Clinical trial NCT04436107
Conditions: Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Sponsor: BeiGene
Start date: 2020-09-11; Completion date: 2024-03-28
Enrollment: 66 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to determine the maximum tolerated doses (MTD) and the recommended Phase 2 dose (RP2D), and safety, tolerability, and efficacy of zanubrutinib in combination with lenalidomide in participants with R/R DLBCL

Detailed description:

Arms: arm 1: Participants received zanubrutinib 160 mg orally twice a day (BID) and lenalidomide 15 mg orally once a day (QD) on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. arm 2: Participants received zanubrutinib 160 mg orally BID and lenalidomide 20 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. arm 3: Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. arm 4: Participants received zanubrutinib 160 mg orally BID and lenalidomide 25 mg orally QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity.
Interventions: intervention 1: Zanubrutinib intervention 2: Lenalidomide
Intervention descriptions: intervention 1: 160 mg administered orally twice daily (BID) intervention 2: Administered orally on Days 1-21 each cycle followed by a mandatory 7-day drug-free interval.

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
Protocol Title: 
A Phase 1, Open Label, Multiple Dose, Dose Escalation 
and Expansion Study of Bruton Tyrosine Kinase (BTK) 
Inhibitor, Zanubrutinib, in Combination With 
Lenalidomide, With or Without Rituximab in Patients With 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma 
Protocol Number: 
BGB-3111-110 
Phase: 
1 
Investigational Product(s): 
Zanubrutinib (BGB-3111) 
Proposed Indication(s): 
Diffuse large B-cell lymphoma 
Sponsor: 
BeiGene (Beijing) Co., Ltd. 
No. 30 Science Park Road 
Zhong-Guan-Cun Life Science Park 
Changping district 
Beijing, China 102206 
Sponsor Medical Monitor: 
 
 
 
Original Protocol Version 0.0: 
Amendment 1.0 
Amendment 2.0: 
20 May 2019 
20 July 2020 
01 December 2020 
Confidentiality Statement 
This Document is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene (Beijing) 
Co., Ltd. and its subsidiaries. This document is for use by individuals and their designated representatives 
for their review, consideration, and/or participation in investigational study(ies). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene (Beijing) Co., Ltd. or one of its subsidiaries. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without prior written 
authorization from BeiGene (Beijing) Co., Ltd. or one of its subsidiaries. 
NCT Number:
NCT04436107


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FINAL PROTOCOL APPROVAL SHEET 
A Phase 1, Open Label, Multiple Dose, Dose Escalation and Expansion Study of Bruton 
Tyrosine Kinase (BTK) Inhibitor, Zanubrutinib, in Combination With Lenalidomide, With or 
Without Rituximab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma 
BeiGene (Beijing) Co., Ltd. Approval:  
 
 
_______ 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
A Phase 1, Open Label, Multiple Dose, Dose Escalation and Expansion 
Study of Bruton Tyrosine Kinase (BTK) Inhibitor, Zanubrutinib, in 
Combination With Lenalidomide With or Without Rituximab in Patients 
With Relapsed/Refractory Diffuse Large B-Cell Lymphoma 
 
Protocol Identifier: 
BGB-3111-110 
 
This protocol is a confidential communication of BeiGene (Beijing) Co., Ltd., and its 
subsidiaries. I confirm that I have read this protocol, I understand it, and I will work according to 
this protocol and the terms of the clinical study agreement governing the study. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from BeiGene 
(Beijing) Co., Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name 
and address of the center in which the study will be conducted.  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________


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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
SYNOPSIS ....................................................................................................................................10 
LIST OF ABBREVIATIONS AND TERMS ................................................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Diffuse Large B-Cell Lymphoma ...............................................................................21 
1.1.1. 
Subtype of DLBCL .....................................................................................................22 
1.2. 
Standard Treatment of DLBCL ..................................................................................22 
1.3. 
Bruton Tyrosine Kinase and B-cell Lymphoma .........................................................22 
1.4. 
Zanubrutinib ...............................................................................................................23 
1.4.1. 
Nonclinical Data for Zanubrutinib ..............................................................................23 
1.4.2. 
Clinical Pharmacology ................................................................................................24 
1.4.3. 
Summary of Relevant Clinical Experience with Zanubrutinib ...................................25 
1.5. 
Lenalidomide ..............................................................................................................26 
1.5.1. 
Venous and Arterial Thromboembolism ....................................................................27 
1.5.2. 
Second New Cancers ..................................................................................................27 
1.5.3. 
Serious Infection due to Neutropenia .........................................................................27 
1.5.4. 
Embryo-fetal Toxicity ................................................................................................27 
2. 
STUDY OBJECTIVES ..............................................................................................28 
2.1. 
Part 1 ...........................................................................................................................28 
2.1.1. 
Primary .......................................................................................................................28 
2.1.2. 
Secondary ...................................................................................................................28 
2.1.3. 
Exploratory .................................................................................................................28 
2.2. 
Part 2 ...........................................................................................................................28 
2.2.1. 
Primary .......................................................................................................................28 
2.2.2. 
Secondary ...................................................................................................................28 
2.2.3. 
Exploratory .................................................................................................................29 
3. 
STUDY DESIGN .......................................................................................................30 
3.1. 
Study Rationale ...........................................................................................................30 


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3.1.1. 
Rationale for Combination .........................................................................................30 
3.1.2. 
Rationale for Dose ......................................................................................................31 
3.2. 
Summary of Study Design ..........................................................................................31 
3.2.1. 
Part 1 ...........................................................................................................................31 
3.2.2. 
Part 2 ...........................................................................................................................33 
3.3. 
Study Assessments......................................................................................................34 
3.4. 
Blinding ......................................................................................................................34 
4. 
ELIGIBILITY CRITERIA .........................................................................................35 
4.1. 
Inclusion Criteria ........................................................................................................35 
4.2. 
Exclusion Criteria .......................................................................................................36 
5. 
ENROLLMENT AND STUDY PROCEDURES ......................................................39 
5.1. 
Informed Consent .......................................................................................................39 
5.2. 
Females of Childbearing Potential and Contraception ...............................................39 
5.3. 
Enrollment ..................................................................................................................40 
5.3.1. 
Patient Numbering ......................................................................................................40 
5.3.2. 
Medical and Cancer History .......................................................................................40 
5.3.3. 
Confirmation of Eligibility .........................................................................................41 
5.3.4. 
Enrollment ..................................................................................................................41 
5.4. 
Safety Assessments .....................................................................................................41 
5.4.1. 
Physical examination and Vital signs .........................................................................41 
5.4.2. 
ECOG performance status ..........................................................................................41 
5.4.3. 
Electrocardiogram .......................................................................................................41 
5.4.4. 
Echocardiogram ..........................................................................................................41 
5.4.5. 
Adverse Events Review ..............................................................................................41 
5.5. 
Efficacy Assessments .................................................................................................42 
5.5.1. 
Radiographic Imaging ................................................................................................42 
5.5.2. 
Positron Emission Tomography .................................................................................42 
5.5.3. 
Bone Marrow Aspiration/Biopsy ................................................................................43 
5.6. 
Pharmacokinetics ........................................................................................................43 
5.6.1. 
Part 1 ...........................................................................................................................43 
5.6.2. 
Part 2 ...........................................................................................................................43 
5.7. 
Laboratory Assessments .............................................................................................44 


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5.7.1. 
Urinalysis ....................................................................................................................44 
5.7.2. 
Hematology .................................................................................................................44 
5.7.3. 
Chemistry ....................................................................................................................44 
5.7.4. 
Coagulation Profile .....................................................................................................44 
5.7.5. 
Thyroid function .........................................................................................................45 
5.7.6. 
Serum immunoglobulins .............................................................................................45 
5.7.7. 
Hepatitis Serology ......................................................................................................45 
5.7.8. 
Pregnancy Test ............................................................................................................46 
5.8. 
Biomarker Assessments ..............................................................................................46 
5.9. 
Unscheduled Visits .....................................................................................................47 
5.10. 
End of Treatment Period .............................................................................................47 
5.11. 
Safety Follow-Up Visit ...............................................................................................47 
5.12. 
Follow-up Phase .........................................................................................................48 
5.12.1. 
Response Follow-up ...................................................................................................48 
5.12.2. 
Long-term Follow-up ..................................................................................................48 
5.13. 
End of Study ...............................................................................................................48 
5.14. 
Lost to Follow-up .......................................................................................................48 
6. 
STUDY TREATMENT ..............................................................................................50 
6.1. 
Zanubrutinib ...............................................................................................................50 
6.1.1. 
Packaging and Labeling ..............................................................................................50 
6.1.2. 
Handling and Storage .................................................................................................50 
6.1.3. 
Compliance and Accountability .................................................................................50 
6.1.4. 
Disposal and Destruction ............................................................................................51 
6.1.5. 
Dosage and Administration ........................................................................................51 
6.1.6. 
Precautions of Zanubrutinib .......................................................................................51 
6.1.7. 
Dose Interruption and Modification ...........................................................................52 
6.2. 
Lenalidomide ..............................................................................................................53 
6.2.1. 
Formulation, Packaging, and Storage of Lenalidomide .............................................53 
6.2.2. 
Dosage, Preparation and Administration of Lenalidomide ........................................53 
6.2.3. 
Dose Delay, Reduction or Discontinuation of Lenalidomide .....................................54 
6.2.4. 
Dose Modification of Lenalidomide during a Cycle (Applies to Days 1-21) ............54 
6.2.5. 
Overdose .....................................................................................................................56 


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7. 
PRIOR AND CONCOMITANT THERAPY .............................................................57 
7.1. 
Prior Therapy ..............................................................................................................57 
7.2. 
Concomitant Therapy .................................................................................................57 
7.2.1. 
Permitted Medications ................................................................................................57 
7.2.2. 
Prohibited Medications ...............................................................................................58 
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................58 
7.3.1. 
CYP-Inhibiting/Inducing Drugs .................................................................................58 
8. 
SAFETY MONITORING AND REPORTING .........................................................59 
8.1. 
Adverse Events ...........................................................................................................59 
8.1.1. 
Definitions ..................................................................................................................59 
8.1.2. 
Laboratory Test Abnormalities ...................................................................................61 
8.1.3. 
Lack of Efficacy .........................................................................................................62 
8.2. 
Serious Adverse Events ..............................................................................................62 
8.2.1. 
Definitions ..................................................................................................................62 
8.2.2. 
Suspected Unexpected Serious Adverse Reaction .....................................................63 
8.3. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................63 
8.3.1. 
Adverse Event Reporting Period ................................................................................63 
8.3.2. 
Eliciting Adverse Events ............................................................................................63 
8.3.3. 
Disease Progression ....................................................................................................63 
8.3.4. 
Death ...........................................................................................................................63 
8.4. 
Safety Monitoring Committee ....................................................................................64 
8.5. 
Prompt Reporting of Serious Adverse Events ............................................................64 
8.5.1. 
Time Frames for Submitting Serious Adverse Events ...............................................64 
8.5.2. 
Completion and Transmission of the Serious Adverse Event Report ........................65 
8.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................65 
8.6. 
Pregnancy Reporting ..................................................................................................65 
8.7. 
Recording Poststudy Adverse Events .........................................................................65 
8.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................66 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................67 
9.1. 
Study Endpoints ..........................................................................................................67 


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9.1.1. 
Part 1 ...........................................................................................................................67 
9.1.2. 
Part 2 ...........................................................................................................................68 
9.2. 
Statistical Analysis ......................................................................................................69 
9.2.1. 
Analysis Sets ...............................................................................................................69 
9.2.2. 
Patient Disposition ......................................................................................................69 
9.2.3. 
Demographics and Other Baseline Characteristics .....................................................69 
9.2.4. 
Prior and Concomitant Therapy ..................................................................................69 
9.3. 
Efficacy Analyses .......................................................................................................70 
9.3.1. 
Hypothesis Test ..........................................................................................................70 
9.3.2. 
Efficacy Analysis for Categorical Endpoints .............................................................70 
9.3.3. 
Efficacy Analysis for Time to Event Endpoints .........................................................70 
9.3.4. 
Biomarker Analyses ....................................................................................................71 
9.3.5. 
Subgroup Analyses .....................................................................................................72 
9.4. 
Safety Analyses ..........................................................................................................72 
9.4.1. 
Extent of Exposure .....................................................................................................72 
9.4.2. 
Adverse Events ...........................................................................................................72 
9.4.3. 
Laboratory Analyses ...................................................................................................73 
9.4.4. 
Vital Signs ..................................................................................................................73 
9.5. 
Pharmacokinetic Analyses ..........................................................................................74 
9.6. 
Sample Size Determination ........................................................................................74 
9.7. 
Interim Analysis ..........................................................................................................75 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................76 
10.1. 
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 ...........................................................................................................78 


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11.2.7. 
Data Management/Coding ..........................................................................................79 
11.2.8. 
Drug Accountability ...................................................................................................79 
11.2.9. 
Inspections ..................................................................................................................80 
11.2.10. 
Protocol Adherence ....................................................................................................80 
11.2.11. 
Financial Disclosure ...................................................................................................80 
11.2.12. 
Protocol Modifications ...............................................................................................80 
11.3. 
Study Report and Publications....................................................................................81 
11.4. 
Study and Study Center Closure .................................................................................81 
11.5. 
Records Retention and Study Files .............................................................................82 
11.6. 
Information Disclosure and Inventions ......................................................................83 
11.7. 
Joint Investigator/Sponsor Responsibilities ................................................................84 
11.7.1. 
Access to Information for Monitoring ........................................................................84 
11.7.2. 
Access to Information for Auditing or Inspections ....................................................84 
12. 
REFERENCES ...........................................................................................................85 
APPENDIX 1. THE LUGANO CLASSIFICATION FOR NON-HODGKIN 
LYMPHOMA .............................................................................................................88 
APPENDIX 2. NEW YORK HEART ASSOCIATION CLASSIFICATION ...........................92 
APPENDIX 3. DOSE MODIFICATION TABLE FOR ZANUBRUTINIB WHEN CO-
ADMINISTERED WITH STRONG/MODERATE CYP3A INHIBITORS 
OR INDUCERS ..........................................................................................................93 
APPENDIX 4. CYP3A INHIBITORS AND INDUCERS .........................................................94 
APPENDIX 5. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .....................................................................................................................95 
APPENDIX 6. SCHEDULE OF ASSESSMENTS ....................................................................96 
 
LIST OF TABLES 
Table 1: 
Part 1 Dosing Levels ...................................................................................................31 
Table 2: 
Pharmacokinetic Sampling in Part 1 ...........................................................................43 
Table 3: 
Zanubrutinib Dose Reduction Levels .........................................................................52 
Table 4: 
Dose Modification or Interruption for Lenalidomide Toxicity during a Cycle ..........55 
Table 5: 
Dose Reduction of Lenalidomide ...............................................................................56 
Table 6: 
Time Frame for Reporting SAEs to the Sponsor or Designee ....................................64 
 


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SYNOPSIS 
Name of 
Sponsor/Company:  
BeiGene (Beijing) Co., Ltd. 
Investigational Product(s): 
Zanubrutinib (BGB-3111) 
Title of Study: 
A Phase 1, Open Label, Multiple Dose, Dose Escalation and Expansion 
Study of Bruton Tyrosine Kinase (BTK) Inhibitor, Zanubrutinib, in 
Combination With Lenalidomide, With or Without Rituximab in 
Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma 
Protocol Identifier: 
BGB-3111-110 
Phase of Development: 
1 
Number of Patients: 
The number of dose levels examined and the emerging toxicities of the 
combination therapy will determine the sample size.  It is anticipated 
that approximately 27 patients in Part 1 and approximately 36 patients 
in Part 2 will be required. With an anticipated dropout rate of 10% for 
Part 2, approximately 67 patients will be enrolled. 
Study Objectives: 
Part 1 
Primary: 
• 
To determine the maximum tolerated doses (MTD) and the recommended Phase 2 dose 
(RP2D) of zanubrutinib in combination with lenalidomide, by dose escalation of lenalidomide 
in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). 
• 
To determine the safety and tolerability of zanubrutinib in combination with lenalidomide in 
patients with R/R DLBCL by dose escalating lenalidomide. 
Secondary: 
• 
To evaluate the efficacy of zanubrutinib in combination with lenalidomide in patients with R/R 
DLBCL as measured by overall response rate (ORR) assessed by investigator. 
• 
To characterize the pharmacokinetic (PK) profiles of zanubrutinib and lenalidomide after a 
single dose and at steady state when given in combination.  
• 
To evaluate the efficacy, as measured by ORR, based on the DLBCL subtypes. 
Exploratory: 
• 
To evaluate the efficacy of zanubrutinib in combination with lenalidomide as measured by 
complete response rate (CRR), time to response (TTR), duration of response (DOR), 
progression-free survival (PFS) and overall survival (OS), in patients with R/R DLBCL as well 
as in patients with different subtypes of R/R DLBCL. 
• 
To evaluate the correlation of clinical/genetic risk factors and clinical outcomes.  
• 
To explore mechanisms of disease resistance. 
Part 2 
Primary: 
• 
To evaluate the efficacy of zanubrutinib in combination with lenalidomide in patients with R/R 
DLBCL as measured by ORR. 


