first.  After this period, the 
investigator should only report any serious adverse events that are believed to be related to 
zanubrutinib. 
8.4.2. 
Eliciting Adverse Events  
The investigator or designee will ask about adverse events 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? 
8.5. 
Specific Instructions for Recording Adverse Events and Serious 
Adverse Events  
8.5.1. 
Disease Progression  
Disease progression, which is expected in this study population and measured as an efficacy 
endpoint, should not be recorded as an adverse event term.  Similarly, nonserious adverse events 
which are clearly consistent with the pattern of progression of the underlying disease and are 
considered unequivocally due to disease progression should not be recorded.  However, if there 
is any uncertainty as to whether a nonserious adverse event is due to disease progression, it 
should be recorded as an adverse event.  All serious adverse events and deaths regardless of 
relatedness to disease progression should be recorded and reported. 
8.5.2. 
Death  
Death is an outcome and not usually considered an event.  If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death,” 
“death of unknown cause,” or “death unexplained.” 
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8.6. 
Reporting of Serious Adverse Events  
8.6.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an adverse event meets the protocol definition of a 
serious adverse event, the event must be reported promptly (within 24 hours) to the sponsor or 
designee as described in Table 5. 
Table 5: 
Time Frame for Reporting Serious Adverse Events to the Sponsor or 
Designee  
 