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Secondary: 
• 
To evaluate the efficacy of zanubrutinib in combination with lenalidomide, as measured by 
CRR, TTR, PFS and DOR. 
• 
To determine the safety and tolerability of zanubrutinib in combination with lenalidomide in 
patients with R/R DLBCL. 
• 
To further characterize the PK profiles of zanubrutinib and lenalidomide after single dose and 
at steady state when given in combination. 
• 
To evaluate the efficacy (ORR, CRR, TTR, PFS, and DOR) based on the DLBCL subtypes. 
Exploratory: 
• 
To further evaluate the efficacy as measured by OS.  
• 
To evaluate the correlation of clinical/genetic risk factors and clinical outcomes (eg, ORR, 
CRR, PFS, TTR and DOR).  
• 
To explore mechanisms of disease resistance.   
Study Design:   
This Phase 1 study is designed to assess the safety and efficacy of zanubrutinib in combination with 
lenalidomide in patients with R/R DLBCL.  
One cycle of treatment is 28 days in length. 
Part 1 
Part 1 will be the dose escalation portion, consisting of lenalidomide dose escalation with zanubrutinib 
fixed dose as the table below: 
Dose Level 
Zanubrutinib 
Lenalidomide 
Dose Level -1 
160 mg BID 
10 mg QD 
Dose Level 1  
(Starting dose) 
160 mg BID 
15 mg QD 
Dose Level 2 
160 mg BID 
20 mg QD 
Dose Level 3 
160 mg BID 
25 mg QD 
BID=twice daily; QD=once daily 
For dose escalation, 3+3 principles will be followed for MTD determination.  
The dose of zanubrutinib will remain fixed with up to 3 dose levels of lenalidomide to be explored 
according to the table above. Zanubrutinib will be administered orally at 160 mg twice daily. 
Lenalidomide will be administered orally once daily at the designated dose levels in the table above on 
Days 1-21 of each 28-day cycle. Both zanubrutinib and lenalidomide will continue until disease 
progression or unacceptable toxicity.  
PK blood sampling will be performed at predose (0 hr), 0.5, 1, 2, 3, 4, 8hr on Cycle 1 Day 1 and Cycle 
1 Day 21 for measurement of plasma zanubrutinib and lenalidomide concentrations. 
After the RP2D of lenalidomide is defined, further enrollment into Part 2 will commence. 
Part 2 
Part 2 will be conducted as an open label, single arm, multicenter, expansion study with Simon’s 
two-stage design.  Eligible R/R DLBCL patients will receive zanubrutinib combined with 
lenalidomide. The dose of lenalidomide will be the RP2D identified in Part 1. Both treatment 
medications will continue until disease progression or unacceptable toxicity.  


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PK blood sampling will be performed for 12 patients from the first stage enrollment at predose (0 hr), 
0.5, 1, 2, 3, 4, 8 hr on Cycle 1 Day 1 and Cycle 1 Day 21 for measurement of plasma zanubrutinib and 
lenalidomide concentrations. 
During Part 1 and 2, both immunohistochemistry (IHC) and gene expression profiling (GEP) will be 
used to assess enrolled patients’ status with respect to subtype of DLBCL. IHC allows a distinction 
between patients as either non-germinal-center B-cell like (GCB) or GCB phenotype.  With GEP, the 
patients can be further categorized into three subtypes: activated B-cell like (ABC), GCB and 
unclassified.  
Study Assessments: 
Response will be evaluated using the Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma (The Lugano Classification, 2014).  All patients 
should undergo positron emission tomography (PET) and contrast computed tomography (CT) at 
screening; PET and contrast CT should be repeated every 12 weeks for the first 48 weeks, every 16 
weeks for the next 48 weeks, and every 24 weeks thereafter until disease progression, use of alternative 
anti-cancer therapy, withdrawal of consent, death, lost to follow-up,  or end of study, whichever occurs 
first. Response will be assessed on the basis clinical and radiologic evaluations.  Bone marrow biopsy 
and aspiration will be required for confirmation of CT-based CR at first occurrence of radiologic and 
clinical evidence of CR in patients with bone marrow tumor involvement at baseline. 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. 
The sponsor, leading investigator, and possibly other investigators will establish a Safety Monitoring 
Committee (SMC) for ongoing safety assessment throughout the study. The SMC charter will define 
the organization members and procedures. The SMC will evaluate safety data from the dose escalation 
portion (Part 1) and decide the dose level for next group or enroll more eligible patients, based on the 
safety data from the previous dose level. The SMC will continue monitoring safety data during Part 2 
periodically as needed. 
Patients will be evaluated for adverse events (AEs) (all grades, according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version [v]5.0) and serious adverse 
events (SAEs). Patients who have an AE that leads to treatment discontinuation will be followed until 
the event resolves, the investigator assesses the event as stable, the patient is lost to follow-up, or the 
patient starts a different antitumor therapy. 
Key Eligibility Criteria: 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Histologically confirmed DLBCL, all patients must provide sufficient archival or fresh tumor 
tissue samples for evaluation by immunohistochemistry (IHC) and GEP.   
2. Relapsed or refractory disease, defined as either: 1) progression of disease after having 
achieved disease remission (complete response [CR] or partial response [PR]) at the latest 
treatment regimen or 2) stable disease (SD), or progressive disease (PD) at the completion of 
the latest treatment regimen preceding entry to the study. 
3. Patients who have not received high dose therapy/stem cell transplantation (HDT/SCT) must 
be ineligible for HDT/SCT. 
4. Men and women ≥18 years of age.  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  
6. Measurable disease as defined by at least 1 nodal lesion >1.5 cm in longest diameter, or at least 
1 extra-nodal lesion >1.0 cm in longest diameter, and measurable in 2 perpendicular 
dimensions. 


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7. Previously received at least 1 line of adequate systemic anti-DLBCL therapy, defined as an 
anti-CD20 antibody and an appropriate anthracycline-based combination therapy for at least 
2 cycles, unless the patient is intolerant or had disease progression before Cycle 2. 
8. Adequate hematologic function, defined as: 
a. Absolute neutrophil count (ANC) ≥1 x 109/L, independent of growth factor support for 
at least 7 days 
b. Platelet count ≥75 x 109/L, independent of growth factor support or transfusion for at 
least 7 days 
c. Hemoglobin >80 g/L, independent of transfusion for at least 7 days. 
9. Adequate hepatic function, defined as: 
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper 
limit of normal (ULN) 
b. Bilirubin ≤2 x ULN (unless documented Gilbert’s syndrome, then up to 5 x ULN 
allowed) 
10. Adequate renal function, defined as creatinine clearance of ≥60 mL/min (as estimated by the 
Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the modification 
of diet in renal disease [MDRD]). 
11. International normalized ratio (INR) ≤1.5 x ULN and activated partial thromboplastin time 
(aPTT) ≤1.5 x ULN. 
12. Patients who relapse at least 100 days after autologous stem cell transplant may be enrolled. 
13. Two negative pregnancy tests (at least one blood test) must be obtained for female patients of 
childbearing potential before initiating therapy. The first test must be performed within 
10-14 days before lenalidomide therapy and the second test within 24 hours before 
lenalidomide therapy. 
14. Female patients of childbearing potential must commit either to sexual abstinence or to use 
2 methods of reliable birth control simultaneously (Section 5.2) beginning 4 weeks before 
initiating treatment with lenalidomide, throughout the course of the study and at least up to 
90 days after last dose of zanubrutinib or lenalidomide, whichever is longer. Male patients will 
be eligible if abstinent, or must use a latex or synthetic condom (even if they have undergone a 
successful vasectomy) in combination with other highly effective contraception methods 
described in Section 5.2, and must not donate sperm, throughout the course of the study and at 
least up to 90 days after last dose of zanubrutinib or lenalidomide, whichever is longer.  
15. Patients must not donate blood during treatment with lenalidomide and for 4 weeks after 
discontinuation of the drug because the blood might be given to a pregnant female patient 
whose fetus must not be exposed to lenalidomide. 
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. Current or history of central nervous system (CNS) lymphoma. 
2. Histologically transformed lymphoma. 
3. History of allogeneic stem-cell transplantation. 
4. Prior exposure to a BTK inhibitor. 
5. Prior exposure to lenalidomide or thalidomide. 


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6. Receipt of the following treatment before first dose of study drug: 
a. Corticosteroids (at doses >20 mg/day prednisone equivalent) given with anti-neoplastic 
intent within 7 days. 
b. Chemotherapy or radiotherapy within 4 weeks. 
c. Monoclonal antibody within 4 weeks. 
d. Investigational therapy within 4 weeks. 
e. Chinese patent medicine with anti-neoplastic intent within 4 weeks. 
f. Chimeric antigen receptor T-cell (CAR-T) therapy. 
7. Major surgery within 4 weeks before the first dose of study drug. 
8. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, ANC, hemoglobin 
and platelets. For ANC, hemoglobin and platelets, please follow inclusion criterion #8. 
9. History of other active malignancies within 2 years before study entry, with exception of (1) 
adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell 
carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
10. 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 msecs 
e. History of second-degree atrioventricular (AV) block Type II or third-degree AV block 
f. New York Heart Association (NYHA) class III or IV congestive heart failure 
g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure 
measurements showing systolic blood pressure > 170 mm Hg and diastolic blood 
pressure > 105 mm Hg at Screening 
11. 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. 
12. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug. 
13. Unable to swallow capsules or having a disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
14. Uncontrolled systemic infection requiring parenteral intravenous anti-infective therapy. 
15. Known human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B 
or C infection as follows:  
a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb).  Patients with presence of HBcAb, but absence of HBsAg, are eligible if 
hepatitis B virus (HBV) DNA is undetectable (<20 IU/mL), and if they are willing to 
undergo monthly monitoring for HBV reactivation.  
b. Presence of hepatitis C virus (HCV) antibody.  Patients with presence of HCV 
antibody are eligible if HCV RNA is undetectable. 
16. Known hypersensitivity to lenalidomide, or compounds of similar chemical or biologic 
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17. Pregnant or lactating women. 
18. Any life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the patient’s safety, or put the study at risk. 
19. Requires ongoing treatment with strong and moderate CYP3A inhibitors or inducers. If 
patients have been on a strong or moderate CYP3A inhibitors or inducers in the past, they will 
not be eligible if the administration was within 7 days (or 5 half-lives of these drugs) before the 
first dose of study drug.  
20. History of deep-vein thrombosis (DVT) or pulmonary embolism (PE) within the past 12 
months. 
Test Product, Dose, and Mode of Administration:   
Zanubrutinib will be administered as two 80-mg capsules orally twice a day (160 mg twice daily) with 
or without food. Patients will take zanubrutinib with water at approximately the same time every day, 
with a minimum of 8 hours between consecutive doses.  
Lenalidomide will be administered orally daily with or without food on Day 1-21 of each 28-day cycle. 
Lenalidomide should be administered with water. 
Reference Therapy, Dose, and Mode of Administration: 
None. 


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Endpoints 
Part 1 
Primary Endpoints 
• 
The safety of zanubrutinib combined with lenalidomide will be assessed throughout the study 
by monitoring AEs and SAEs, per the NCI-CTCAE v5.0, physical examination and laboratory 
measurements. 
• 
The RP2D of lenalidomide will be determined based on safety data.  
Secondary Endpoints 
• 
ORR, defined as the proportion of patients whose BORs are either PR or CR based on the 
Lugano classification. 
• 
PK evaluations for zanubrutinib and lenalidomide, as appropriate and allowed by the data: 
− 
Single dose: including but not limited to area under the plasma concentration-time 
curve from time zero to the last measurable time (AUC(0-t)), maximum plasma 
concentration (Cmax), time to maximum plasma concentration (Tmax), and apparent 
clearance after oral administration (CL/F). 
− 
Steady state: including but not limited to AUC(0-t), maximum plasma concentration at 
steady state (Cmax,ss), Tmax, minimal drug concentration at steady state (Ctrough), CL/F, 
and accumulation ratio (Ro). 
• 
Clinical outcomes as measured by ORR based on the GCB and non-GCB identified by IHC 
and ABC and GCB subtype identified by GEP.  
Exploratory Endpoints 
• 
Efficacy endpoints of zanubrutinib combined with lenalidomide, including CRR, DOR, PFS, 
TTR and OS, in the efficacy analysis set as well as subgroups classified by IHC and by GEP. 
Exploratory efficacy endpoints as determined by investigator are as follows:  
− 
CRR, defined as the proportion of patients whose BORs are CR based on the Lugano 
classification in the efficacy analysis set of dose escalation. 
− 
DOR, defined as the time from the first response documentation to the date that 
progression is documented after treatment initiation or death, whichever occurs first. 
− 
PFS, defined as time from treatment initiation to documentation of progression or 
death due to any cause, whichever happens first 
− 
TTR, defined as the time from treatment initiation to the first documentation of 
response. 
− 
OS, defined as the time from treatment initiation until death. 
• 
Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR, OS) by clinical/genetic risk factors.  
• 
Potential resistance biomarkers and mechanisms of resistance.  
Part 2 
Primary Endpoint 
• 
The primary endpoint of Part 2 of is the ORR, defined as the proportion of patients whose 
BORs are either PR or CR based on the Lugano classification. 


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Secondary Endpoints 
• 
Clinical outcomes of zanubrutinib combined with lenalidomide, as determined by 
investigators, including CRR, DOR, PFS and TTR, in the efficacy analysis set. 
• 
The safety and tolerability of zanubrutinib combined with lenalidomide will be assessed 
throughout the study by monitoring AEs and SAEs, per the NCI-CTCAE v5.0, physical 
examination and laboratory measurements. 
• 
PK evaluations for zanubrutinib and lenalidomide. as appropriate and allowed by the data: 
− 
Single dose: including but not limited to AUC(0-t), Cmax, Tmax, CL/F. 
− 
Steady state: including but not limited to AUC(0-t), Cmax,ss, Tmax, Ctrough, CL/F, Ro. 
• 
Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR) based on the GCB and non-GCB 
identified by IHC and ABC and GCB subtype identified by GEP. 
Exploratory Endpoints 
• 
Overall survival (OS) 
• 
Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR, OS) by clinical/genetic risk factors.  
• 
Potential resistance biomarkers and mechanisms of resistance. 
Sample size determination: 
Sample size for Part 1 will depend on the number of dose levels examined and the emerging toxicities 
of the combination therapy. It is expected the number of patients in Part 1 will be approximately 
27 patients.  
For Part 2, Simon's two-stage design will be used. The null hypothesis that the true response rate is 
0.25 will be tested against a one-sided alternative. In the first stage, if there are 4 or fewer responses in 
these 18 patients, the study will be stopped. The null hypothesis will be rejected if 15 or more 
responses are observed in 36 patients. This design yields a type I error rate of 0.025 and power of 96% 
when the true response rate is 0.55. 
With an anticipated dropout rate of 10% for Part 2, approximately 67 patients will be enrolled. 
Statistical Methods: 
Efficacy data in Parts 1 and 2 will be summarized separately. 
Data will be listed and summarized according to the sponsor-agreed reporting standards, where 
applicable. 
Safety analysis set is defined as all patients who are exposed to at least one dose of any medication 
within the combination therapy. Efficacy analysis set is defined as all patients who are exposed to at 
least one dose of any medication with confirmed R/R DLBCL. Patients with no post-baseline response 
assessments will be treated as non-responders. It will be used as the primary analysis set for all the 
efficacy analyses. Efficacy evaluable analysis set is defined as all patients who are exposed to at least 
one dose of any medication with confirmed R/R DLBCL and have at least one post-baseline response 
assessment unless discontinued treatment due to clinical progression or death prior to response 
assessment in the efficacy analysis set. It will be used for sensitivity analyses. All patients who have at 
least one post dose plasma concentration and no major protocol deviation affecting PK would be 
included in the PK analysis set. 
ORR and CRR will be determined in the efficacy analysis set along with 95% confidence interval (CI) 
using Clopper-Pearson method. 


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Kaplan-Meier methodology will be used to estimate TTR, DOR, PFS and OS medians, and their 
95% CI will be constructed using Brookmeyer and Crowley method.  Kaplan-Meier curves will also be 
provided. 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ABC 
activated B-cell like 
AE 
adverse event 
ANC 
absolute neutrophil count 
AUC 
area under the curve 
BTK 
Bruton tyrosine kinase 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmax 
maximum plasma concentration 
CR 
complete response 
CRR 
complete response rate 
CT 
computed tomography 
Ctrough 
minimal drug concentration (trough) at steady state 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep vein thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCB 
germinal-center B-cell like 
GEP 
gene expression profiling 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDT 
high dose therapy 
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
MCL 
mantle cell lymphoma 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
MTD 
maximum tolerated dose  
NCI-CTCAE v5.0 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 5.0 
NHL 
non-Hodgkin lymphoma 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PE 
pulmonary embolism 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
R/R 
relapsed or refractory  
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCT 
stem cell transplant 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
TTR 
time to response 
ULN 
upper limit of normal 
 


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1. 
INTRODUCTION 
1.1. 
Diffuse Large B-Cell Lymphoma 
Diffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive non-Hodgkin 
lymphomas (NHL) in the United States, with an annual incidence that has been rising gradually 
since the 1990s (Fisher and Fisher 2004). It is estimated that 72,580 new NHL patients will be 
diagnosed in the US in 2016, with 20,150 dying from the disease (Siegel 2013). DLBCL 
accounts for approximately 32.5% of NHLs diagnosed annually (Al-Hamadani 2015). The 
estimated rate for DLBCL is approximately 4.68 cases per 100,000 person-years. Based on the 
study report of National Central Cancer Registry of China, an estimated 88,200 new lymphoma 
cases and 52,100 lymphoma deaths would occur in China in 2015, ranked in the 12th and 11th 
place among all cancer cases, respectively (Chen 2016); According to one retrospective analysis 
for lymphoma subtype distribution conducted by China Lymphoma Study Group, DLBCL makes 
up about 40.8% of NHL cases and 35.8% of all lymphoma cases (Li 2012). According to the 
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. 
The major clinical prognostic factors for NHL are well described and have been incorporated 
into the International Prognostic Index (IPI) scoring system. The specific factors are: age 
>60 years, stage III or IV disease, performance status ≥2, elevated lactate dehydrogenase (LDH) 
levels, and extranodal involvement >1 site. These factors are combined in the IPI into 
4 categories, with 5-year progression-ree survival (PFS) ranging from 40% to 70% and 5-year 
overall survival (OS) ranging from 26% to 73% among patients treated with cyclophosphamide, 
doxorubicin, vincristine and prednisone (CHOP) (Ziepert 2010).. 