 
Timeframe for sending 
initial/follow-up report a   
Documentation 
method 
Reporting method 
All SAEs 
Within 24 hours after first 
knowledge of the SAE 
SAE report 
Electronic submission of 
SAE form to safety portal b      
Abbreviations: SAE, serious adverse event. 
 a Report follow-up information that is clinically relevant and pertaining to the serious adverse event, which includes 
but is not limited to the following: update to the serious adverse event, new additional serious adverse event, 
outcome, seriousness criteria, investigator causality, event start date/date of onset, date of death, relationship to 
study drug(s). Follow-up information will also be reported as per the discretion of the investigator if the new or 
updated information changes the medical assessment of the case. 
 b Serious adverse event reports should be submitted to the sponsor safety database electronically from within the 
electronic data capture system. If the electronic submission is not available for any reason, a paper serious adverse 
event form should be submitted by email or fax. 
8.6.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that a serious adverse event has occurred in a patient, he/she 
is to report the information to the sponsor within 24 hours as outlined in Section 8.6.1.  The 
serious adverse event report will always be completed as thoroughly as possible with all 
available details of the event and forwarded to the sponsor or designee within the designated 
time frames.   
If the investigator does not have all information regarding a serious adverse event, he/she is not 
to wait to receive additional information before notifying the sponsor or designee of the serious 
adverse event and completing the form.  The form will be updated when additional information 
is received.  
The investigator must always provide an assessment of causality at the time of the initial report 
as described in Section 8.1.1.2. 
The sponsor will provide contact information for serious adverse event report submission. 
8.6.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all serious adverse events to the sponsor in accordance with 
the procedures detailed in Section 8.6.2.  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.  
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The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of serious adverse events to 
regulatory authorities and the IRB/IEC. 
All SUSARs (as defined in Section 8.3), will be submitted to all applicable regulatory authorities 
and investigators for zanubrutinib studies. 
When a study center receives an initial or follow-up safety report or other safety information  
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC.  The investigator should place copies 
of Safety Reports from the sponsor in the Investigator Site File. 
8.7. 
Pregnancy Reporting  
If a female patient or the partner of a male patient becomes pregnant while receiving study 
treatment or within 30 days after the last dose of zanubrutinib, a pregnancy report form is 
required to be completed and expeditiously submitted to the sponsor to facilitate outcome 
follow-up.  Information on the status of the mother and child will be forwarded to the sponsor.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  
Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered an adverse event, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an adverse event or 
serious adverse event. 
An abortion, whether accidental, therapeutic, or spontaneous should always be reported as a 
serious adverse event.  Similarly, any congenital anomaly/birth defect in a child born to a patient 
exposed to the study drug should be recorded and reported as a serious adverse event. 
8.8. 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees  
The sponsor will promptly assess all serious adverse events 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 serious adverse events, the sponsor will 
assess the expectedness of the serious adverse events using the following reference documents: 
• Zanubrutinib (BGB-3111) Investigator’s Brochure 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
All statistical analyses will be performed by the sponsor or designee after the database is locked 
and released.  Details of the statistical analysis will be included in a separate Statistical Analysis 
Plan.   
9.1. 
Study Endpoints  
All the responses in the efficacy endpoints below are determined by investigator assessment 
according to the Lugano classification for NHL (Cheson et al 2014). 
9.1.1. 
Primary Endpoint  
• Overall response rate determined by the investigator assessment 
9.1.2. 
Secondary Endpoints  
• Efficacy endpoints of zanubrutinib therapy are as follows: 
− Complete response rate determined by investigator assessment 
− Duration of response determined by investigator assessment 
− Progression-free survival determined by investigator assessment 
− Time to response determined by investigator assessment 
− Overall survival 
• Safety parameters, including adverse events and serious adverse events (per 
NCI-CTCAE Version 5.0), clinical laboratory measurements, physical examination, 
and vital signs 
9.1.3. 
Exploratory Endpoints  
• PK evaluations of zanubrutinib, including summary of plasma concentrations 
• Clinical outcomes (eg, overall response rate, complete response rate, duration of 
response, progression-free survival, time to response, and overall survival) by 
clinical/genetic risk factors 
• Potential resistance biomarkers and mechanisms of disease resistance 
9.2. 
Statistical Analysis  
9.2.1. 
Analysis Sets  
Safety Analysis Set: includes all patients who receive at least one dose of zanubrutinib.  The 
Safety Analysis Set will be used for both safety and efficacy analyses. 
PK Analysis Set: includes all patients for whom there is at least one available postdose 
zanubrutinib PK concentration measurement. 
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9.2.2. 
Patient Disposition  
The number of patients screened, enrolled, treated, and discontinued from study drug or the 
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.  Major protocol deviations will be summarized and listed by each 
category. 
9.2.3. 
Demographics and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized in the Safety Analysis Set 
using descriptive statistics.  Continuous variables include but are not limited to age, weight, vital 
signs, time since initial DLBCL diagnosis; categorical variables including but not limited to sex, 
age group, disease stage, ECOG performance status, and prior line of therapy for DLBCL.  
Baseline bone marrow involvement and International Prognostic Index will also be summarized. 
9.2.4. 
Prior and Concomitant Therapy  
Prior medications will be defined as medications that stopped before the first dose of study drug. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the last dose of zanubrutinib.  
Concomitant medications will be assigned a preferred name using the World Health 
Organization Drug Dictionary drug codes.  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.  
9.2.5. 
Efficacy Analyses  
Efficacy assessments will use the Lugano classification to assess overall disease response (see 
Appendix 2). 
9.2.5.1. 
Primary Efficacy Endpoint Analysis  
The primary efficacy endpoint is the overall response rate determined by the investigator 
assessment, where the overall response rate is defined as the proportion of patients in the Safety 
Analysis Set whose best overall response is either CR or PR, and the best overall response is 
defined as the best response recorded from the start of zanubrutinib until the data cutoff date or 
the start of alternative anticancer treatment.  Patients who drop out earlier with no post-baseline 
response assessment (for any reason) will be considered nonresponders for best overall response. 
The overall response rate of historical control in this study is 30% based on the reported overall 
response rate in the literatures (Advani et al 2017; Assouline et al 2016; Budde et al 2018; 
Coiffier et al 2016; Czuczman et al 2017; Jurczak et al 2018; Hutchings et al 2018; 
Lesokhin et al 2016; Kalakonda et al 2020).  Hence, the null and alternative hypotheses are set as 
follows: 
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H0: overall response rate = 30% 
Ha: overall response rate > 30% 
A binomial exact test will be performed for hypothesis testing H0 versus Ha in the Safety 
Analysis Set, and the overall type I error rate will be controlled at 1-sided significance level of 
0.025.  The primary analysis will take place approximately 6 months after the first dose of the 
last patient, as specified in Section 9.6.  If the null hypothesis can be rejected in primary analysis 
at significance level of 0.025, it will be concluded that the historical control of 30% can be ruled 
out.  A 2-sided Clopper-Pearson 95% CI of the overall response rate will also be calculated to 
assess the precision of the estimation. 
Justification of historical control 
At present, no related studies are designed based on BTK inhibitors in the population of R/R 
DLBCL with CD79B mutation.  The overall response rate of historical control in this study is 
chosen based on the reported overall response rate in the literatures (Advani et al 2017; 
Assouline et al 2016; Budde et al 2018; Coiffier et al 2016; Czuczman et al 2017; 
Jurczak et al 2018; Hutchings et al 2018; Lesokhin et al 2016; Kalakonda et al 2020).  It is 
reported that the overall response rates in patients with DLBCL treated by chemo-free therapy 
without BTK inhibitors are less than or approximately 30%, except that an overall response rate 
of 36% is reported in a study with a small sample size of 11 patients (Lesokhin et al 2016).  
Considering that DLBCL patients with CD79B mutation, compared with those without CD79B 
mutations, are associated with worse prognosis and shorter survival after standard treatment, the 
historical control is chosen to be 30%. 
9.2.5.2. 
Secondary Efficacy Endpoint Analyses  
Complete Response Rate by Investigator Assessment 
The complete response rate will be determined by the investigator, and it is defined as the 
proportion of patients in the Safety Analysis Set whose best overall response is CR.  The 
complete response rates along with their 95% CIs, using Clopper-Pearson method, will be 
provided. 
Duration of Response by Investigator Assessment 
The duration of response is defined as the time from the date that the response criteria are first 
met to the date that PD is objectively documented or death, whichever occurs first.  The duration 
of response will be only summarized for responders.  Censoring rules for duration of response 
followed progression-free survival censoring rules.  The Kaplan-Meier method will be used to 
estimate duration of response curves and corresponding quantiles (including the median) 
(Schemper and Smith 1996).  A 2-sided 95% CI of median, if estimable, will be constructed with 
a generalized Brookmeyer and Crowley method (Brookmeyer and Crowley 1982).  The duration 
of response event-free rates at 6 and 12 months will be estimated using the Kaplan-Meier method 
along with the corresponding 95% CI constructed using Greenwood’s formula (Kalbfleisch and 
Prentice 1980). 
Progression-Free Survival by Investigator Assessment 
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Progression-free survival is defined as the time from the starting date of the therapy to the date of 
first documentation of disease progression or death, whichever occurs first.  Patients who do not 
have disease progression will be censored at their last valid response assessment. 
The progression-free survival will be analyzed in a similar fashion as duration of response.  The 
Kaplan-Meier method will be used to estimate progression event-free curves and corresponding 
quantiles (including the median) (Schemper and Smith 1996).  A 2-sided 95% CI of median, if 
estimable, will be constructed with a generalized Brookmeyer and Crowley method (Brookmeyer 
and Crowley 1982).  The progression-free survival probability at 6 and 12 months, defined as the 
percentages of patients in the analysis set who remain alive and progression-free at the specified 
timepoints, will be estimated using the Kaplan-Meier method along with the corresponding 95% 
CI constructed using Greenwood’s formula (Kalbfleisch and Prentice 1980). 
The progression-free survival censoring rule will follow FDA Guidance for Industry Clinical 
Study Endpoints for the Approval of Cancer Drugs and Biologics (FDA 2018). 
Time to Response by Investigator Assessment 
Time to response is defined as time from the starting date of the therapy to the date the response 
criteria are first met.  Time to response will be summarized using sample statistics, such as 
sample mean, median, and standard deviation. 
Overall Survival 
Overall survival is defined as the time from the starting date of the therapy to the date of death 
due to any reason.  Patients who are known to be alive as of their last known status will be 
censored at their date of last contact.  The overall survival will be analyzed similarly as 
progression-free survival. 
Additional details will be provided in the Statistical Analysis Plan. 
9.2.6. 
Biomarker Analyses  
The biomarker-related analysis will be provided in a separate report. 
9.2.7. 
Pharmacokinetic Analyses  
Plasma zanubrutinib concentration data collected sparsely at predose and 2 hours (± 30 minutes) 
postdose on Day 1 of Cycle 1 and Cycle 2 will be tabulated and summarized by cycle.  
Descriptive statistics including means, standard deviations, medians, and ranges as appropriate, 
will be used for the analysis of plasma zanubrutinib concentrations. 