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1.1.1. 
Subtype of DLBCL 
Diffuse large B-cell lymphoma is a heterogeneous disease not only clinically, but also 
morphologically and molecularly. Recent progress has been made in terms of understanding and 
categorizing the molecular heterogeneity of DLBCL. In a retrospective analysis of a large series 
of patients with DLBCL, the Leukemia and Lymphoma Molecular Profiling Project used 
deoxyribonucleic acid (DNA) microarray to identify distinct gene-expression profiles on the 
basis of hierarchical clustering (Rosenwald 2002). Two principal independent gene-expression 
subgroups were identified: germinal-center B-cell-like (GCB) and activated B-cell-like (ABC). 
After standard chemotherapy, the GCB and ABC subgroups were not only prognostically distinct 
in direct comparison (with superior outcome in the GCB subgroup), but this prognostic 
distinction was also independent of the IPI. Therefore, it has provided novel insights into the 
pathogenesis of the respective DLBCL, identified molecules which provided targets for novel 
“targeted therapies” drugs. Incorporating these new drugs into combination immuno-
chemotherapy might result in even higher cure rates of and/or less toxicity for patients with 
DLBCL. 
1.2. 
Standard Treatment of DLBCL 
The current standard regimen for DLBCL is R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine and prednisone), which achieves a cure in many patients. In clinical 
practice, the treatment decision is also determined based on various factors such as the stage, 
age, presence of bulky disease, and IPI. Despite recent progress in improving prognosis, 
30-40% patients develop relapsed/refractory disease and have poor outcomes. High dose therapy 
(HDT) and stem cell transplant (SCT) offer a second chance for a cure, however, for those 
patients not eligible for HDT/SCT, both the U.S. National Comprehensive Cancer Network 
(NCCN) (NCCN 2018) and the European Society for Medical Oncology (ESMO) recommend 
inclusion in a clinical study whenever possible (Tilly 2015). 
1.3. 
Bruton Tyrosine Kinase and B-cell Lymphoma 
B-cell receptor (BCR) signaling is essential for normal B-cell differentiation and function.  In 
addition, several lines of evidence suggest that signaling through the BCR is necessary to sustain 
the viability of B-cell malignancies.  First, expression of a functional BCR is maintained 
throughout lymphoma progression even as the non-expressed immunoglobulin heavy chain is 
involved in oncogenic translocations and despite prolonged treatment of tumor cells with anti-
idiotype therapies (Küppers 2005; Meeker 1985).  Also, selective knockdown of BCR 
components by ribonucleic acid (RNA) interference results in apoptosis in multiple B-cell 
lymphoma cell lines (Gururajan 2006). 
Recent studies indicate that chronic active BCR signaling is a pathogenic mechanism in ABC  
DLBCL and this chronic activation engages the classic nuclear factor kappa-light-chain-enhancer 
of activated B cells (NF-κB) pathway; in contrast GCB DLBCL pathogenesis is independent of 
this pathway (Lenz and Staudt 2010).  This difference in the molecular mechanism of 
pathogenesis (ie, constitutive activation of NF-κB in ABC DLBCL) may explain why the ABC 
subtype is less sensitive to chemotherapy and remains less curable than the GCB subtype.  


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Bruton tyrosine kinase (BTK) plays an essential role in the chronic active BCR signaling cascade 
in which engages NF-κB activation in wild-type Caspase Recruitment Domain Family Member 
11 (CARD11) ABC DLBCL.  In vitro data targeting this pathway in ABC DLBCL cells was 
recently reported by Davis and colleagues (Davis 2010).  Activated B-cell like DLBCL cell lines 
with constitutive BCR signaling undergo cell death when treated with ibrutinib, while these 
drugs had no effect on ABC and GCB DLBCL cell lines that did not rely on constitutive BCR 
signaling.  Clinical evidence that targeting the NF-κB pathway has a favorable response to 
outcome in ABC versus GCB subtypes was reported by Dunleavy and colleagues 
(Dunleavy 2009).  They showed in a Phase 2 study that bortezomib, which indirectly targets the 
NF-κB pathway by inhibiting proteasome degradation of BAY117085 for NF-κB pathway 
(IκBĮ), in combination with chemotherapy had a response rate of 85% in ABC subtype versus 
13% in GCB subtype (P=0.0004).  Thus, inhibition of the BCR-NF-κB pathway by blocking 
BTK activity may represent a novel therapeutic strategy in ABC DLBCL. 
1.4. 
Zanubrutinib 
Zanubrutinib (also known as BGB-3111) 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. 
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 Investigator’s Brochure). 
Zanubrutinib is a potent, specific and irreversible BTK kinase inhibitor with a 50% maximum 
inhibitory concentration (IC50) of 0.3 nM.  Cellular assays confirm that zanubrutinib inhibits 
BCR aggregation-triggered BTK autophosphorylation and blocks downstream phospholipase C 
gamma 2 signaling in mantle cell lymphoma (MCL) cell lines.  Zanubrutinib had an IC50 of 
1.8 nM in a homogeneous time-resolved fluorescence-based BTKpY223 assay.  It potently and 
selectively inhibited cellular growth of several MCL cell lines (REC-1, Mino and JeKo-1), and 
the activated B-cell type DLBCL cell line 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 is significantly more effective than ibrutinib 
when inducing dose-dependent antitumor effects against REC-1 MCL xenografts engrafted 
either subcutaneously or systemically in mice.  Zanubrutinib also demonstrated better antitumor 
activity than ibrutinib in TMD-8 DLBCL subcutaneous xenograft model.  In a 
PK/pharmacodynamics study, oral administration of zanubrutinib resulted in time-dependent 
occupancy of BTK in blood and in spleen in mice and was approximately 3-fold more potent 
than ibrutinib in mouse pharmacodynamic assays.  


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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 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).   
Cytochrome P450 (CYP) phenotyping in human liver microsomes suggests that CYP3A was the 
major CYP isoform responsible for zanubrutinib metabolism.  Zanubrutinib is a weak reversible 
inhibitor toward CYP2C8 and intestinal (not hepatic) CYP3A4, and does not display clinically 
relevant time-dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, or CYP3A.  Zanubrutinib is a weak inducer of CYP2B6 and CYP3A4, but does not 
induce CYP1A2.  Although zanubrutinib is a sensitive CYP3A4 substrate, it does not have a 
clinically relevant effect on its own exposure. Zanubrutinib may inhibit BCRP and P-gp transport 
at clinical doses. The coadministration of oral P-gp or BCRP substrates with a narrow 
therapeutic index (eg, digoxin, methotrexate) with zanubrutinib may increase their 
concentrations. Zanubrutinib does not inhibit the hepatic uptake transporters, OATP1B1 and 
OATP1B3, or the renal uptake transporters, 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 either rats or 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 was 
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 
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) indicated that co-
administration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg once daily 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 daily for 4 days) increased exposure of zanubrutinib 
by 3.8-fold for AUC0-∞, and 2.6-fold for Cmax.  These results are consistent with the role for 
CYP3A isoenzymes as the principal metabolic pathway for zanubrutinib. 


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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 study showed that zanubrutinib has no effect on CYP2C9 enzyme and BCRP activity. 
Zanubrutinib is shown to be a mild CYP3A4 and CYP2C19 inducer per FDA guidelines.  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 
Investigator’s Brochure (zanubrutinib Investigator’s Brochure). 
1.4.3. 
Summary of Relevant Clinical Experience with Zanubrutinib 
1.4.3.1. 
Dose Selection for Zanubrutinib 
A first-in-human study (BGB-3111-AU-003) that investigated the safety and PK of zanubrutinib 
in patients with hematologic malignancy. The preliminary data showed that the maximum 
observed concentration (Cmax) and area under the concentration curve (AUC) increased in a 
nearly dose-proportional manner from 40 mg to 320mg after singe-dose administration and at 
steady-state during repeat-dose administration (zanubrutinib Investigator’s Brochure).  The 
absorption of zanubrutinib is rapid, with a median time to maximum plasma concentration (Cmax) 
of 2 hours. The mean t1/2 was between 2 to 4 hours with minimal accumulation observed after 
repeated dosing.  Results from a food effect study showed that zanubrutinib exposure was not 
altered by a high-fat breakfast. Mean area under the curve (AUC) and Cmax were increased by 
12% and 51% by a low-fat breakfast, respectively. The 51% and 12% increases in the geometric 
means of Cmax and AUC0-inf observed when zanubrutinib was given with a low-fat meal as 
compared to the fasted state are not considered to be clinically relevant, as these increases fall 
within the range of exposures in which zanubrutinib is safe and well-tolerated, therefore, 
zanubrutinib can be administered with or without food. 
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 daily and 320 mg once daily (Tam 2015).  At the 160 mg twice daily 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 chronic lymphocytic leukemia, MCL, 
Waldenström macroglobulinemia and follicular lymphoma) at all tested dose levels; thus, a 
minimum effective dose cannot be established at this time.  Conversely, there is now extensive 
experience at the 160 mg twice daily and 320 mg once daily doses, 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 daily has been selected as the 
recommended Phase 2 dose based on sustained target occupancy, high rates of objective 
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1.4.3.2. 
Preliminary Efficacy and Safety Data for Zanubrutinib 
Please refer to the zanubrutinib Investigator’s Brochure (zanubrutinib Investigator’s Brochure) 
for preliminary efficacy and safety data. 
1.5. 
Lenalidomide 
Lenalidomide is currently approved in the United States for the treatment of relapsed or 
refractory MCL at a recommended starting dose of 25 mg orally once daily for 21 days every 
28 days.  
Lenalidomide is a more potent molecular analog of thalidomide, in vitro, lenalidomide has three 
main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulation. In 
vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone 
marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by 
immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited 
to treat many hematologic and solid cancers. 
Lenalidomide is rapidly absorbed after oral administration. After single and multiple doses of 
lenalidomide in patients with multiple myeloma (MM) or myelodysplastic syndrome (MDS), the 
maximum plasma concentrations occurred at 1 hour (approximately 0.5-6 hours) postdose. 
Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation. 
Administration of a single 25 mg dose of lenalidomide with a high-fat meal in healthy subjects 
reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease 
in Cmax. In the studies where the efficacy and safety were established for lenalidomide, the drug 
was administered without regard to food intake. The prescribing information of lenalidomide 
suggested lenalidomide can be administered with or without food.  The mean half-life of 
lenalidomide is 3 to 5 hours in patients with MM, MDS or MCL. Lenalidomide is not anticipated 
to be subjected to pharmacokinetic drug-drug interactions when co-administered with CYP 
inhibitors, inducers, or substrates. Despite being a weak substrate of P-gp in vitro, lenalidomide 
does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors 
in controlled studies. Renal function is the only important factor affecting lenalidomide plasma 
exposure, starting dose need to be adjusted based on the creatinine clearance value (<60 
mL/min). Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological 
malignancies (MM, MDS or MCL) did not have a clinically relevant effect on lenalidomide 
clearance in adult patients. 
The safety data for 134 patients receiving monotherapy for MCL has been evaluated.  The most 
common treatment-emergent adverse events (AEs) (>15%) were neutropenia (49%), 
thrombocytopenia (36%), fatigue (34%), diarrhea (31%), anemia (31%), nausea (30%), cough 
(28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritis (17%), constipation (16%), and 
peripheral edema (16%).  The most common Grade 3 or 4 adverse events were hematologic in 
nature: neutropenia (43%), thrombocytopenia (28%), and anemia (11%).  Pneumonia (9%) was 
the most frequent non-hematologic Grade 3 or 4 adverse event. 
The median duration of treatment in this patient population was 95 days (1-1002 days).  
Seventy-six patients (57%) required at least one dose interruption for an AE, while 51 patients 
(38%) had at least one dose reduction due to toxicity.  Twenty-six patients (19%) discontinued 
treatment due to AEs.  


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Lenalidomide has a black box warning for embryo-fetal toxicity, hematologic toxicity and 
venous and arterial thromboembolism.  
1.5.1. 
Venous and Arterial Thromboembolism  
Venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism 
(PE), has been reported in patients during treatment for NHL generally, occurring at incidences 
from approximately 7% up to 20% (Zhou 2010; Park 2012; Lyman 2013).  In lenalidomide 
clinical studies, DVT and PE were reported in 7 (2.6%) and 6 (2.2%) of 266 subjects with 
relapsed or refractory NHL receiving lenalidomide in clinical studies NHL-002 and NHL-003 
(Wiernik 2008; Witzig 2011). Anti-thrombotic prophylaxis was not suggested in NHL-002 but 
was required for subjects considered to be at high risk of developing DVT in NHL-003.  Patients 
with known risk factors, including prior thrombosis, may be at greater risk, and actions should be 
taken to try to minimize all modifiable factors (eg, hyperlipidemia, hypertension, smoking). 
1.5.2. 
Second New Cancers  
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer.  In clinical studies of newly diagnosed multiple 
myeloma, a higher number of second cancers were reported in patients treated with induction 
therapy (treatment as first step to reducing number of cancer cells) and/or bone marrow 
transplant then lenalidomide for a long period of time compared to patients treated with 
induction therapy and/or bone marrow transplant then placebo (a capsule containing no 
lenalidomide).  Patients should make their doctors aware of their medical history and any 
concerns they may have regarding their own increased risk of other cancers. 
1.5.3. 
Serious Infection due to Neutropenia  
In clinical trials, neutropenia has been reported as a consequence of lenalidomide treatment; 
≥ Grade 4 and ≥ Grade 3 infections have occurred in the context of neutropenia (any grade). 
Lenalidomide treatment in combination with dexamethasone in multiple myeloma patients with 
at least one prior therapy is associated with a higher incidence of Grade 4 neutropenia compared 
to placebo-dexamethasone treated patients. Patients should report signs and symptoms of 
infection promptly. 
1.5.4. 
Embryo-fetal Toxicity 
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey 
study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during 
pregnancy, it may cause birth defects or embryo-fetal death.  
In the current study, two negative pregnancy tests must be obtained prior to initiating therapy. 
Contraception must begin 4 weeks before initiating treatment with lenalidomide, throughout the 
course of the study and at least up to 90 days after last dose of lenalidomide. 
For more complete safety information, refer to the prescribing information (REVLIMID® 
Prescribing Information 2019). 


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2. 
STUDY OBJECTIVES  
2.1. 
Part 1 
2.1.1. 
Primary 
• To determine the maximum tolerated doses (MTD) and the recommended Phase 2 
dose (RP2D) of zanubrutinib in combination with lenalidomide by dose escalation of 
lenalidomide in patients with relapsed/refractory (R/R) DLBCL. 
• To determine the safety and tolerability of zanubrutinib in combination with 
lenalidomide in patients with R/R DLBCL by dose escalating lenalidomide. 
2.1.2. 
Secondary 
• To evaluate the efficacy of zanubrutinib in combination with lenalidomide, in patients 
with R/R DLBCL as measured by overall response rate (ORR) assessed by 
investigator. 
• To characterize the pharmacokinetic (PK) profiles of zanubrutinib and lenalidomide 
after single dose and at steady state when given in combination.  
• To evaluate the efficacy, as measured by ORR, based on the DLBCL subtypes. 
2.1.3. 
Exploratory 
• To evaluate the efficacy of zanubrutinib in combination with lenalidomide, as 
measured complete response rate (CRR), time to response (TTR), duration of 
response (DOR), PFS and OS, in patients with R/R DLBCL as well as in patients 
with different subtypes of R/R DLBCL. 
• To evaluate the correlation of clinical/genetic risk factors and clinical outcomes.  
• To explore mechanisms of disease resistance. 
2.2. 
Part 2 
2.2.1. 
Primary 
• To evaluate the efficacy of zanubrutinib in combination with lenalidomide in patients 
with R/R DLBCL as measured by ORR. 
2.2.2. 
Secondary 
• To evaluate the efficacy of zanubrutinib in combination with lenalidomide, as 
measured by CRR, TTR, DOR and PFS. 
• To determine the safety and tolerability of zanubrutinib in combination with 
lenalidomide in patients with R/R DLBCL. 


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• To further characterize the PK profiles of zanubrutinib and lenalidomide after single 
dose and at steady state when given in combination.  
• To evaluate the efficacy (ORR, CRR, TTR, PFS, and DOR) based on the DLBCL 
subtypes. 
2.2.3. 
Exploratory 
• To further evaluate the efficacy as measured by OS.  
• To evaluate the correlation of clinical/genetic risk factors and clinical outcomes (eg, 
ORR, CRR, PFS, TTR, DOR, and OS).  
• To explore mechanisms of disease resistance. 