Additional analyses such as population PK analysis may be performed together with data from 
other studies, and the results from such analysis will be reported separately from the Clinical 
Study Report. 
9.2.8. 
Subgroup Analyses  
Primary and selected secondary endpoints will be summarized descriptively in the specified 
subgroups, including but not limited to sex, age group, disease stage at study entry, disease 
status, ECOG performance status, number of prior lines of therapy, International Prognostic 
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Index, and bulky disease.  Within group values (rates or means/medians) and CIs will be 
presented in forest plots. 
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording of all adverse events graded by  
NCI-CTCAE Version 5.0.  Laboratory values (CBC, serum chemistry, coagulation and 
urinalysis), vital signs, physical exams, ECG, echocardiogram/MUGA, and pulmonary function 
test findings will also be used in assessing safety.  Descriptive statistics will be used to analyze 
all safety data in the Safety Analysis Set.  
9.3.1. 
Extent of Exposure  
Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity (mg/day), and relative dose intensity. 
The number (percentage) of patients requiring dose reductions, dose interruption, and drug 
discontinuation due to adverse events will be summarized.  The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics.  Frequency of 
reductions and dose interruptions will be summarized. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events  
The adverse event verbatim descriptions (investigator terms from the eCRF) will be classified 
into standardized medical terminology defined by the Medical Dictionary for Regulatory 
Activities (MedDRA).  Adverse events will be coded to the MedDRA lowest level term that 
most closely resembled the verbatim adverse event term.  The linked MedDRA preferred term 
(PT) and primary system organ class (SOC) will also be captured in the database.   
A treatment-emergent adverse event is defined as an adverse event that had an onset date or 
worsening in severity from baseline (pretreatment) on or after the first dose of study drug and up 
to 30 days after the last dose of zanubrutinib, or the initiation of any alternative anticancer 
therapy, whichever comes first.  Worsening of an event to Grade 5 beyond Day 30 after last dose 
of study drug of a treatment-emergent adverse event is also considered a treatment-emergent 
adverse event.  Treatment-related adverse events include those adverse events considered by the 
investigator to be related to study drug or with missing assessment of the causal relationship. 
Only those adverse events that were treatment-emergent will be included in summary tables.  All 
adverse events, treatment-emergent or otherwise, will be presented in patient data listings.  The 
incidence of treatment-emergent adverse events will be reported as the number (and percentage) 
of patients with treatment-emergent adverse events by SOC and PT.  A patient will be counted 
only once by the highest severity grade according to NCI-CTCAE Version 5.0 within a SOC and 
PT, even if the patient experienced more than 1 treatment-emergent adverse event within a 
specific SOC and PT.  The number (percentage) of patients with treatment-emergent adverse 
events will also be summarized by relationship to the study drug.  The patient incidence of 
serious adverse events, treatment-emergent adverse events of Grade 3 or higher, 
treatment-emergent adverse events leading to death, treatment-emergent adverse events leading 
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to treatment discontinuation and dose modification (dose reduction or dose interruption), and all 
above treatment-related treatment-emergent adverse events will be summarized.  Deaths and 
cause of deaths will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (ie, hematology, serum chemistry, coagulation, and qualitative urinalysis) 
values will be evaluated for each laboratory parameter by patient.  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 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 Version 5.0 will be summarized by 
CTCAE grade.  In the summary of laboratory parameters by CTCAE grade, parameters with 
CTCAE grading in both high and low directions (eg, calcium, glucose, magnesium, potassium, 
sodium) will be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
temperature, and respiratory rate) and changes from baseline will be presented by visit. 
9.3.5. 
Electrocardiogram  
ECG assessments will be performed at the Screening Visit and as clinically indicated.  
Descriptive statistics for baseline ECG parameters will be presented. 
9.3.6. 
Echocardiogram/Multiple Gated Acquisition Scan  
Echocardiogram/MUGA assessments will be performed at the Screening Visit unless one has 
been performed within 30 days before the first dose of study drug.  Descriptive statistics for 
baseline electrocardiogram/MUGA parameters will be presented. 
9.3.7. 
Pulmonary Function Test  
Pulmonary function assessments will be performed at the Screening Visit and as clinically 
indicated.  Descriptive statistics for baseline pulmonary function parameters will be presented. 
9.4. 
Sample Size Consideration  
The sample size of the study is planned based on the level of precision of overall response rate 
estimate as well as the power of a hypothesis testing against a historical rate.  The targeted 
overall response rate in this study is 50%, which is deemed a clinically meaningful improvement 
based on a historical control of 30%.  Assuming a true overall response rate of 50% in the study 
population, 66 patients will provide 90% power to reject the null hypothesis of 30% ORR at the 
one-sided significance level of 0.025.  The 95% Clopper-Pearson CI will be (37.4%, 62.6%) with 
a sample size of 66 patients, when the observed overall response rate is 50%.  The historical 
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control rate is obtained from referenced studies (Advani et al 2017; Assouline et al 2016; 
Budde et al 2018; Coiffier et al 2016; Czuczman et al 2017; Jurczak et al 2018; 
Hutchings et al 2018; Lesokhin et al 2016; Kalakonda et al 2020). 
9.5. 
Interim Analysis  
No interim analysis is planned for this study.  
9.6. 
Primary Analysis  
The primary analysis will take place approximately 6 months after the first dose of the last 
patient.  The null hypothesis H0 is rejected if the p-value from an exact binomial test statistic is 
less than 0.025.  Correspondingly, at least 28 responders are required in 66 patients.  
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Safety Monitoring Committee  
No safety monitoring committee is planned in this study. 
10.2. 
Provision of Study Results and Information to Investigators  
When the Clinical Study Report is completed, the sponsor will provide the major findings of the 