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3. 
STUDY DESIGN 
3.1. 
Study Rationale 
3.1.1. 
Rationale for Combination 
Ibrutinib has demonstrated single agent activity in the treatment of R/R DLBCL. In a phase 1/2 
clinical study that involved 80 patients with R/R DLBCL, ibrutinib produced complete or partial 
responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of patients with 
GCB DLBCL (P = 0.0106) (Wilson 2015). A similar result is seen in an ongoing, single-arm, 
phase 2 study of zanubrutinib in patients with R/R non-GCB DLBCL. 
Lenalidomide is a second-generation immunomodulatory imide drug (IMiD) that is also 
interesting to consider with respect to targeting BCR signaling in DLBCL. A phase 2/3 
randomized study was conducted in patients with R/R DLBCL. Lenalidomide treated patients 
had an ORR of 27.5% versus 11.8% in investigator's choice (ORR were similar regardless of 
IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide 
(13.6 weeks) versus investigator's choice (7.9 weeks; P=0.041), with greater improvements in 
non-GCB patients (15.1 vs. 7.1 weeks, respectively; P=0.021) compared with GCB (10.1 vs. 
9.0 weeks, respectively; P=0.550). Exploratory analyses suggested that this preferential benefit 
was more pronounced in the GEP-defined ABC population (Czuczman 2017).  
Preclinical studies document the potential synergy of ibrutinib and lenalidomide in the treatment 
of ABC DLBCL based upon their mechanism of action and specificity for the genetic alterations 
seen in ABC DLBCL (Yang 2012).  ABC DLBCL tumors depend upon both the BCR and 
MYD88 signal pathways for survival.  Lenalidomide kills ABC DLBCL cells by augmenting 
interferon b (IFNb) production, owing to the oncogenic MYD88 mutations in these lymphomas. 
In a cereblon-dependent fashion, lenalidomide down regulates IRF4 and SPIB, transcription 
factors that together prevent IFNb production by repressing IRF7 and amplify prosurvival NF-kB 
signaling by transactivating CARD11. Blockade of B-cell receptor signaling using the BTK 
inhibitor ibrutinib also down regulates IRF4 and consequently synergizes with lenalidomide in 
killing ABC DLBCLs, suggesting attractive therapeutic strategies.  
Preclinical study also demonstrated that combining zanubrutinib and lenalidomide may lead to 
synergetic effect.  
In a phase 1 clinical study which involved 25 R/R B-NHL patients (9 DLBCL), combined 
therapy with ibrutinib and lenalidomide in B-NHL was well tolerated. Preliminary efficacy was 
observed in R/R DLBCL patients, ORR was 33%. (Christian 2015).  
Based upon the safety profile of zanubrutinib monotherapy and the lack of significant 
myelosuppression, the combination of lenalidomide and zanubrutinib may be well tolerated with 
the potential to exploit synergistic effects for improvement in outcomes in a frail population with 
minimal therapeutic options and poor prognosis. 


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3.1.2. 
Rationale for Dose 
The rationale for the current dose and schedule of each agent is based not only upon the 
approved dose for these treatments, but also based upon the safety data known regarding the use 
of these therapies for the treatment of NHL in the relapsed and refractory setting.  Besides, based 
on metabolic profiles of zanubrutinib and lenalidomide, these two drugs are not expected to have 
PK-related drug-drug interaction when co-administered.  
The established dose in monotherapy studies of lenalidomide is 25 mg administered orally once 
daily for 21 days of a 28-day cycle (Witzig 2011).   
The escalation cohort will begin lenalidomide at one dose level with a dose level-1 built in to 
allow for further evaluation of the 2-drug combination if a lower lenalidomide dose is needed.  
Since zanubrutinib has been studied at the 320 mg dose on a continuous daily dosing schedule 
and is well tolerated, it will be administered daily until disease progression or unacceptable 
toxicity. 
3.2. 
Summary of Study Design 
This Phase 1 study is designed to assess the safety and efficacy of zanubrutinib in combination 
with lenalidomide in patients with R/R DLBCL.  
One cycle of treatment is 28 days in length.  
3.2.1. 
Part 1 
Part 1 will be the dose escalation portion, consisting of lenalidomide dose escalation with 
zanubrutinib fixed dose as the table below: 
Table 1: 
Part 1 Dosing Levels 
Dose Level 
Zanubrutinib 
Lenalidomide 
Dose Level -1 
160 mg BID 
10 mg QD 
Dose Level 1  
(Starting dose) 
160 mg BID 
15 mg QD 
Dose Level 2 
160 mg BID 
20 mg QD 
Dose Level 3 
160 mg BID 
25 mg QD 
BID=twice daily; QD=once daily 
For dose escalation, 3+3 principles will be followed for MTD determination.  
The dose of zanubrutinib will remain fixed with up to 3 dose levels of lenalidomide to be 
explored according to Table 1. Zanubrutinib will be administered orally at 160 mg twice daily. 
Lenalidomide will be administered orally once daily at the dose designated by dose levels in 
Table 1 on Days 1-21 of each 28-day cycle. Both zanubrutinib and lenalidomide will continue 
until disease progression or unacceptable toxicity.  
The starting dose of lenalidomide will be 15 mg/day. The dose-limiting toxicity (DLT) 
observation period is 28 days (1 cycle) of therapy followed by evaluation for toxicity on Cycle 2 
Day 1.  


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Enrollment will proceed as follows: 
• If no DLT is observed during the DLT observation period in the initial 3 patients of a 
cohort (0/3), dose escalation to the next higher dose level cohort will occur. 
• If 1 DLT is observed, 3 additional patients will be enrolled at the same dose level for 
a total of at least 6 patients. If no further DLT(s) are observed (1/6), escalation to the 
next higher dose level cohort will occur. 
• If 2 or more DLTs (≥2/6) are observed in the 6 patients, the MTD is considered to 
have been exceeded and no further patients will be enrolled at that dose.  
• If there are 2 or more DLTs in Dose Level 1, Dose Level -1 will be enrolled.  
• The MTD is defined as the highest dose at which <33% of the patients enrolled at one 
dose level experience a DLT. If all evaluated dose levels demonstrate an observed 
incidence of DLT in <33% of patients, the MTD of lenalidomide in the combination 
has not been reached. At least 6 patients should be treated at the MTD or highest 
tested dose.  
• If a patient experiences a DLT during the DLT observation period, the patient will 
discontinue treatment.  
• The decision to proceed to the next dose level or an interim dose level will be made in 
a Dose Level Review Meeting by the sponsor in conjunction with the investigators 
after careful consideration of all available safety and laboratory information. Safety 
data from patients on preceding cohorts that remain on continuous dosing will also be 
considered. 
• According to study results and other relevant information, more additional patients, 
up to 12 patients, may be allowed to enroll to tested doses at or below MTD by SMC 
to collect more safety data.    
3.2.1.1. 
Dose-Limiting Toxicity 
A DLT is defined as events related to the study treatment as below: 
• Hematologic: 
− Grade 4 neutropenia lasting for > 7 days, despite growth factor support 
− ≥ Grade 3 neutropenia with a fever ≥ 38.3ºC 
− Grade 4 thrombocytopenia lasting for > 7 days, despite holding treatment 
− Grade 3 thrombocytopenia with ≥ Grade 2 bleeding or requiring RBC or platelet 
transfusions 


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• Non-Hematologic: 
− Any Grade 3 or higher non-hematologic adverse event (Note: excludes 
asymptomatic chemistry abnormalities that are not clinically significant and 
resolve to Grade 2 or better in < 7 days) 
− ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive care 
and persisting > 7 days 
− ≥ Grade 3 fatigue persisting for > 7 days 
− Treatment delay of any drug > 7 days for toxicity 
In the Dose Escalation Phase, if a patient is non-compliant with the prescribed therapy or ends 
treatment within the first cycle for reasons other than study drug(s) related toxicity, ie, withdraws 
consent, they will be replaced. Any patient that misses >4 doses of zanubrutinib or lenalidomide 
for reasons other than toxicity will be replaced. 
PK blood sampling will be performed at predose (0 hr), 0.5, 1, 2, 3, 4, 8hr on Cycle 1 Day 1 and 
Cycle 1 Day 21 for measurement of plasma zanubrutinib and lenalidomide concentration. 
After the RP2D of lenalidomide is defined, further enrollment into Part 2 will commence. 
3.2.2. 
Part 2 
Part 2 will be conducted as an open label, single arm, multicenter, expansion study with Simon’s 
two-stage design.  Eligible R/R DLBCL patients will receive zanubrutinib combined with 
lenalidomide. The dose of lenalidomide will be based upon the RP2D identified in Part 1. Both 
treatment medications will continue until disease progression or unacceptable toxicity.  
PK blood sampling will be performed for 12 patients from the first stage enrollment at predose 
(0 hr), 0.5, 1, 2, 3, 4, 8 hr on Cycle 1 Day 1 and Cycle 1 Day 21 for measurement of plasma 
zanubrutinib and lenalidomide concentration.  
During Part 1 and 2, both IHC and GEP will be used to assess enrolled patients’ status with 
respect to subtype of DLBCL. IHC allows a distinction between patients as either non-GCB or 
GCB phenotype.  With GEP, the patients can be further categorized into three subtypes: ABC, 
GCB and unclassified.  


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3.3. 
Study Assessments 
Response will be evaluated using the Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (The Lugano Classification) 
(Cheson 2014).  All patients should undergo positron emission tomography (PET) and contrast 
computed tomography (CT) at screening; PET and contrast CT should be repeated every 
12 weeks for the first 48 weeks, every 16 weeks for the next 48 weeks, and every 24 weeks 
thereafter until disease progression, use of alternative anti-cancer therapy, withdrawal of consent, 
death, lost to follow-up, or end of study, whichever occurs first. Response will be assessed on the 
basis clinical and radiologic evaluations.  Bone marrow biopsy and aspiration will be required 
for confirmation of CT-based CR at first occurrence of radiologic and clinical evidence of CR in 
patients with bone marrow tumor involvement before study drug. 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. 
The sponsor, leading investigator and possibly other investigators will establish a Safety 
Monitoring Committee (SMC) for ongoing safety assessment throughout the study. The SMC 
charter will define the organization members and procedures. The SMC will evaluate safety data 
from the dose escalation potion (Part 1) and decide the dose level for next group or enroll more 
eligible patients, based on the safety data from the former dose level. The SMC will continue 
monitoring safety data during Part 2 periodically as needed. In the case of major toxicity or 
efficacy concerns, the SMC can recommend modifying the study conduct. 
Patients will be evaluated for adverse events (AEs) (all grades, according to National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version [v]5.0) and 
serious adverse events (SAEs). Patients who have an AE that leads to treatment discontinuation 
will be followed until the event resolves, the investigator assesses the event as stable, the patient 
is lost to follow-up, or the patient starts a different antitumor therapy. 
3.4. 
Blinding 
Treatment with zanubrutinib, and lenalidomide is open-label.  


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4. 
ELIGIBILITY CRITERIA 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Histologically confirmed DLBCL, all patients must provide sufficient archival or fresh 
tumor tissue samples for evaluation by immunohistochemistry (IHC) and gene expression 
profiling (GEP).  
2. Relapsed or refractory disease, defined as either: 1) progression of disease after having 
achieved disease remission (complete response [CR] or partial response [PR]) at the latest 
treatment regimen or 2) stable disease (SD), or progressive disease (PD) at the 
completion of the latest treatment regimen preceding entry to the study. 
3. Patients who have not received HDT/SCT must be ineligible for HDT/SCT. 
4. Men and women ≥18 years of age.  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  
6. Measurable disease as defined by at least 1 nodal lesion >1.5 cm in longest diameter, or 
at least 1 extra-nodal lesion >1.0 cm in longest diameter, and measurable in 2 
perpendicular dimensions.  
7. Previously received at least 1 line of adequate systemic anti-DLBCL therapy, defined as 
an anti-CD20 antibody and an appropriate anthracycline-based combination therapy for at 
least 2 cycles, unless the patient is intolerant or had disease progression before Cycle 2. 
8. Adequate hematologic function, defined as: 
a. Absolute neutrophil count (ANC) ≥1 x 109/L, independent of growth factor support 
for at least 7 days. 
b. Platelet count ≥75 x 109/L, independent of growth factor support or transfusion for at 
least 7 days. 
c. Hemoglobin >80 g/L, independent of transfusion for at least 7 days. 
9. Adequate hepatic function, defined as: 
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper 
limit of normal (ULN). 
b. Bilirubin ≤2 x ULN (unless documented Gilbert’s syndrome, then up to 5 x ULN 
allowed). 
10. Adequate renal function, defined as creatinine clearance of ≥60 mL/min (as estimated by 
the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the 
modification of diet in renal disease [MDRD]). 
11. International normalized ratio (INR) ≤1.5 x ULN and activated partial thromboplastin 
time (aPTT) ≤1.5 x ULN. 
12. Patients who relapse at least 100 days after autologous stem cell transplant may be 
enrolled. 


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13. Two negative pregnancy tests (at least one blood test) must be obtained for female 
patients of childbearing potential before initiating therapy. The first test must be 
performed within 10-14 days before lenalidomide therapy and the second test within 
24 hours before lenalidomide therapy.  
14. Female patients of childbearing potential must commit either to sexual abstinence or to 
use 2 methods of reliable birth control simultaneously (Section 5.2) beginning 4 weeks 
before initiating treatment with lenalidomide, throughout the course of the study and at 
least up to 90 days after last dose of zanubrutinib or lenalidomide, whichever is longer. 
Male patients will be eligible if abstinent, or must use a latex or synthetic condom (even 
if they have undergone a successful vasectomy) in combination with other highly 
effective contraception methods described in Section 5.2, and must not donate sperm, 
throughout the course of the study and at least up to 90 days after last dose of 
zanubrutinib or lenalidomide, whichever is longer.  
15. Patients must not donate blood during treatment with lenalidomide and for 4 weeks after 
discontinuation of the drug because the blood might be given to a pregnant female patient 
whose fetus must not be exposed to lenalidomide. 
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. Current or history of central nervous system (CNS) lymphoma. 
2. Histologically transformed lymphoma. 
3. History of allogeneic stem-cell transplantation. 
4. Prior exposure to a BTK inhibitor. 
5. Prior exposure to lenalidomide or thalidomide. 
6. Receipt of the following treatment before first dose of study drug: 
a. Corticosteroids (at doses >20 mg/day prednisone equivalent) given with anti-
neoplastic intent within 7 days. 
b. Chemotherapy or radiotherapy within 4 weeks. 
c. Monoclonal antibody within 4 weeks. 
d. Investigational therapy within 4 weeks. 
e. Chinese patent medicine with anti-neoplastic intent within 4 weeks. 
f. Chimeric antigen receptor T-cell (CAR-T) therapy. 
7. Major surgery within 4 weeks before the first dose of study drug. 
8. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, ANC, 
hemoglobin and platelets. For ANC, hemoglobin and platelets, please follow inclusion 
criteria #8. 


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9. History of other active malignancies within 2 years before study entry, with exception of 
(1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous 
cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or 
other modality) with curative intent. 
10. 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 msecs 
e. History of second-degree atrioventricular (AV) block Type II or third-degree AV 
block 
f. New York Heart Association (NYHA) class III or IV congestive heart failure (see 
Appendix 2) 
g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic 
blood pressure > 105 mm Hg at Screening. 
11. 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. 
12. History of stroke or intracranial hemorrhage within 6 months before first dose of study 
drug. 
13. Unable to swallow capsules or having a disease significantly affecting gastrointestinal 
function such as malabsorption syndrome, resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
14. Uncontrolled systemic infection requiring parenteral intravenous anti-infective therapy. 
15. Known human immunodeficiency virus (HIV), or serologic status reflecting active 
hepatitis B or C infection as follows:  
a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if 
hepatitis B virus (HBV) DNA is undetectable (<20 IU/mL), and if they are willing to 
undergo monthly monitoring for HBV reactivation.  
b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV 
antibody are eligible if HCV RNA is undetectable. 
16. Known hypersensitivity to lenalidomide, or compounds of similar chemical or biologic 
composition to lenalidomide. 
17. Pregnant or lactating women. 
18. Any life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the patient’s safety, or put the study at risk. 


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19. Requires ongoing treatment with a strong and moderate CYP3A inhibitors or inducers 
(Appendix 4). If patients have been on a strong or moderate CYP3A inhibitors or 
inducers in the past, they will not be eligible if the administration was within 7 days (or 
5 half-lives of these drugs) before the first dose of study drug.  
20. History of deep-vein thrombosis (DVT) or pulmonary embolism (PE) within the past 
12 months. 


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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 6). 
5.1. 
Informed Consent 
At the 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 informed consent form 
will be given to the patient to read, and the patient must have adequate time to understand the 
content and ask questions. 
Study site personnel must obtain signed informed consent before any study-specific procedures 
are conducted, unless the procedures are part of routine standard of care, and must document the 
informed consent process in the patient’s clinical record.  Informed consent may be obtained 
before the 28-day screening period.  Consent must be obtained using the most current version of 
the form approved by the institutional review board (IRB) / independent ethics committee (IEC).  
Repeating screening procedures or tests is allowed if the patient did not previously meet the 
inclusion and exclusion criteria, or if needed to have a documented result within the protocol-
specified screening window.  
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.  
5.2. 
Females of Childbearing Potential and Contraception 
A female is considered of childbearing potential, ie, fertile, after menarche and until becoming 
postmenopausal unless permanently sterile.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 consecutive months without an alternative medical cause.  A high 
follicle-stimulating hormone level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy.  However, in the absence of 12 consecutive months of amenorrhea, a single follicle-
stimulating hormone measurement is insufficient.   
Female patients of childbearing potential must commit either to sexual abstinence or to use 
2 methods of reliable birth control simultaneously beginning 4 weeks before initiating treatment 
with lenalidomide, throughout the course of the study and at least up to 90 days after last dose of 
zanubrutinib or lenalidomide, whichever is longer. 
Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatment. 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 (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to investigational medicinal product, and withdrawal are 
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Two methods of reliable birth control consist of one highly effective form of contraception and 
one additional effective contraceptive method. 
Highly effective contraception methods include the following: 
• Tubal ligation 
• An intrauterine device  
• Hormonal (e.g., oral, injectable, intravaginal, or transdermal hormonal contraception) 
• Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success) 
Additional effective contraceptive methods include the following: 
• Male latex or synthetic condom 
• Diaphragm 
• Cervical cap 
Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must 
always use a latex or synthetic condom during any sexual contact with females of childbearing 
potential while taking lenalidomide and for up to 4 weeks after discontinuing lenalidomide, even 
if they have undergone a successful vasectomy.  
5.3. 
Enrollment 
All screening procedures must be performed within 28 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. 
5.3.1. 
Patient Numbering 
After obtaining informed consent, a unique patient number will be assigned to the potential study 
participant by sponsor medical monitor.  A patient number 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.  
5.3.2. 
Medical and Cancer History 
Background information to be collected includes history of disease (including the date of initial 
diagnosis and current disease status), staging, sites of disease, and presence or absence of 
disease-related constitutional symptoms.  Prior medications/significant non-drug therapies and 
demographic data (gender, year of birth [or age] and race/ethnicity) will also be collected. 