study to the investigator. 
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s). 
The sponsor will not routinely inform the investigator or patient of the test results, because the 
information generated from this study will be preliminary in nature, and therefore, the 
significance and scientific validity of the results cannot be determined at such an early stage of 
research.   
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11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS  
11.1. 
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. 
11.2. 
Investigator Responsibilities  
11.2.1. 
Good Clinical Practice  
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki,” International Council on Harmonisation guidelines, the basic 
principles of “Good Clinical Practice” by National Medical Products Administration (NMPA) in 
April 2020, Section 4 “Investigators,” and the basic principles of “Good Clinical Practice” as 
outlined in 21 Code of Federal Regulations (CFR) 312, Subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, Part 50, and 21 CFR, Part 56. 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval  
This study will be conducted in accordance with Good Clinical Practice and all applicable 
regulatory requirements, including, where applicable, the current version of the Declaration of 
Helsinki. 
The sponsor’s sample ICF will be provided to each investigator who shall adapt it, subject to 
sponsor’s approval, for use at his/her site.  The investigator (or sponsor, where applicable) is 
responsible for ensuring that this protocol, the study center’s ICF, and any other information that 
will be presented to potential patients (eg, advertisements or information that supports or 
supplements the informed consent) are reviewed and approved by the appropriate IRB/IEC.  The 
IRB/IEC must be constituted in accordance with all applicable regulatory requirements.  The 
sponsor will provide the investigator with relevant document(s)/data that are needed for IRB/IEC 
review and approval of the study.  Before the study drug(s) can be shipped to the study center, 
the sponsor or its authorized representative must receive copies of the IRB/IEC approval, the 
approved ICF, and any other information that the IRB/IEC has approved for presentation to 
potential patients. 
If the protocol, the ICF, or any other information that the IRB/IEC has approved for presentation 
to potential patients is amended during the study, the investigator is responsible for ensuring the 
IRB/IEC reviews and approves, where applicable, these amended documents.  The investigator 
must follow all applicable regulatory requirements pertaining to the use of an amended ICF 
including obtaining IRB/IEC approval of the amended form before new patients can consent to 
take part in the study using this version of the form.  Copies of the IRB/IEC approval of the 
amended ICF/other information and the approved amended ICF/other information must be 
forwarded to the sponsor promptly. 
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11.2.3. 
Informed Consent  
The investigator is responsible for obtaining a signed ICF from each individual participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures.  The investigator must utilize an 
IRB/IEC-approved consent form for documenting written informed consent.  Each informed 
consent will be appropriately signed and dated by the patient or the patient’s legally authorized 
representative and the person obtaining consent. 
Informed consent will be obtained before the patient can participate in the study.  The contents 
and process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
In the event that the ICF or other forms signed by the patient is amended during their 
participation in the study, patients must be reconsented to the most current version of the ICF or 
form.  For any updated or revised ICFs or other forms, the case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
reobtained 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 
master study file and must be available for verification by study monitors at any time. 
11.2.4. 
Investigator Reporting Requirements  
As indicated in Section 8.6.3, the investigator (or sponsor, where applicable) is responsible for 
reporting serious adverse events to the IRB/IEC, in accordance with all applicable regulations.  
Furthermore, the investigator may be required to provide periodic safety updates on the conduct 
of the study at his/her study center and notification of study closure to the IRB/IEC.  Such 
periodic safety updates and notifications are the responsibility of the investigator and not of the 
sponsor. 
11.2.5. 
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 Good Clinical Practice Guideline, as 
implemented locally.  Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study.  
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
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• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• 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 kinds 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, 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 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 United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (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 
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third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor.  The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
11.2.6. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system in a 
timely manner.  
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee as identified in the Statement of 
Investigator Form must sign the completed casebooks 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.  
11.2.7. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies and completeness. 
During the course of the study, a study monitor (clinical research associate) will make site visits 
to review protocol compliance, compare eCRFs against individual patient’s medical records and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.  Checking the 
eCRFs for completeness, clarity and cross-checking with source documents is required to 
monitor the progress of the study.  Direct access to source data is also required for inspections 
and audits, and will be carried out giving due consideration to data protection and medical 
confidentiality. 
Adverse events will be coded using MedDRA.  Concomitant medications will be coded using the 
World Health Organization Drug Dictionary.  Concomitant diseases/medical history will be 
coded using MedDRA. 
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11.2.8. 
Drug Integrity and In-house Blinding  
Due to the open-label design of the study, access to the patient-level clinical data in the EDC 