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5.3.3. 
Confirmation of Eligibility 
The investigator will assess and confirm the eligibility of each patient.  All screening procedure 
results and relevant medical history must be available before eligibility can be determined.  All 
inclusion criteria must be met and none of the exclusion criteria should be met.  No eligibility 
waiver will be granted.   
After a patient is screened and the investigator determines the patient is eligible for enrollment, 
study site personnel will complete an Eligibility Authorization Packet, and the medical monitor 
or designee provides final approval for enrollment in writing.  Study site personnel should ensure 
that a medical monitor–approved Eligibility Packet is in the patient’s file before proceeding with 
study procedures. 
5.3.4. 
Enrollment 
After a patient has been approved by the medical monitor or designee to enroll in the study, 
study treatment must commence within 5 days after enrollment. 
5.4. 
Safety Assessments 
5.4.1. 
Physical examination and Vital signs 
Physical examination, and weight will be performed at screening, Day 1 of each cycle and Safety 
follow-up visit. Height (cm) is determined at screening only. A complete physical examination 
includes an assessment of systems per standard of care at the study site and as clinically 
indicated by symptoms. Vital signs (sitting blood pressure, pulse, and body temperature) will be 
performed after the patient has rested in the sitting position for ≥3 minutes at screening visit, 
each visit during study treatment and Safety follow-up visit.  
5.4.2. 
ECOG performance status 
ECOG performance status will be assessed at screening visit, each visit during study treatment 
and Safety follow-up visit. 
5.4.3. 
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 obtaining the ECGs. 
5.4.4. 
Echocardiogram 
An echocardiogram is to be performed at screening unless one has been performed within 
30 days before the first dose of study drug. 
5.4.5. 
Adverse Events Review 
Record AEs that occurred during screening on the medical history case report form and in the 
patient’s source document. 


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Collect non-serious AE information from the time of first dose of study drug to 30 days after the 
last dose of zanubrutinib or lenalidomide, whichever occurs later.  Information on all SAEs 
(regardless of relatedness) will be collected from the time of signing of informed consent to 
screen failure or to 30 days after the last dose of zanubrutinib or lenalidomide, whichever occurs 
later. The AE reporting period is defined in Section 8.3.1. 
The accepted regulatory definition for an AE is provided in Section 8.1.1 and the definition of an 
SAE is provided in Section 8.2.1.  Important additional requirements for reporting SAEs are 
explained in Section 8.  
5.5. 
Efficacy Assessments 
Response will be assessed per the Lugano Classification. The secondary endpoint for Part 1 and 
the primary endpoint for Part 2 is ORR, defined as the achievement of either PR or CR according 
to the Lugano Classification (Cheson 2014) at any time on study drug. Response parameters will 
include assessment of lymphadenopathy, organomegaly, and bone marrow examination. In the 
event of a treatment delay, disease assessments are to continue per the Schedule of Assessments 
(Appendix 6). 
5.5.1. 
Radiographic Imaging 
CT with contrast unless contraindicated of neck, chest, abdomen, and pelvis will be performed at 
screening, every 12 weeks for the first 48 weeks, every 16 weeks for the next 48 weeks, and 
every 24 weeks thereafter until disease progression, use of alternative anti-cancer therapy until 
disease progression, withdrawal of consent, death, lost to follow-up, or end of study, whichever 
occurs first. 
A magnetic resonance image (MRI) may be used in place of CT only for patients who cannot 
undergo CT due to contrast allergy. 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. 
5.5.2. 
Positron Emission Tomography 
A PET/CT scan or PET scan will be performed at screening. For patients with PET-avid disease 
at screening, PET scans will also be performed at the same visits as CT scan. An assessment of 
CR must be confirmed by PET scan. 
NOTE: PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
parameters, and includes the use of intravenous (IV) contrast.  
If using a hybrid machine to acquire both PET and CT, the PET must be performed before the 
CT with IV contrast as to not compromise PET results. If independent CT and PET scanners are 
used, and the patient is receiving both scans on the same day, the PET must be performed before 
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5.5.3. 
Bone Marrow Aspiration/Biopsy 
A unilateral bone marrow aspiration and biopsy must be performed at screening if not performed 
within 60 days before the first dose for all patients, provided it is performed as part of their 
standard care and there has been no intervening therapy between the time of the biopsy and start 
of study drug. In those patients who had evidence of bone marrow disease at screening, upon 
achieving a possible CR (eg, physical examination or imagine indicating a possible CR), a bone 
marrow aspiration and biopsy should be obtained to confirm the CR. 
5.6. 
Pharmacokinetics 
5.6.1. 
Part 1 
Blood will be collected to characterize the PK profile of zanubrutinib and lenalidomide after 
single dose and at steady state. Blood samples (4 mL) will be collected into EDTA collection 
tubes from all patients of dose escalation after the morning dose at the timepoints shown in 
Table 2.  Details concerning handling of the PK plasma samples, including labeling and shipping 
instructions will be provided in the Lab Manual for this study.   
On Cycle 1 Day 1 and Cycle 1 Day 21, patients will receive oral dosing of zanubrutinib and 
lenalidomide at the clinic, and dosing time and PK collection time will be collected on electronic 
case report form (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 Cycle 1 Day 21. 
Table 2: 
Pharmacokinetic Sampling in Part 1 
Procedure 
Cycle 1 Day 1 
Hours  
Predose 
(-30 min) 
0.5 
(± 10 min) 
1 
(± 10 min) 
2 
(± 10 min) 
3 
(± 15 min) 
4 
(± 15 min) 
8 
(± 30 min) 
Pharmacokinetics 
blood sampling 
X 
X 
X 
X 
X 
X 
X 
Procedure 
Cycle 1 Day 21 
Hours  
Predose 
(-30 min) 
0.5 
(± 10 min) 
1 
(± 10 min) 
2 
(± 10 min) 
3 
(± 15 min) 
4 
(± 15 min) 
8 
(± 30 min) 
Pharmacokinetics 
blood sampling 
X 
X 
X 
X 
X 
X 
X 
Additional PK samples may be taken if needed, to further evaluate zanubrutinib and 
lenalidomide exposure. The investigator will record the time of blood collection and the time of 
administration in the eCRF. 
5.6.2. 
Part 2 
Blood will be collected to characterize the PK profile of zanubrutinib and lenalidomide after 
single dose and at steady state. Blood samples (4 mL) for PK analysis will be collected into 
EDTA collection tubes after the morning dose at the timepoints shown in Table 2 (same as 
Part 1).  


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On Cycle 1 Day 1 and Cycle 1 Day 21, patients will receive oral dosing of zanubrutinib and 
lenalidomide at the clinic and dosing time and PK collection time will be collected on 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 Cycle 1 Day 21. 
PK blood sampling for zanubrutinib and lenalidomide will be performed for twelve patients from 
the first stage enrollment. The PK sample size and sampling timepoints may be modified based 
on PK results of Part 1. Details concerning handling of the PK plasma samples, including 
labeling and shipping instructions, will be provided in the Laboratory Manual for this study. 
5.7. 
Laboratory Assessments 
Laboratory assessments should be performed at a local certified laboratory. 
Chemistry, complete blood count (CBC), coagulation, urinalysis, serum immunoglobins, 
hepatitis serologies, and thyroid function will be performed at the timepoints specified in the 
Schedule of Assessments (Appendix 6) and may also be performed as medically necessary.  In 
Cycle 1, laboratory assessments should be done before the first dose of study drug.   
Screening tests (including CBC, chemistry and coagulation) performed within 72 hours of the 
first study drug administration do not need to be repeated in Cycle 1. Screening hepatitis 
serologies performed within 4 weeks before the first study drug administration do not need to be 
repeated in Cycle 1. 
5.7.1. 
Urinalysis 
Urinalysis (which includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose) 
will be performed at screening. 
5.7.2. 
Hematology 
Hematology assessments (which include hemoglobin, hematocrit, platelets, red blood cells, white 
blood cells, neutrophils, lymphocytes, monocytes, eosinophils and basophils) are required to be 
performed at Screening, every visit during the treatment phase and Safety follow-up visit (if 
necessary, as defined in Section 5.11). 
5.7.3. 
Chemistry 
Chemistry assessments include sodium, potassium, chloride, urea or blood urea nitrogen (BUN), 
creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total 
bilirubin, LDH, phosphate or phosphorus, uric acid, magnesium and bicarbonate (or CO2 
combining performance, CO2CP). Chemistry assessments will be performed at screening, at 
Cycle 1, weekly on Day 1 of subsequent cycles and Safety follow-up visit (if necessary, as 
defined in Section 5.11). 
5.7.4. 
Coagulation Profile 
The coagulation profile includes prothrombin time (which will also be reported as international 
normalized ratio) and activated partial thromboplastin time.  The coagulation profile will be 
performed at screening, Day 1 of subsequent cycles and Safety follow-up visit. 


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5.7.5. 
Thyroid function 
Thyroid stimulating hormone (TSH) will be used to evaluate thyroid function. If abnormal, 
further testing should be performed as clinically appropriate. Testing will be performed at 
Screening and at the Safety follow-up visit. Testing at additional timepoints may be performed at 
the Investigator’s discretion. 
5.7.6. 
Serum immunoglobulins 
Quantitative serum immunoglobulins (IgG, IgM, IgA) will be measured at screening. 
5.7.7. 
Hepatitis Serology 
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 hepatitis B surface antibody (HBsAb) as well as HBV DNA by 
polymerase chain reaction (PCR) if the patient is negative for HBsAg, but 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.   
Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo at 
least monthly 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 antivirals, HBV DNA screening by PCR must be done at least 
every 90 days. 
If, during monthly monitoring of HBV DNA by PCR, the value is between 20 IU/mL and 
100 IU/mL, then the HBV DNA level should be rechecked within 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 positive for HCV antibody, but negative for HCV RNA, must undergo monthly HCV 
RNA screening.  Patients with HCV RNA of 15 IU/mL or greater should stop study drug and 
antiviral therapy should be initiated.  Resumption of 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. 
Section 4.2 describes how the results for HBV and HCV testing at Screening relate to study 
eligibility. 


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5.7.8. 
Pregnancy Test 
Two negative pregnancy tests must be obtained for all women of childbearing potential before 
initiating therapy. The first test must be performed within 10-14 days before lenalidomide 
therapy and the second test within 24 hours before lenalidomide therapy. At least one test should 
be a blood pregnancy test.  
Urine pregnancy tests will be performed weekly during the first 4 weeks of use, then pregnancy 
testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual 
cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy tests must be 
continued every 4 weeks (cycle) for at least 90 days after the last dose of zanubrutinib and 
lenalidomide, whichever comes last.  Pregnancy testing and counseling should be performed if a 
patient misses her period or if there is any abnormality in her menstrual bleeding. Lenalidomide 
treatment must be discontinued during this evaluation. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. A patient who has a positive pregnancy test result 
at any time after the study drug administration will be immediately withdrawn from participation 
in the study. 
5.8. 
 Biomarker Assessments  
Tissue and blood samples for biomarker assessment will be collected as stated in Appendix 6. 
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory.  Refer to the 
Laboratory Manual for details of sample handling. 
No less than 15 unstained slides must be sent to the central laboratory for biomarker analysis 
including assessments of DLBCL subtype by both IHC and GEP methods, EBV infection status, 
MYC/BCL2/BCL6 rearrangement or expression status, TCL1A expression status, Ki67 and 
other protein expression related to disease or treatment mechanism, presence of immune cells in 
tumor microenvironment assessment, genetic alterations, gene expression and proteomics, etc.  
The archival tumor tissues are mandatory for all patients who consent to participate in the study, 
although a fresh baseline tumor biopsy is strongly recommended.  If no archival samples are 
available, a fresh tumor biopsy collected at screening is required.   For these patients, an optional 
biopsy for biomarker analysis after approximately 3 cycles of treatment is strongly 
recommended.  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. Enrollment of 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.  
Optional biopsy will also be taken from the patients who have confirmed disease progression 
during the study at accessible tumor sites to explore resistance mechanism. Drug 
resistance -associated genetic alterations, gene expressions, and presence of immune cells in 
tumor microenvironment will be determined. If feasible, any follow-up biopsy should be ideally 
taken from the same tumor lesion as the baseline biopsy.  Written patient consent is required for 
fresh tumor biopsies.   


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Blood samples will be collected at screening, scheduled response assessment visits, and at 
unscheduled visits when disease progression is to be confirmed.  Blood-based biomarker analysis 
such as DNA/ctDNA sequencing, GEP, cfDNA assessment, immune cell and cytokine profiling, 
plasma protein, etc will be performed to explore their association with response, resistance and 
prognosis.  
5.9. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and 
may include vital signs/focused physical examination, ECOG performance status, AE review, 
concomitant medications and procedures review, radiographic assessments, physical 
examination, disease-related constitutional symptoms, and hematology and chemistry laboratory 
assessments.  The date and reason for the unscheduled visit must be recorded in the source 
documentation.   
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
5.10. 
End of Treatment Period 
The treatment period starts with the first day of assigned study treatment and ends 30 days after 
date of permanent study drug discontinuation (30 days after the final administered dose of 
zanubrutinib or lenalidomide, whichever is later).   
Patients will discontinue study drug for any one of the following reasons: 
• Pregnancy 
• Disease progression 
• AE(s) 
• Patient withdraw consent 
• Investigator decision 
• Other 
5.11. 
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 study drug (zanubrutinib or lenalidomide, 
whichever is later) or before the start of a new anticancer treatment, whichever occurs first, to 
collect AEs, including AEs that may have occurred or been ongoing after the patient 
discontinued study treatment.  The investigator or his/her designee will also continue to collect 
information on new anticancer therapy given after the last dose of study drug.  A laboratory 
assessment is only required if the patient had an ongoing laboratory abnormality at the previous 
visit that the investigator considered to be related to study drug.  If the patient is unable to return 
to the clinic and no laboratory assessment is necessary, the investigator or his/her designee will 
contact the patient or guardian to collect this information.  


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All adverse events, including SAEs, will be collected as described in Section 8. 
5.12. 
Follow-up Phase 
Once a patient has completed the Safety follow-up visit, he/she will enter the Follow-Up Phase.  
Patients who withdraw from treatment for reasons other than PD will participate in ongoing 
Response Follow-Up. 
5.12.1. 
Response Follow-up 
Patients who discontinue the study treatment for reasons other than PD continue to be followed 
for efficacy evaluations per protocol schedule until patient exhibits first progression, starts new 
anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or study termination from 
sponsor, whichever occurs first.  During this period, CT/MRI and PET scans will be done per 
Investigator discretion. 
5.12.2. 
Long-term Follow-up 
Once patients progress or start use of alternative anticancer therapy (for patients who have not 
withdrawn consent), they will be contacted approximately every 3 months (±14 days) by 
telephone to assess survival and the use of alternative anticancer therapy.  Patients will be 
contacted until death, patient withdrawal, lost to follow-up, or study termination by the Sponsor, 
whichever occurs first. 
If the patient refuses to do so, every effort should be made to contact him/her or the patient’s 
guardian by telephone to determine the patient’s disease status and survival.  
5.13. 
End of Study 
Reasons for complete withdrawal from the study (including treatment and all follow-up visits) 
will occur under the following circumstances: 
• Patient withdrew consent 
• Death  
• Study termination by sponsor 
• Other 
Patients may voluntarily withdraw consent from the study at any time.  
The end of the study is defined as the last visit (the safety follow-up contact) of the last patient 
undergoing study treatment on this protocol or the last patient undergoing study treatment has 
been transitioned onto an extension study. 
5.14. 
Lost 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.   