system will be assigned only to predefined study personnel.  Functions/persons with access to the 
EDC system shall be prohibited from using the EDC system to generate unnecessary 
listings/summaries that may introduce unwanted bias or to share such outputs from the EDC 
system with other functions/persons who do not have access to the EDC. 
11.2.9. 
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.  Dispensing records will document quantities received from BeiGene 
and quantities dispensed to patients, including lot number, date dispensed, patient identifier 
number, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements.  At the end of 
the study, following final drug inventory reconciliation by the monitor, the study site will dispose 
of and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet BeiGene’s requirements for disposal, arrangements will be 
made between the site and BeiGene or its representative for destruction or return of unused study 
drug supplies. 
All drug supplies and associated documentation will be reviewed periodically and verified by the 
study monitor over the course of the study. 
11.2.10. 
Inspections, Audits, and Monitoring Visits  
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, 
or to regulatory authority or health authority inspectors. 
11.2.11. 
Protocol Adherence  
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, if applicable, to the IRB/IEC, in accordance with established 
IRB/IEC policies and procedures. 
11.2.12. 
Financial Disclosure  
Investigators and subinvestigators (as designated on the Form FDA1572) are required to provide 
the sponsor with sufficient accurate financial information in accordance with regulations to allow 
the sponsor to submit complete disclosure or certification to the absence of certain financial 
interest of clinical investigators and/or disclose those financial interests, as required, to the 
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appropriate health authorities.  This is intended to ensure that financial interests and 
arrangements of 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, the last patient’s last visit). 
11.3. 
Protocol Modifications  
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene.  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. 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming willingness to remain in the study. 
11.4. 
Study Report and Publications  
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 International Council on 
Harmonisation Guideline for Structure and Content of Clinical Study Reports (International 
Council on Harmonisation 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 
regulator 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.  As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor.  Thereafter, any secondary publications will reference the original 
publication(s).  Authorship will be determined by mutual agreement and all authors must meet 
the criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria  
(International Committee of Medical Journal Editors 2019). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation in 
accordance with the clinical study agreement.  This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy.  The process of 
reviewing manuscripts and presentations that are based on the data from this study is detailed in 
the investigator’s clinical study agreement.  Each investigator agrees that, in accordance with the 
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terms of clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings in advance of the publication/presentation. 
11.5. 
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 
• Resolve and close all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• 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 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 IRB/IEC 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 return of all unused study drug(s) in accordance with the 
applicable sponsor procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
11.6. 
Records Retention and Study Files  
The investigator must maintain adequate and accurate records so that the conduct of the study 
can be fully documented and the study data subsequently verified.  These documents should be 
classified into at least the following 2 categories: (1) investigator’s study file, and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
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 (although not be limited to) 
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the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECGs, electroencephalogram, x-ray, pathology and special 
assessment reports, consultant letters, screening and enrollment log, etc.  
After closure of the study, the investigator must maintain all study records in a safe and secure 
location.  The records must be maintained to allow easy and timely retrieval, when needed (eg, 
audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel.  Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken.  The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable back up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of the 
records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples remaining after this study may be retained in storage by the sponsor for a 
period up to 10 years or as allowed by the IRB/IEC.  A longer storage period may apply in the 
event that patients consent to BeiGene retaining remaining samples for future research. 
11.7. 
Information Disclosure and Inventions  
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) is the sole property of the 
sponsor. 
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. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) will be kept 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.   
These restrictions do not apply to the following: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study 
• Information that is necessary to disclose in order to provide appropriate medical care 
to a patient 
• Study results that may be published as described in Section 11.4 
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. 
11.8. 
Joint Investigator/Sponsor Responsibilities  
11.8.1. 
Access to Information for Monitoring  
In accordance with International Council on Harmonisation Good Clinical Practices 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 in the course of these monitoring visits are resolved. 
11.8.2. 
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. 
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Study Phase or Visit 
Prescreening 
Screening 
Treatment (1 Cycle = 28 days) 
Safety Follow-Up 
Visit after End of 
Treatmentb  
Long-
Term 
Follow-
upc  
Zanubrutinib Monotherapy 
Suspected 
Cycle/Perioda 
Cycle 1 Cycle 2 Cycle 3 
Every 12 weeks after C4D1 
through the end of Year 2, 
then every 24 weeks 
CR 
PD 
Day 
 