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After unsuccessful telephone contact, an effort to contact the patient by mail using a method that 
provides proof of receipt should be attempted.  Alternate contacts are permissible if the patient is 
not reachable (eg, primary care providers, referring physician, or relatives).  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, ensuring 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 bottles 
(used and unused) are to be provided at scheduled study visits. 
6.1.1. 
Packaging and Labeling  
The capsule supplied for zanubrutinib will be provided in a child-resistant, high-density, 
polyethylene bottle with induction seal and bottle label.  Labels will be prepared in accordance 
with Good Manufacturing Practices (GMP) and local regulatory guidelines of the participating 
country.  Label text will be translated into local language as required.  The contents of the label 
will be in accordance with all applicable local regulatory requirements. 
6.1.2. 
Handling and Storage 
The study drug 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.  The 
study drugs must be kept at the temperature condition as specified on the labels.  
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 
Compliance will be assessed by the investigator and/or study personnel at each patient visit, and 
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 
At appropriate times during the conduct of the study or at the end of the study following final 
drug inventory reconciliation by the monitor, the study site will 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 
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 on the appropriate eCRF. 
Zanubrutinib will be administered as two 80-mg capsules orally twice daily (160 mg twice daily) 
with or without food.  Patients will take zanubrutinib with water at approximately the same time 
every day, with a minimum of 8 hours between consecutive doses.  Zanubrutinib capsules should 
not be opened, broken, or chewed at any time. 
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. 
Zanubrutinib dosing is continuous (without interruption) throughout the treatment phase. If Day 
1 lenalidomide dosing is delayed for toxicity that does not require zanubrutinib to be held for 
toxicity, dosing of zanubrutinib should continue. 
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. AEs associated with an overdose of study drug will be recorded on the adverse event 
eCRF.  Any SAEs associated with an overdose are required to be reported within 24 hours of 
awareness via SAE reporting process as described in Section 8.5.1. There is no specific antidote 
for zanubrutinib overdose.  In an 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 upon the type of 
surgery and the risk of bleeding.   


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6.1.7. 
Dose Interruption and Modification 
The guidelines in Table 3 should be followed for dose interruption or modification of 
zanubrutinib for hematologic (Section 6.1.7.1) and non-hematologic toxicities (other than 
hypertension adequately controlled with oral medication or asymptomatic laboratory events; 
laboratory events indicating liver or renal dysfunction will not be considered asymptomatic 
laboratory events) (Section 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 
medical monitor. 
6.1.7.1. 
Dose Reduction for Hematologic Toxicity 
Dosing will be held for individual patients under any of the following conditions based on 
investigator assessment of zanubrutinib relatedness: 
• Grade 4 neutropenia (lasting > 10 days)  
• Grade 4 thrombocytopenia (lasting > 10 days) 
• ≥ Grade 3 thrombocytopenia associated with significant bleeding 
• ≥ Grade 3 febrile neutropenia 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery 
of the toxicity to ≤ Grade 1 or baseline.  If the same event recurs, patients will restart at 1 dose 
level lower (level -1) upon recovery of the toxicity to ≤ Grade 1 or baseline.  A maximum of 
2 dose reductions will be allowed.   
Patients with ≥ Grade 3 thrombocytopenia associated with significant bleed requiring medical 
intervention will be discontinued from study treatment. 
Asymptomatic treatment-related lymphocytosis should not be considered an AE.  Patients with 
asymptomatic treatment-related lymphocytosis should remain on study treatment and continue 
with all study-related procedures. 


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6.1.7.2. 
Dose Reduction for Non-Hematologic Toxicity 
For non-hematological toxicities ≥ Grade 3, other than hypertension adequately-controlled with 
oral medication or asymptomatic laboratory events (laboratory events indicating liver or renal 
dysfunction will not be considered asymptomatic laboratory events) suspected to be related to 
zanubrutinib treatment, zanubrutinib will be held until recovery to ≤ Grade 1 or baseline, then 
restart at original dose level.  
If the event recurs at ≥ Grade 3, study drug will be held until recovery to ≤ Grade 1 or baseline, 
then restart at 1 dose level lower (level -1).  If the event recurs at ≥ Grade 3 at level -1, drug will 
be held until recovery to ≤ Grade 1 or baseline, then restart at level -2.  If the event recurs at 
≥ Grade 3 at level -2, the patient will be discontinued from study treatment.  
For patients with symptomatic and/or incompletely controlled ≥ Grade 3 atrial fibrillation, study 
drug may be restarted at either the original dose or at dose level -1 atrial fibrillation is controlled 
at the discretion of the treating investigator.   
Zanubrutinib should be permanently discontinued for any intracranial hemorrhage. 
For information on study drug holds based on the results of hepatitis B or hepatitis C testing, see 
Section 5.7.7. 
6.2. 
Lenalidomide 
All patients of this study will receive lenalidomide and will follow guidelines for lenalidomide 
dosing and toxicity management.  
6.2.1. 
Formulation, Packaging, and Storage of Lenalidomide  
Lenalidomide (Revlimid®) will be supplied as capsules for oral administration by sponsor. 
Lenalidomide will be shipped to the pharmacy at the study site in individual blister packs. Blister 
packs will contain sufficient capsules to last for one cycle of dosing.  Lenalidomide must be 
dispensed in the original packaging with the label clearly visible.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
Lenalidomide should be stored at the temperature conditions as specified on the label. 
6.2.2. 
Dosage, Preparation and Administration of Lenalidomide  
The first dose of lenalidomide will be administered orally on Cycle 1 Day 1, of the Treatment 
Phase, after which lenalidomide will be self-administered daily by the patients on Days 1-21 of 
each cycle.  
Lenalidomide will be dosed at the same time as zanubrutinib. 
Lenalidomide should be administered with water.  The capsule should be swallowed intact and 
patients should not attempt to chew capsules, open capsules, or dissolve them in water.  Each 
dose of lenalidomide should be taken with or without food, at approximately the same time each 
day.    
Females of childbearing potential are suggested not to handle or administer lenalidomide unless 
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If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If a 
dose is missed for the entire day, it should not be made up.  
Lenalidomide dosing during the Treatment Phase occurs on Days 1-21 each cycle followed by a 
mandatory 7-day drug-free interval.  If a Day 1 (of any Cycle) is delayed due to scheduling, 
instruct the patient that lenalidomide dosing should not be initiated until Day 1 assessments can 
occur.  
Treatment will continue until disease progression or other reason for treatment discontinuation as 
outlined in Section 5.10 . 
Dose modifications for toxicity are outlined in Section 6.2.4, Table 4 and Table 5. For 
instructions regarding drug accountability and disposal/return of unused lenalidomide refer to the 
Pharmacy Manual. 
6.2.3. 
Dose Delay, Reduction or Discontinuation of Lenalidomide  
In order to initiate a new cycle of therapy with lenalidomide, the patient must have an ANC 
≥1,000/μL and a platelet count ≥50,000/μL and no lenalidomide-related ≥ Grade 3 toxicity on 
Day 1.  If these two criteria are not met, a repeat assessment is to be performed per the 
Investigator’s decision.   The initiation of lenalidomide should be delayed until the patient meets 
the above criteria at which time the patient will initiate drug without dose modification.  The 
initiation of lenalidomide may occur on any day of the cycle but missed doses must be omitted.  
Omitted doses should not be made up, and lenalidomide dosing must end no later than Day 21 of 
any given cycle.  Once a cycle has initiated, if lenalidomide must be held for toxicity during 
dosing, lenalidomide will not resume until Day 1 of the subsequent cycle, provided the patient 
meets the cycle initiation criteria above, with dose adjustments as per Table 4. 
Treatment with lenalidomide should be withheld for any unmanageable, potentially study drug-
related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity as described in Table 4.  In the event the patient is diagnosed with a thyroid condition or 
experiences a drop in creatinine clearance to ≤60 mL/min, refer to Table 4 for further 
instructions. 
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor.  
Lenalidomide may be withheld for a maximum of 28 consecutive days for toxicity.   
Lenalidomide treatment should be discontinued in the event of a lenalidomide related toxicity 
lasting more than 28 days, unless approved by the Medical Monitor.  
6.2.4. 
Dose Modification of Lenalidomide during a Cycle (Applies to Days 1-21) 
The dose of lenalidomide should be modified according to the dose modification guidelines in 
Table 4 based on investigator assessment of lenalidomide relatedness if any of the following 
toxicities occur: 


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Table 4: 
Dose Modification or Interruption for Lenalidomide Toxicity during a Cycle 
Toxicity 
Intervention 
Thrombocytopenia:  
• 
Grade 3 (decrease to 
<50,000/μL) associated with 
≥ Grade 2 bleeding,  
OR 
• 
Grade 4 (decrease to 
<25,000/μL) 
 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle   
• 
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria (see 
Section 6.2.3).  Do not dose below 5 mg daily. 
Neutropenia:  
• 
ANC <1,000/μL for > 7 days, 
OR  
• 
ANC <1,000/μL with an 
associated temperature 
≥38.5°C,  
OR  
ANC <500/μL 
 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle  
• 
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria (see 
Section 6.2.3).  Do not dose below 5 mg daily. 
Rash: 
• 
Any Grade desquamating 
(blistering)  
• 
Grade 4 non-blistering 
 
• 
Discontinue lenalidomide permanently 
Venous thromboembolism (VTE) 
≥ Grade 3 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle  
• 
Initiate VTE treatment  
• 
Resume lenalidomide without dose modification at the 
start of the next cycle if the benefit of therapy on this 
study outweighs the risk for bleeding. 
Hyperthyroidism or hypothyroidism 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle  
• 
Evaluate etiology and initiate appropriate therapy  
• 
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria (see 
Section 6.2.3).  Do not dose below 5 mg daily. 


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Toxicity 
Intervention 
Creatinine Clearance <60 mL/min 
(Cockcroft-Gault) 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle  
• 
Reduce the dose of lenalidomide according to the 
recommendations below based upon creatinine clearance 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria (see 
Section 6.2.3).  Do not dose below 5 mg daily. 
o Creatine clearance (CrCl) 30-60 mL/min: 10 mg 
every 24 hours 
o CrCl <30 mL/min (not requiring dialysis): 15 mg 
every 48 hours  
• 
If creatinine clearance becomes ≥60 mL/min for a 
minimum of 2 cycles then one may re-escalate to the dose 
before reduction for renal dysfunction at the discretion of 
the investigator. 
Any other Grade 3 or 4 non-
hematologic toxicities attributed to 
lenalidomide 
• 
Interrupt lenalidomide treatment for the remainder of the 
cycle. 
• 
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria (see 
Section 6.2.3).  Do not dose below 5 mg daily. 
Table 5: 
Dose Reduction of Lenalidomide 
Current Dose Level  
15 mg  
20 mg  
25 mg  
Dose Reduction 1  
10 mg  
15 mg  
20 mg  
Dose Reduction 2  
5 mg  
10 mg  
15 mg  
Dose Reduction 3  
Discontinue  
5 mg  
10 mg  
Dose Reduction 4  
NA  
Discontinue  
5 mg  
Dose Reduction 5  
NA  
NA  
Discontinue  
6.2.5. 
Overdose 
There is no specific experience in the management of lenalidomide overdose in patients; 
although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose 
studies, some patients were exposed to up to 400 mg. 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 


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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 on the eCRF and in the patient’s source documents. 
All prior therapies for DLBCL, including immunochemotherapy, chemotherapy, transplant, 
targeted therapy, radiation therapy, etc. will be recorded on the eCRF with the 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 or lenalidomide, whichever occurs later) 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 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 of corticosteroids (at doses ≤20 mg/day prednisone equivalent) 
given with antineoplastic intent is allowed within 7 days prior the first dose of 
study drug 
− Chronic systemic corticosteroid use is not permitted, except for adrenal 
replacement, and 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 those having received prior 
lymphodepleting chemotherapy or having prolonged corticosteroid exposure, are pre-disposed 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 anti-cancer therapy (eg, chemotherapy, biologics, or 
immunotherapy) while on treatment in this study. 
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications 
7.3.1. 
CYP-Inhibiting/Inducing Drugs 
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers 
(refer to Appendix 4 for a list of these medications) and grapefruit juice and Seville oranges 
should be done with caution, as they 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 table 
in Appendix 3. The medical monitor 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 study 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, as 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, a second barrier 
method of contraception (eg, condoms) is recommended to be used.  The coadministration of 
oral P-gp substrates with a narrow therapeutic index (eg, digoxin) should be used with caution as 
zanubrutinib may increase their concentrations. 
Lenalidomide has a low potential for pharmacokinetic drug interactions. But periodic monitoring 
of digoxin concentration is recommended in accordance with clinical judgement and based on 
standard clinical practice during therapy since the digoxin Cmax and AUCinf were increased by 
14% when digoxin was co-administered with lenalidomide. Erythropoietic agents, or other 
agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be 
used with caution after making a benefit-risk assessment in patients. For detail information of 
lenalidomide investigators could consult the relevant prescribing information and Summary of 
Product Characteristics. 


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8. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  
8.1. 
Adverse Events 
8.1.1. 
Definitions  
An AE is defined as any untoward medical occurrence in a patient temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product 
(zanubrutinib in combination with lenalidomide). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
drug. 
Examples of an AE include: 
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome  
• New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results and diagnostics reports) relative to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all patient identifiers will be blinded on the 
copies of the medical records before submission to the sponsor.  
8.1.1.1. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study.  When 
applicable, AEs and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or non-invasive 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 AE 
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions.  Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.2. 
8.1.1.2. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE.  The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the AE or SAE to the study drug will be considered 
and investigated.  The investigator will also consult the Investigator’s Brochure and/or 
Prescribing Information, for marketed products, in the determination of his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to the sponsor.  However, it is very important that the investigator 
always makes an assessment of causality for every SAE before transmission of the SAE report to 
the sponsor since the causality assessment is one of the criteria used when determining 
regulatory reporting requirements.  The investigator may change his/her opinion of causality 
considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.”  An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation).  A number of factors should be considered in making this assessment, 
including: 
• Temporal relationship of the AE to the administration of study treatment/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
• Biological plausibility 


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An AE 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. 
• There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
• There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug).  However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs). 
8.1.1.3. 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact are designated as ongoing and will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.5.1. 
8.1.2. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, CBC, or coagulation) or other abnormal 
assessments (eg, ECG, radiographical studies, or vital signs) that are judged by the investigator 
as clinically significant will be recorded as AEs or SAEs.  This includes clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline and 
significantly worsen during the study.  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 AEs or SAEs.  The definition of clinically significant is left to the 
judgment of the investigator; in general, these are events that result in clinical signs or 
symptoms, require active medical intervention, or lead to dose interruption or discontinuation, 
require close observation, more frequency follow-up assessments or further diagnostic 
investigation. 


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Asymptomatic treatment-related lymphocytosis should not be considered an AE. 
For information on procedures for the monitoring and prevention of hepatitis B and hepatitis C, 
see Section 5.7.7. 
8.1.3. 
Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE. The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the AE or SAE definition (including 
clarifications). 
8.2. 
Serious Adverse Events 
8.2.1. 
Definitions 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death. 
• Is life threatening. 
NOTE: The term “life threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event. It does not refer to an 
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 has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-
patient 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 or prevent 
everyday life functions, but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect. 
• Is considered a significant medical AE by the investigator based on medical judgement 
(eg, may jeopardize the patient or may require medical/surgical intervention to prevent 
one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 


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8.2.2. 
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 current protocol and/or Investigator’s Brochure. 
8.3. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.3.1. 
Adverse Event Reporting Period 
After informed consent has been signed but before the administration of the study drug, only 
SAEs should be reported to the sponsor.  Any arising or worsening condition experienced by the 
patient after signing the informed consent but before first dose of study drug that does not meet 
the definition of serious should be reported only as medical history.   
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of zanubrutinib, or lenalidomide, whichever occurs 
later. 
After this period, the investigator should report any SAEs that are believed to be related to prior 
study drug treatment. 
8.3.2. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.3.3. 
Disease Progression 
Disease progression which is expected in this study population and measured as an efficacy 
endpoint, should not be reported as an AE term.  Instead, the symptoms, signs or clinical 
sequelae that result from disease progression should be reported as the AE term(s).   
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of disease 
progression. If a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression”.  
8.3.4. 
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 unknow cause”, or “death unexplained”. 


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8.4. 
Safety Monitoring Committee 
All enrolled patients will be evaluated clinically and with standard laboratory tests during their 
participation in this study.  Safety evaluations will consist of medical interviews, recording of 
adverse events (AEs), physical examinations, and laboratory measurements (hematology, 
chemistry, and urinalysis).  
Patients will be evaluated for AEs (all grades, according to NCI-CTCAE v5.0) and serious 
adverse events (SAEs). Patients who have an AE that leads to treatment discontinuation will be 
followed until the event resolves, the investigator assesses the event as stable, the patient is lost 
to follow-up, or the patient starts a different antitumor therapy. 
A SMC will monitor safety data periodically throughout the study.  As the efficacy endpoints 
require longer length of follow-up to be adequately evaluated, a formal interim review of data 
collected during the study by the SMC will focus on the safety aspects of the study. The SMC 
will evaluate safety data from the dose escalation potion (Part 1) and decide the dose level for 
next group or if enroll more eligible patients, based on the safety data from the former dose level. 
The SMC will continue monitoring safety data during Part 2 periodically as needed.  No 
recruitment stop is planned for this interim safety review for Part 2.  At the safety review, special 
attention will be paid to significant safety events (SSE).  Subsequent safety data review is 
outlined in SMC charter.  
An SSE is defined as any of the following: 
• General toxicity (NCI-CTCAE v5.0): Grade 3 and Grade 4 AEs and SAEs 
• Any adverse event that requires dose interruption, reduction or discontinuation of the 
study drug. 
• A patient’s death 
In the case of major toxicity concerns, the SMC can recommend modifying the study conduct. 
8.5. 
Prompt Reporting of Serious Adverse Events 
8.5.1. 
Time Frames for Submitting Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 6. 
Table 6: 
Time Frame for Reporting SAEs to the Sponsor or Designee  
Type 
Initial Report 
Document 
Follow-up SAE 
Report 
Document 
Reporting 
Method 
All SAEs 
Within 24 hours 
of first 
knowledge of 
the AE 
SAE form 
As 
expeditiously as 
possible 
Updated SAE 
form 
Email or fax 
SAE form  
Abbreviations: AE, adverse event; SAE, serious adverse event. 