-21 to -1 
Day 1 
Day 1 
Day 1 
Every 12 weeks or every 24 
weeks as per above 
 
 
30 days after End 
of Treatmentb 
Every 12 
weeks 
Window (Days) 
– 
– 
 
± 7 
± 7 
± 7 
– 
– 
± 7 
± 14 
Survival status 
 
 
 
 
 
 
 
 
 
X 
Second primary 
malignances 
 
 
 
 
 
 
 
 
 
X 
Subsequent anticancer 
therapy 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BCL, 
B-cell lymphoma; CR, complete response; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; DNA, deoxyribonucleic acid; EBV, 
Epstein-Barr virus; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; FDG, 
fluorodeoxyglucose; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, 
hepatitis C virus; INR, international normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition scan; 
MYC, myelocytomatosis; PCR, polymerase chain reaction; PD, progressive disease; PET, positron emission tomography; QTcF, Fridericia’s correction; RNA, 
ribonucleic acid. 
Note: On Cycle 1 Day 1, all assessments unless otherwise noted should be performed predose. 
a Treatment cycle length = 28 days.  
b A Safety Follow-up Visit is conducted approximately 30 days (± 7 days) after the last dose of zanubrutinib, to perform the planned safety assessments and 
laboratory assessments, and to collect information on alternative anticancer therapy given after the last dose of study drug.  Refer to Note q and Note r for 
more details about the collection of concomitant medications and adverse events, respectively. 
c Long-term follow-up includes monitoring survival status, second primary malignances, subsequent therapies for DLBCL, and may also include imaging and 
tumor response assessments for patients who have not yet had confirmed radiographic progression.  Visits repeat every 12 weeks (± 14 days) until the end of 
the study.  For patients who permanently discontinue study drug treatment before radiographic progression is documented and confirmed by the investigator, 
tumor assessments will continue until disease progression, start of alternative anticancer therapy, loss to follow-up, or the end of the study, whichever comes 
first. 
d Zanubrutinib will be administered orally as two 80-mg capsules twice a day (160 mg twice a day) with or without food.  Patients will receive zanubrutinib 
monotherapy until disease progression, unacceptable toxicity, loss to follow-up, or the end of the study, whichever occurs first.  A patient diary will be 
provided to each patient to record the zanubrutinib dose taken each day.  Any missed doses with explanation should be recorded in the diary.  The diary 
should be returned to the site personnel for review and will be reviewed by the study coordinator on a regular basis. 
e This must occur before any study-specific procedures are conducted for prescreening and screening and may be obtained before the 21-day screening window 
for the screening evaluations.  Consent must be obtained using the current version of the form approved by the Independent Ethics Committee/Institutional 
Review Board. 
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f Prior to enrollment, the investigator is responsible for assessing and confirming that each patient meets all inclusion eligibility criteria for this study and that 
none of the exclusion criteria apply. All results from the screening procedures and relevant medical history must be available and reviewed by the investigator 
before eligibility can be determined.  No eligibility waivers will be granted.  Sponsor verification of patient eligibility will be managed by way of source data 
verification in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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. 
g Review any medical and cancer history any time after obtaining informed consent, including presence or absence of disease-related constitutional symptoms.  
Other background information including history of disease, including the date of initial diagnosis and current disease status, staging, and sites of disease.  
Prior medications/significant non-drug therapies and demographic data (gender, year of birth [or age] and race/ethnicity) will also be collected. 
h Approximately 10 unstained slides must be sent to the central laboratory for detection of CD79B mutation status at the Prescreening Visit.  A fresh tumor 
biopsy is preferred at prescreening.  If fresh tumor biopsies are not available, then an archival tumor tissue taken within 2 years before prescreening will be 
requested. 
i For patients who proceed to screening stage, 5 more unstained slides should be sent to the central laboratory for analysis of other potential predictors of 
response including assessment of subtypes, MYD88L265P mutation, and BCL2/MYC/TCL1A expression.  DLBCL characteristic markers may also be 
assessed.  Optional biopsy will be taken from patients who have confirmed disease progression during the study at accessible tumor sites to explore genetic 
alterations associated with drug resistance, including DNA alterations and analyses of the subtype (based on the gene expression profile). 
j Blood samples will be collected at screening, time of first response, and time of disease progression.  CD79B mutation status in the blood will be assessed.  
Blood-based biomarker analysis such as DNA/ctDNA alterations, etc, will be performed to explore their association with response, resistance, and prognosis. 
k Safety assessments will be conducted on Day 1 of every cycle, unless otherwise specified. 
l Vital signs (blood pressure, pulse rate, body temperature, and respiratory rate) will be assessed after the patient has rested in the sitting position for 
10 minutes.  Vital signs will be performed at the Screening Visit, each visit during study treatment, and the Safety Follow-up Visit. 
m Physical examination and weight will be performed at the Screening Visit, each visit during study treatment, and the Safety Follow-up Visit.  Assessment of 
physical examination on the first day of Cycle 1 may be skipped if performed within previous 7 days.  A complete physical examination is performed at the 
study site and includes an assessment of systems per standard of care and as clinically indicated by symptoms.  Physical examination will include an 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and a basic 
nervous system evaluation.  Height is determined at screening only. 
n An echocardiogram/MUGA is to be performed at screening unless one has been performed within 30 days before the first dose of study drug. 
o A 12-lead ECG will be performed in triplicate (≥ 1 minute apart) at screening and as clinically indicated.  The calculated QTcF average of 3 ECGs must be 
≤ 480 msec for eligibility.  Patients should in a supine position and resting for at least 10 minutes before obtaining the ECGs. 
p Pulmonary function test will be assessed at screening and as clinically indicated. 
q Record any new medications, changes in ongoing medications or procedures, and medications discontinued within 21days before the first dose of study drug, 
and on study thereafter until 30 days after the last dose of zanubrutinib.  If any AE or SAE is reported during the prescreening phase, related medications 
should also be recorded in the eCRF. 
r Any AE or SAE evaluated by the investigators as related to the procedures for study-relevant tumor tissue collection (eg, biopsy) after signing the 
prescreening informed consent form should be recorded in the eCRF.  After the screening informed consent has been signed but before the administration of 
the study drug, only serious adverse events should be reported.  After initiation of study drug, all adverse events and serious adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of zanubrutinib or the initiation of any alternative anticancer therapy, whichever 
comes first. 
s Response will be assessed by the investigator according to the Lugano classification.  Response parameters will include assessment of lymphadenopathy, 
hepatomegaly and splenomegaly, and bone marrow biopsy and aspirate. 
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t All patients must have a baseline PET-CT and CT scan with contrast of the chest, abdomen, pelvis, and neck if clinically indicated (within 21days before the 
first dose of study drug).  PET-CT should be done at screening, at Week 12 and Week 24 after treatment, and the time when CR or PD is suspected.  For FDG 
non-avid disease, only CT scans will be required for post-baseline visit.  Contrast CT should be performed at screening, every 12 weeks for 24 months, and 
every 24 weeks thereafter until disease progression, start of alternative anticancer therapy, loss to follow-up, or the end of the study, whichever occurs first.  
PET-CT may be used in lieu of a CT with contrast only if the CT of the PET-CT has been performed with diagnostic quality and contrast is administered.  
When both PET-CT and CT evaluations are available for the same tumor assessment visit, the results of PET-CT shall prevail.  MRI and a non-contrast chest 
CT scan may be used instead of contrast CT for patients with serious contrast allergy; whichever method is used should be used consistently.  Clinical 
suspicion of disease progression at any time will require radiologic confirmation to be performed promptly, rather than waiting for the next scheduled 
radiologic assessment. 
u Bone marrow biopsy and aspirate must be performed at screening for all patients to assess bone marrow involvement of lymphoma if not performed within 
60 days before the first dose as part of the standard care and there has been no intervening therapy from the time of the biopsy/aspirate until the start of study 
drug.  For patients with bone marrow involvement of lymphoma at baseline, repeated bone marrow biopsy and aspirate are required if CR is suspected. 
v Complete blood counts (CBC) with differential is required to be performed at screening (a repeated CBC test is required if not done within 7 days before the 
first dose of study drug), and at every visit during the treatment phase and the Safety Follow-up Visit.  CBC includes hemoglobin, hematocrit, platelet count, 
red blood cell count, white blood cell (WBC) count with differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
w Serum chemistry assessments include sodium, potassium, chloride, uric acid, bicarbonate/total carbon dioxide, glucose, urea or blood urea nitrogen, 
creatinine, calcium, phosphate/phosphorus, magnesium, total bilirubin, total protein, albumin, ALT, AST, LDH, and alkaline phosphatase.  Chemistry 
assessments are required at screening, every visit during the treatment phase, and the Safety Follow-up Visit. 
x Coagulation assessments (prothrombin time, INR, aPTT) are required at screening, Day 1 of subsequent cycles, and the Safety Follow-up Visit. 
y Hepatitis B serology includes HBsAg, HBcAb, and HBsAb.  Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative will undergo viral 
load measurement (HBV DNA by PCR) monthly (± 7 days) or at least every 90 days (± 7 days) for patients receiving prophylactic antiviral therapy.  Hepatitis 
C serology includes HCV antibody.  Patients who are HCV antibody positive, but negative for HCV RNA, will undergo viral load testing (HCV RNA by 
PCR) monthly (± 7 days).  Hepatitis B and hepatitis C testing may be performed by local laboratories if the laboratory is able to perform the tests to the 
required sensitivity (< 20 IU/mL and < 15 IU/mL for hepatitis B and C respectively); otherwise the results must be confirmed by the central laboratory. 
z Urinalysis (which includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose) will be performed at screening. 
aa A serum pregnancy test will be performed at screening and end of treatment for women of childbearing potential.  Patients must have a negative serum 
pregnancy test at screening.  Pregnancy tests must be performed at each visit during the treatment period and at the Safety Follow-up Visit.  Any patient who 
is pregnant will not be eligible for the study.  Subsequent tests in each visit may be urine tests, and 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 initiation of study treatment will be immediately withdrawn 
from participation in the study. 
bb Pharmacokinetic samples for zanubrutinib will be collected sparsely at predose and 2 hours (± 30 minutes) postdose on Day 1 of Cycle 1 and Cycle 2.  
Procedures for collection of samples are described in the Laboratory Manual.  Additional pharmacokinetic samples may be taken if needed.  The investigator 
will record the actual time of blood collection on eCRF.  Patients will also be instructed to record the dosing time of the evening dose at home (and be 
recorded on the eCRF) prior to coming in for the predose sample on Day 1 of Cycle 2. 
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PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment).  Measured 
dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extra-nodal lesions selected to be clearly measurable in two diameters.  
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas.  Non-nodal 
lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), gastrointestinal involvement, cutaneous lesions, or those noted on palpation.  
Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured.  These 
sites include any nodes, nodal masses, and extra-nodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extra-nodal sites (eg, 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 
Splenomegaly defined as vertical spleen length > 13 cm for purposes of the CT reads. 
c 
PET 5-point scale (Deauville Criteria): 
• 
1: no uptake above background 
• 
2. uptake ≤ mediastinum 
• 
3. uptake > mediastinum but ≤ liver 
• 
4. uptake moderately > liver 
• 
5. uptake markedly higher than liver and/or new lesions 
• 
X. new areas of uptake unlikely to be related to lymphoma 
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APPENDIX 3. NEW YORK HEART ASSOCIATION CLASSIFICATION  
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, eg, 
no shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, eg, walking short distances (20-100 m).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound 
patients. 
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APPENDIX 4. CYP3A INHIBITORS AND INDUCERS  
Strong CYP3A Inhibitors 
Antibiotics:  clarithromycin, telithromycin, troleandomycin 
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals:  boceprevir, telaprevir 
Food products:  grapefruit juicea 
Other:  cobicistat, idelalisib, nefazodone 
Protease inhibitors:  nelfinavir, ritonavir or ritonavirb in combination with 
danoprevir/elvitegravir/indinavir/lopinavir/paitaprevir and (ombitasvir and/or 
dasabuvir)/saquinavir/tipranavir 
Moderate CYP3A Inhibitors 
Antibiotics:  ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Calcium channel blockers:  diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer):  imatinib, crizotinib 
Others:  conivaptan, aprepitant, cyclosporine, dronedarone, tofisopam 
Strong CYP3A Inducers 
Apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
Moderate CYP3A Inducers 
Bosentan, efavirenz, etravirine, phenobarbital, primidone 
Abbreviation: CYP3A, cytochrome P450, family 3, subfamily A; HCV, hepatitis C virus. 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers (03 December 2019) (FDA 2019). 
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. 
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 and clinical 
pharmacologist. 
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APPENDIX 5. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: As published by (Oken et al 1982).  Eastern Cooperative Oncology Group, Robert Comis MD, Group 
Chair. 
 
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