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8.5.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the sponsor within 24 hours as outlined in Section 8.5.1. The SAE report will 
always be completed as thoroughly as possible with all available details of the SAE and 
forwarded to the sponsor or designee within the designated time frames.   
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form.  The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.1.1.2. 
The sponsor will provide contact information for SAE receipt. 
8.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.5.2.  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. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the responsible person according to local 
requirements is required to promptly notify his/her IRB or IEC. 
8.6. 
Pregnancy Reporting 
If a female patient or the partner of a male patient becomes pregnant while receiving study 
treatment or within 90 days of the last dose of zanubrutinib or lenalidomide, whichever comes 
last, a pregnancy report form should be completed and expeditiously submitted to the sponsor to 
facilitate outcome follow-up.  Information on the status of the mother and child will be 
forwarded to the sponsor.  Generally, follow-up will be no longer than 6 to 8 weeks after the 
estimated delivery date.  Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as a SAE. 
8.7. 
Recording Poststudy Adverse Events 
A poststudy AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period 
that is defined in Section 8.3.1. 


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Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will 
notify the sponsor. 
8.8. 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following RSI documents:  
• Zanubrutinib Investigator’s Brochure 
• Prescribing information for lenalidomide 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released.   
Details of the statistical analyses will be included in a separate Statistical Analysis Plan. 
9.1. 
Study Endpoints 
9.1.1. 
Part 1 
9.1.1.1. 
Primary Endpoint 
The primary endpoint is the safety of zanubrutinib combined with lenalidomide. It will be 
assessed throughout the study by monitoring AEs and SAEs, per the NCI-CTCAE v5.0, physical 
examination and laboratory measurements. 
The RP2D of lenalidomide will be determined based on safety data.  
9.1.1.2. 
Secondary Endpoints 
Define the best overall response (BOR) as the best response recorded from the start of the 
combination therapy until data cut or start of new anti-neoplastic treatment. 
The secondary endpoints are: 
• ORR, defined as the proportion of patients whose BORs are either PR or CR based on 
the Lugano classification (Cheson 2014). 
• PK evaluations for zanubrutinib and lenalidomide, as appropriate and allowed by the 
data: 
− Single dose: including but not limited to AUC(0-t), Cmax, Tmax, CL/F. 
− Steady state: including but not limited to AUC(0-t), Cmax,ss, Tmax, Ctrough, CL/F, Ro. 
• Clinical outcomes, as measured by ORR, based on the GCB and non-GCB identified 
by IHC and ABC and GCB subtype identified by GEP. 
9.1.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Efficacy endpoints of zanubrutinib combined with lenalidomide, including CRR, 
DOR, PFS, TTR and OS, in the efficacy analysis set as well as the subgroups 
classified by IHC and by GEP. Exploratory efficacy endpoints as determined by 
investigator are as follows:  
− CRR, defined as the proportion of patients whose BORs are CR based on the 
Lugano classification (Cheson 2014). 


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− DOR, defined as the time from the first response documentation to the date that 
progression is documented after treatment initiation or death, whichever occurs 
first. 
− PFS, defined as time from treatment initiation to documentation of progression or 
death due to any cause, whichever happens first 
− TTR, defined as the time from treatment initiation to the first documentation of 
response. 
− OS, defined as the time from treatment initiation until death. 
• Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR, OS) by clinical/genetic risk 
factors. 
• Potential resistance biomarkers and mechanisms of resistance. 
9.1.2. 
Part 2 
9.1.2.1. 
Primary Endpoint 
The primary endpoint of Part 2 of this study is the ORR, defined as the proportion of patients 
whose BORs are either PR or CR based on the Lugano classification (Cheson 2014). 
9.1.2.2. 
Secondary Endpoint 
• Clinical outcomes of zanubrutinib combined with lenalidomide, as determined by 
investigators, including CRR, DOR, PFS and TTR, in the efficacy analysis set as well 
as the subgroups classified by IHC and by GEP. 
• The safety and tolerability of zanubrutinib combined with lenalidomide will be 
assessed throughout the study by monitoring AEs and SAEs, per the NCI-CTCAE 
v5.0, physical examination and laboratory measurements. 
• PK evaluations for zanubrutinib and lenalidomide, as appropriate and allowed by the 
data: 
− Single dose: including but not limited to AUC(0-t), Cmax, Tmax, CL/F. 
− Steady state: including but not limited to AUC(0-t), Cmax,ss, Tmax, Ctrough, CL/F, Ro. 
• Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR) based on the GCB and non-
GCB identified by IHC and ABC and GCB subtype identified by GEP. 
9.1.2.3. 
Exploratory Endpoints 
• OS 
• Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR and OS) by clinical/genetic risk 
factors. 
• Potential resistance biomarkers and mechanisms of resistance. 


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9.2. 
Statistical Analysis 
Data will be listed and summarized according to the sponsor-agreed reporting standards, where 
applicable.  
9.2.1. 
Analysis Sets   
Safety analysis set is defined as all patients who are exposed to at least one dose of any 
medication within the combination therapy.  
Efficacy analysis set is defined as all patients who are exposed to at least one dose of any 
medication with confirmed R/R DLBCL. Patients with no post-baseline response assessments 
will be treated as non-responders. It will be used as the primary analysis set for all the efficacy 
analyses. 
Efficacy evaluable analysis set is defined as all patients who are exposed to at least one dose of 
any medication with confirmed R/R DLBCL and have at least one post-baseline response 
assessment unless discontinued treatment due to clinical progression or death prior to response 
assessment in the efficacy analysis set. It will be used for sensitivity analyses.  
All patients who have at least one postdose plasma concentration and no major protocol 
deviation affecting PK would be included in the PK analysis set. 
Major protocol deviations will be summarized and listed by each category. 
9.2.2. 
Patient Disposition 
The number of patients enrolled, treated, and discontinued from study drug or study will be 
summarized.  The primary reason for study drug discontinuation will be summarized according 
to the categories recorded in the eCRF.  The end of study status (alive, death, withdrew consent, 
or lost to follow-up) at the data cut-off date will be summarized using the data from the eCRF. 
9.2.3. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized. Continuous variables 
include age, weight, vital signs, time since initial DLBCL diagnosis; categorical variables 
include sex, age group, disease stage, ECOG-PS, prior line of therapy for DLBCL, IPI, EBV and 
Ki67, subtype of GCB, non-GCB and ABC. 
9.2.4. 
Prior and Concomitant Therapy 
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.  Prior medications will be defined as medications that started 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, or lenalidomide, whichever occurs later.  


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9.3. 
Efficacy Analyses 
9.3.1. 
Hypothesis Test 
No hypothesis testing will be done for Part 1. 
 In Part 2, the ORR with the combination therapy is estimated as 55% in the overall R/R DLBCL 
patient population, which is deemed a clinical meaningful improvement. Hence, the null and 
alternative hypotheses are set as follows:  
H0: ORR=25%  
Ha: ORR > 25%  
A binomial exact test will be performed for hypothesis testing H0: ORR=25% vs. Ha: ORR > 
25% in the efficacy analysis set. If 15 or more responses are observed in 36 patients, then the 
historical control rate of 25% can be ruled out at one-sided alpha of 0.025. Therefore, the 
superiority of the combination therapy will be demonstrated.  
As stated in the study design, for Part 2, Simon's two-stage design will be used. If within the first 
18 patients in Part 2, 4 or fewer responses are observed, the study will be stopped.  
9.3.2. 
Efficacy Analysis for Categorical Endpoints 
ORR, defined as the achievement of either a PR or CR in the best overall response (BOR) at any 
time on study drug. BOR is defined as the best response recorded from the start of the 
combination therapy until data cut or start of new anti-neoplastic treatment.  Patients with no 
post-baseline response assessment (due to any reason) will be considered non-responders for 
BOR. 
Two-sided Clopper-Pearson 95% confidence interval (CI) of ORR will be constructed to assess 
the precision of the ORR. The proportion and its corresponding Clopper-Pearson 95% CI for 
each of the response categories (CR, PR, SD, and PD) will be presented. 
9.3.3. 
Efficacy Analysis for Time to Event Endpoints 
PFS is defined as the time from the starting date of the combination 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 tumor assessment. 
Kaplan-Meier method will be used to estimate progression event-free curves and corresponding 
quantiles (including the median).  A two-sided 95% CIs of median, if estimable, will be 
constructed with a generalized Brookmeyer and Crowley method.  The PFS 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. 
The PFS censoring rule will follow FDA Guidance for Industry Clinical Study Endpoints for the 
Approval of Cancer Drugs and Biologics (2007). 
TTR is defined as time from the starting date of combination therapy to the date the response 
criteria are first met. Patients who do not have response will be censored at their last valid 
assessment.  


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DOR 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.  Patients who do not have disease 
progression will be censored at their last valid assessment.  
OS is defined as the time from the starting date of the combination 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.  
Time to event endpoints (DOR, TTR and OS) will be similarly analyzed using the Kaplan-Meier 
method as described above for PFS.  The Kaplan-Meier estimates of TTR, DOR and OS will be 
plotted over time. 
9.3.4. 
Biomarker Analyses 
9.3.4.1. 
Predictive biomarkers 
The primary predictive biomarker analysis is based on a subset of the patients with both a valid 
subtype classification measured by IHC and/or GEP, and at least one disease assessment post-
treatment. Clinical outcomes (ORR, CRR, DOR, PFS, TTR) will be analyzed in subgroups 
identified by these biomarker subtypes (ie, GCB, non-GCB, ABC or unclassified) using the same 
methods described in Section 9.3. 
A supportive analysis is based on patients with a valid subtype classification measurement, 
irrespective of the availability of post-treatment disease assessments.  In this analysis, those 
without post-treatment disease assessments will be imputed with the worst outcome in tumor 
response. Similar analyses described above will also be used. 
Other statistical models (ie, logistic model for ORR, or Cox's proportional model for time to 
event endpoints) may be explored with biomarker subtype index as covariate to explore the 
correlation between the two variables. 
Exploratory analyses of other predictive biomarkers or clinical/genetic risk factors such as Ki67, 
EBV infection status, MYC/BCL2/BCL6 rearrangement status, genomic alteration status, tumor 
infiltrating lymphocytes (TIL) levels, etc will be conducted similarly if data is available. 
9.3.4.2. 
Other biomarkers  
For patients with paired tumor biopsies or blood, correlation between changes in the tumor 
tissues or peripheral blood, including but not limited to BTK pathway gene expression, TIL 
levels, RNA expression and DNA mutational profiling, immune cell and cytokine profiling, 
ctDNA levels, and tumor response will be analyzed to identify potential pharmacodynamics and 
monitoring biomarkers.  
When deemed necessary, correlation analyses described for the predictive biomarkers will also 
be performed for these pharmacodynamics and monitoring biomarkers versus clinical outcomes. 
These biomarkers may be treated as continuous and/or categorical variables (if suitable threshold 
can be identified) in these analyses. 


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Tumor biopsy and blood samples taken at disease progression or response during the study will 
be used to identify potential resistance biomarkers to study mechanisms of resistance. Similar 
analyses described for above monitoring biomarker will also be performed for these resistance 
biomarkers, by replacing the efficacy endpoint of the response status with progression status. 
9.3.5. 
Subgroup Analyses 
Primary and selected secondary endpoints will be summarized descriptively in the specified 
subgroups: sex, age group (≥60), disease stage, disease status (relapsed vs. refractory), 
ECOG-PS (0 vs. ≥1), number of prior lines of therapy, IPI, bulky disease (>7.5 cm).  Within 
group values (rates or means/medians) will be presented in forest plots. 
9.4. 
Safety Analyses 
The sponsor, leading investigator and maybe other investigators will establish a SMC for 
ongoing safety assessment throughout the study. The SMC charter will define the organization 
members and procedures. The SMC will evaluate safety data from the dose escalation potion 
(Part 1) and decide the dose level for next group or if enroll more eligible patients, based on the 
safety data from the former dose level. The SMC will continue monitoring safety data during 
Part 2 periodically as needed. 
Patients will be evaluated for AEs (all grades, according to NCI-CTCAE v5.0) and serious 
adverse events (SAEs). Patients who have an AE that leads to treatment discontinuation will be 
followed until the event resolves, the investigator assesses the event as stable, the patient is lost 
to follow-up, or the patient starts a different antitumor therapy. 
9.4.1. 
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 AEs 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. 
9.4.2. 
Adverse Events 
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified 
into standardized preferred terms (PT) and system organ class (SOC) using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 20.0 or higher.   
A treatment-emergent AE (TEAE) is defined as an AE that had an onset date on or after the first 
dose of study drug and up to 30 days after the last dose of zanubrutinib or lenalidomide  
(whichever comes later), or the start of new anti-cancer therapy, whichever comes first.  
Worsening of an event to Grade 5 beyond day 30 after last dose of study drug is also considered 
a TEAE (if it is prior to new anticancer therapy start). Only those AEs that were treatment 
emergent will be included in summary tables.  All AEs, treatment emergent or otherwise, will be 
presented in patient data listings.  


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The incidence of TEAEs will be reported as the number (and percentage) of patients with TEAEs 
by SOC and PT.  A patient will be counted only once by the highest severity grade according to 
NCI-CTCAE v5.0 within a SOC and PT, even if the patient experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of patients with TEAEs will also be 
summarized by relationship to the study drug.  Treatment-related AEs include those events 
considered by the investigator to be related to study drug or with missing assessment of the 
causal relationship.  Serious AEs, deaths, TEAEs ≥ Grade 3, treatment-related AEs, and TEAEs 
that led to treatment discontinuation, dose reduction or dose interruption, will be summarized.  
9.4.3. 
Laboratory Analyses 
Clinical laboratory (ie, hematology, serum chemistry, 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 CSR for this protocol.  Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables) for laboratory parameters and their changes from 
baseline will be calculated.  Laboratory values will be summarized by visit and by worst post-
baseline visit. 
Laboratory parameters that are graded in CTCAE v5.0 will be summarized by CTCAE grade.  In 
the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading in 
both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
9.4.4. 
Vital Signs 
Vital signs (actual value and change from baseline), including systolic and diastolic blood 
pressure, pulse, temperature, and weight, will be summarized by visit.   


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9.5. 
Pharmacokinetic Analyses 
Plasma zanubrutinib and lenalidomide concentration time data will be summarized and displayed 
in both tabular and graphical form. Individual and mean plasma concentration versus time data 
will be tabulated and plotted by dose level.  
The PK parameters will be estimated based on non-compartmental analysis methods and will be 
computed using Phoenix WinNonlin® Version 7.0.  
The PK parameter estimates for a single dose profile includes but is not limited to the following: 
AUC(0-t): Area under the plasma concentration-time curve from zero to the last measurable 
concentration  
Cmax: 
Maximum plasma concentration  
Tmax: 
Time to maximum plasma concentration  
CL/F: 
Apparent clearance, calculated as dose/AUC0-t 
The PK parameter estimates following multiple doses included but not limited to the following: 
AUC(0-t): Area under the plasma concentration-time curve from zero to the last measurable 
concentration 
Cmax,ss: 
Maximum plasma concentration at steady state 
Tmax: 
Time to maximum plasma concentration 
Ctrough: 
Minimal drug concentration (trough) at steady state 
Ro: 
Accumulation ratio (RAUC: AUC on Day 21 of Cycle 1/AUC on Day 1 of Cycle 1, 
RCmax: Cmax on Day 21 of Cycle 1/Cmax on Day 1 of Cycle 1) 
CL/F: 
Apparent clearance, calculated as dose/AUC0-t 
These and additional PK parameters will be calculated if deemed appropriate and allowed by the 
data.  
Estimates for these parameters will be tabulated and summarized by the dose level, schedule, and 
collection day (ie, sample size, mean, standard deviation, inter-patient variability (CV%), 
median, min, and max, geometric mean and geometric CV%). 
Possible drug-drug interactions between zanubrutinib and lenalidomide may be evaluated as 
exploratory analysis by comparison of the pharmacokinetic data generated in the present study 
and historical data.   
9.6. 
Sample Size Determination 
The number of dose levels examined and the emerging toxicities of the combination therapy will 
determine the sample size.  It is anticipated that approximately 27 patients in Part 1 and 
approximately 36 patients in Part 2 will be required.  With about 10% dropout rate for Part 2, 
approximately 67 patients will be enrolled. 


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Sample size for Part 1 will depend on the number of dose levels examined and the emerging 
toxicities of the combination therapy.  It is expected the maximum of patients in Part 1 will not 
exceed 27 patients. 
For Part 2, Simon's two-stage design (Simon 1989) will be used.  The null hypothesis that the 
true response rate is 0.25 will be tested against a one-sided alternative.  In the first stage, if there 
are 4 or fewer responses in these 18 patients, the study will be stopped.  The null hypothesis will 
be rejected if 15 or more responses are observed in 36 patients.  This design yields a type I error 
rate of 0.025 and power of 96% when the true response rate is 0.55.  
9.7. 
Interim Analysis 
For Part 2 , one futility interim analysis will be conducted based on the Simon 2-stage design 
(see Section 9.6 for details). 


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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
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.  
The sponsor will not routinely inform the investigator or patients of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results would be undetermined 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 
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, and that the basic 
principles of “Good Clinical Practice,” as outlined in 21 Code of Federal Regulations 312, 
Subpart D, “Responsibilities of Sponsors and Investigators,” 21 Code of Federal Regulations, 
Part 50, and 21 Code of Federal Regulations, Part 56, are adhered to. 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted by the principal investigator and the study center in accordance 
with Good Clinical Practice and all applicable regulatory requirements, including, where 
applicable, the current version of the Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s informed consent form, 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 informed 
consent form, and any other information that the IRB/IEC has approved for presentation to 
potential patients. 
If the protocol, the informed consent form, or any other information that the IRB/IEC has 
approved for presentation to potential patients is amended during the study, the investigator (or 
sponsor, where applicable) 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 informed consent form 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 informed 
consent form/other information and the approved amended informed consent form/other 
information must be forwarded to the sponsor promptly. 


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11.2.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent 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. 
11.2.4. 
Investigator Reporting Requirements 
As indicated in Section 8.5.3, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs 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 
Information on maintaining patient confidentiality and privacy in accordance with individual 
local and national patient privacy regulations must be provided to each patient as part of the 
informed consent form process, either as part of the informed consent form or as a separate 
signed document (for example, in the US, a site-specific Health Insurance Portability and 
Accountability Act consent may be used).  The investigator must assure that patients’ anonymity 
will be strictly maintained and that their identities are protected from unauthorized parties.  Only 
patient age, date of independent central review, and an identification code (ie, not names) should 
be recorded on any form or biological sample submitted to the sponsor, IRB, or laboratory.  The 
investigator must keep a screening log showing codes, names, and addresses for all patients 
screened and for all patients enrolled in the study. 
The investigator agrees that all information received from BeiGene, including, but not limited to, 
the Investigator’s Brochure, this protocol, eCRFs, the investigational drug, and any other study 
information, remain the sole and exclusive property of BeiGene during the conduct of the study 
and thereafter.  This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from BeiGene.  The investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study site to any third party or otherwise 
into the public domain. 
If a written contract for the conduct of the study is executed that includes confidentiality 
provisions inconsistent with this section, 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 EDC system in a timely manner.  


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Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee must sign the completed 
casebooks to attest to their accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of 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. 
Electronic CRF entries will be verified with source documentation.  The review of medical 
records will be performed in a manner to ensure that patient confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study.  Direct access to source data is also required for 
inspections and audits and will be carried out giving due consideration to data protection and 
medical confidentiality. 
AEs will be coded using the MedDRA Version 20.0 or higher.  Concomitant medications will be 
coded using the World Health Organization Drug Dictionary.  Concomitant diseases/medical 
history will be coded using the MedDRA Version 20.0 or higher. 
11.2.8. 
Drug Accountability 
The investigator or designee (eg, 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, 
quantities dispensed to patients, and quantities destroyed or returned to BeiGene, including lot 
number, date dispensed, patient identifier number, and the initials of the person dispensing the 
medication. 


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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, after 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 periodically reviewed and verified by the 
study monitor over the course of the study. 
11.2.9. 
Inspections 
The investigator should understand that the facilities used for this study and all 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. 
11.2.10. 
Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to sponsor. 
11.2.11. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient, accurate financial information 
in accordance with regulations to allow the sponsor to submit complete disclosure or certification 
to the absence of certain financial interest of clinical investigators and/or disclose those financial 
interests as required to the appropriate health authorities.  This is intended to ensure financial 
interests and arrangements of clinical investigators with BeiGene that could affect reliability of 
data submitted to health authorities are identified and disclosed by the sponsor.  Investigators are 
responsible for providing information about their financial interests before participation in the 
study and to update this information if any relevant changes occur during the study and for 1 
year after completion of the study (ie, last patient, last visit). 
11.2.12. 
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 informed consent form 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 
informed consent form confirming willingness to remain in the study. 


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11.3. 
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 2013). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement.  This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. 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 
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.   
11.4. 
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 
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 any reason including, but not 
limited to, safety or ethical issues or severe noncompliance with this protocol, Good Clinical 
Practice, the clinical study agreement, or applicable laws and regulations.  If the sponsor 
determines such action is needed, the sponsor will discuss this with the investigator (including 
the reasons for taking such action) at that time.  When feasible, the sponsor will provide advance 
notification to the investigator of the impending action before it taking effect. 


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The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action.  If 
required by applicable regulations, the investigator must inform the IRB/IEC promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor.  In 
addition, arrangements will be made for all unused study 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. 
11.5. 
Records Retention and Study Files 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
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) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECG, electroencephalogram, X-ray, pathology and special 
assessment reports, consultant letters, screening and enrollment log, etc.  
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 these records can be maintained in a 
format other than hard copy (eg, microfiche, scanned, or 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. 


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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 or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that 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 the 
shorter of: a period of up to 10 years or as allowed by your IRB/IEC. 
11.6. 
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) are the sole property of the 
sponsor.  Use of the provided study drug for purposes other than this study is strictly prohibited 
and any data or property rights generated are forfeit and the sole property of the sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during 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 that includes ownership provisions inconsistent 
with this statement is executed between the sponsor and the study center, that contract’s 
ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) will be kept by the investigator 
and other study center personnel.  This information and data will not be used by the investigator 
or other study center personnel for any purpose other than conducting the study.   
These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose in order to provide appropriate medical care 
to a patient 
• Study results which may be published as described in Section 11.3. 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 


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11.7. 
Joint Investigator/Sponsor Responsibilities 
11.7.1. 
Access to Information for Monitoring 
In accordance with International Council on Harmonisation Good Clinical Practice guidelines, 
the study monitor must have direct access to the investigator’s source documentation to verify 
the data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.7.2. 
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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distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the 
National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015 Sep;90(9):790-5. doi: 
10.1002/ajh.24086. 
BeiGene Investigator’s Brochure, Zanubrutinib (BGB-3111). Edition 7, January 2020. 
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 
Mar-Apr;66(2):115-32. 
Cheson B, Fisher R, Barrington S, et al.  Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.  J 
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Christian BA, Kuruvilla JG, Smith SM, et al. Updated Results of a Phase I Study of Ibrutinib and 
Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma. 
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Coiffier B. Diffuse large cell lymphoma. Curr Opin Oncol. 2001 Sep;13(5):325-34. Review. 
PubMed PMID: 11555708. 
Czuczman MS, Trněný M, Davies A, et al. A Phase 2/3 Multicenter, Randomized, Open-Label 
Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in 
Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Clin Cancer Res. 2017 
Aug 1;23(15):4127-37. doi: 10.1158/1078-0432.CCR-16-2818. 
Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signaling in diffuse large B-
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Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus 
chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 2009;113: 
6069-6076. 
Food and Drug Administration (FDA). Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed 22 June 
2020. 
Fisher SG, Fisher RI. The epidemiology of non-Hodgkin's lymphoma. Oncogene. 
2004;23(38):6524-6534. 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28(27):4184-90. 
Gururajan M, Jennings CD, Bondada S. Cutting edge: Constitutive B-cell receptor signaling is 
critical for basal growth of B lymphoma. Journal of Immunology 2006;176:5715-5719. 
International Committee of Medical Journal Editors, 2013. http://www.icmje.org. 
Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nature Reviews Cancer 2005 
Apr;5:251-262. 
Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010;362:1417-1429. 


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Li ZM, Zhu YJ, Xia Y, Huang JJ, Jiang WQ. Clinical characteristics of the patients with 
Hodgkin's lymphoma involving extranodal sites. Chin J Cancer. 2012;31(7):342-7. 
Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and 
treatment in patients with cancer: American Society of Clinical Oncology clinical practice 
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Meeker T, Lowder J, Cleary ML, et al. Emergence of idiotype variants during treatment of B-cell 
lymphoma with anti-idiotype antibodies. N Engl J Med 1985;312:1658-1665. 
National Comprehensive Cancer Network. Cancer – B-Cell Lymphomas. 
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Park LC, Woo SY, Kim S, et al. Incidence, risk factors and clinical features of venous 
thromboembolism in newly diagnosed lymphoma patients: results from a prospective cohort 
study with Asian population. Thromb Res. 2012;130(3):e6-12. 
REVLIMID® [lenalidomide prescribing information ]. Summit, NJ: Celgene Corporation; 2019. 
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after 
chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346(25):1937 47. 
Siegel, R, Naishadham, D and Jemal, A. (2013), Cancer statistics, 2013. CA: A Cancer Journal 
for Clinicians, 63: 11-30. doi:10.3322/caac.21166 
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Surveillance Epidemiology and End Results (SEER), NCI, US National Institutes of Health, Fast 
Facts; Statistics Stratified by Cancer Site, 2010. 
Tam C, Grigg AP, Opat S, et al. The BTK Inhibitor, BGB-3111, Is Safe, Tolerable, and Highly 
Active in Patients with Relapsed/ Refractory B-Cell Malignancies: Initial Report of a Phase 1 
First-in-Human Trial. Blood 2015;126:832. 
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Sep;26 Suppl 5:v116-25. 
Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide Monotherapy in Relapsed or 
Refractory Aggressive Non-Hodgkin’s Lymphoma. JCO 2008;26:4962-4957. 
Wilson WH, Young RM, Schmitz R, et al. Targeting B-cell receptor signaling with ibrutinib in 
diffuse large B-cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. doi: 10.1038/nm.3884. 
Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent 
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Oncology 2011;22:1622-1627. 
Yang Y, Shaffer AL, Tolga Emre NC, et al. Exploiting Synthetic Lethality for the Therapy of 
ABC Diffuse Large B-Cell Lymphoma. Cancer Cell 2012;21:723-737. 
Zhou X, Teegala S, Huen A, et al. Incidence and risk factors of venous thromboembolic events 
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Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a 
valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab 
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APPENDIX 1. THE LUGANO CLASSIFICATION FOR NON-HODGKIN LYMPHOMA 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete  
Complete metabolic response 
Complete radiologic response (all of the following): 
Lymph nodes and 
extra-lymphatic sites 
Score 1, 2, 3* with or without a residual mass on 5PS 
It is recognized that in Waldeyer’s ring or extra-nodal sites 
with physiologic uptake or with activation within spleen or 
marrow (eg, with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater than normal 
mediastinum and/or liver.  In this circumstance, complete 
metabolic response may be inferred if uptake at sites of initial 
involvement is no greater than surrounding normal tissue even 
if the tissue has high physiologic uptake 
Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi 
No extra-lymphatic sites of disease 
Non-measured lesions 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology (if BMA involved at screening),  
if indeterminate, IHC negative 
Partial 
Partial metabolic response: 
Partial remission (all of the following): 
Lymph nodes and 
extra-lymphatic sites 
Score 4 or 5 with reduced uptake compared with baseline and 
residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual disease 
≥ 50% decrease in SPD of up to 6 target measurable nodes 
and extra-nodal sites 
When a lesion is too small to measure on CT, assign 5 mm x 5 
mm as the default value 
When no longer visible, 0 x 0 mm 
For a node > 5 mm x 5 mm, but smaller than normal, use 
actual measurement for calculation 
Non-measured lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal 
New lesions 
None 
None 


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Response and Site 
PET-CT-Based Response 
CT-Based Response 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in the context of a 
nodal response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan 
Not applicable 
No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extra-nodal 
lesions 
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extra-nodal sites; no criteria for 
progressive disease are met 
Non-measured lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the following: 
Individual target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or new FDG-avid foci consistent with lymphoma 
at interim or end of treatment assessment 
An individual node/lesion must be abnormal with: 
• 
LDi > 1.5 cm and 
• 
Increase by ≥ 50% from PPD nadir and 
• 
An increase in LDi or SDi from nadir 
o 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 


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Response and Site 
PET-CT-Based Response 
CT-Based Response 
Non-measured lesions 
None 
New lesions or clear progression of pre-existing non-
measured lesions: 
• 
Regrowth of previously resolved lesions 
• 
A new node > 1.5 cm in any axis 
• 
A new extra-nodal site > 1.0 cm in any axis; if < 1.0 
cm in any axis, its presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size unequivocally attributable to 
lymphoma 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (eg, infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan may 
be considered 
 
Organ enlargement 
Not applicable 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must increase to > 16 cm).   
If no prior splenomegaly, must increase by at least 2 cm from 
baseline 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; BMA, bone marrow assessment; CT, computed tomography; FDG, F-fluoro-2-deoxy-d-glucose; IHC, immunohistochemistry; LDi, longest 
diameter; PET, positron emission tomography; PPD, product of the perpendicular diameters; SDi, shortest diameter; SPD, sum of the products of diameters.  
Source: Cheson 2014. 
*A score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials involving PET where de-escalation 
is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment).   
Splenomegaly defined as vertical spleen length > 13 cm.   
PET 5-point scale (Deauville Criteria): 
1: no uptake above background 
2. uptake ≤ mediastinum 
3. uptake > mediastinum but ≤ liver 
4. uptake moderately > liver 
5. uptake markedly higher than liver and/or new lesions 
X. new areas of uptake unlikely to be related to lymphoma 
 
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, or lungs), gastrointestinal involvement, cutaneous lesions, or those noted on palpation.   


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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, or 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. 
 


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APPENDIX 2. 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 to 100 meters).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound patients. 
Abbreviations: NYHA, New York Heart Association. 
 


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APPENDIX 3. DOSE MODIFICATION TABLE FOR ZANUBRUTINIB 
WHEN CO-ADMINISTERED 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: CYP3A, cytochrome P450, family 3, subfamily A.  


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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/paritaprevir 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 
Abbreviations: 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. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work/office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
 
 


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APPENDIX 6. 
SCHEDULE OF ASSESSMENTS 
Cycle 
C1 
C2 
C3 
C4 
C5 
C6 
C7 & 
Beyond 
Suspected 
 
SFUa 
RFUb 
LTFU 
CR 
PD 
Day 
1 
8 
15 
21 
1 
15 
1 
15 
1 
1 
1 
1 
 
 
30 days 
after 
EOTc 
 
Every 3 
months 
Window (Days)  
± 1 
± 2 
± 2 
± 3 
± 3 
± 3 
± 3 
 
 
 
± 7 
 
± 14 
Study Drug Administration 
Zanubrutinib (continuous) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Lenalidomide (Days 1-21 of each cycle) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Procedure 
Screening 
Day -28 to -1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue Assessment Until Disease Progression 
 
 
 
Biomarker tissue 
sampled 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X  
 
 
 
Biomarker blood 
samplee 
X 
 
 
 
 
  
 
 
 
X 
 
 
X 
 
X  
 
 
 
Medical history & 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Complete physical 
exam & weight (height 
Screening only)h  
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
ECHOj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triplicate 12-Lead 
ECGk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspiration/biopsyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


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Cycle 
C1 
C2 
C3 
C4 
C5 
C6 
C7 & 
Beyond 
Suspected 
 
SFUa 
RFUb 
LTFU 
CR 
PD 
Day 
1 
8 
15 
21 
1 
15 
1 
15 
1 
1 
1 
1 
 
 
30 days 
after 
EOTc 
 
Every 3 
months 
Window (Days)  
± 1 
± 2 
± 2 
± 3 
± 3 
± 3 
± 3 
 
 
 
± 7 
 
± 14 
Procedure 
Screening 
Day -28 to -1 
 
 
Confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments 
Hematologym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Serum chemistryn 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
Coagulation (PT, INR, 
aPTT)o 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
Thyroid function panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis serologiesp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative serum 
immunoglobulins (IgG, 
IgM, IgA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testr 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
PK blood samplings 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic Tumor Assessment 
CT neck, chest, 
abdomen, pelvist 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Xu 
 
 
X 
 
PET or PET/CTt 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Xu 
 
X 
 
Other 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subsequent anticancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: aPTT=activated partial thromboplastin time; C=cycle; CR=complete response; CT=computed tomography; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment visit; INR=international normalized ratio; LTFU=Long-term Follow Up; 
PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetic; PO=oral; PT=prothrombin time; QTcF=Fridericia’s corrected QT 
interval; RFU=Response Follow Up; SFU = Safety Follow Up 


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a An SFU visit will occur 30 days (±7) after the last dose of study drug (zanubrutinib, or lenalidomide, whichever is later), or before the start of a new 
anticancer treatment, whichever occurs first. 
b Patients who discontinue for reasons other than PD continue to be followed for efficacy evaluations per protocol schedule until patient exhibits first 
progression, starts new anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or study termination from sponsor, whichever occurs first. 
c EOT is defined as end of treatment of zanubrutinib, or lenalidomide, whichever is later. 
d No less than 15 unstained slides with adequate tumor contents and quality must be sent to central laboratory for biomarker analysis, including determination 
of DLBCL subtype, EBV infection status, MYC/BCL2/BCL6 rearrangement or expression status, TCL1A expression, etc. If no archival samples are 
available, a fresh tumor biopsy collected at screening is required. For these patients, an optional biopsy for biomarker analysis after approximately 3 cycles 
of treatment is strongly recommended. Optional biopsy will be taken from patients who have confirmed disease progression during the study at accessible 
tumor sites to explore resistance mechanism.  
e Blood samples will be collected at screening, scheduled response assessment visits, and at unscheduled visits when disease progression is to be confirmed to 
explore the association of blood-based biomarkers with response, resistance and prognosis. For more details, please refer to the Laboratory Manual. 
f Record any new medications, changes in ongoing medications or procedures, and medications discontinued within 4 weeks before Cycle 1 Day 1, and on 
study thereafter until 30 days after the last dose of zanubrutinib, or lenalidomide, whichever occurs later. 
g After informed consent has been signed but before the administration of the study drug, only SAEs should be reported. After initiation of study drug, all AEs 
and SAEs, regardless of relationship to study drug, will be reported until 30 days after the last dose of zanubrutinib, or lenalidomide, whichever occurs later. 
See Section 8 for details regarding the reporting of AEs. 
h Assess systems per standard of care at the study site and as clinically indicated by symptoms. Includes weight (height at Screening only). 
i Vital signs (blood pressure, pulse, and temperature) will be assessed after the patient has rested in the sitting position for ≥3 minutes. 
j An echocardiogram is to be performed at screening unless one has been performed within 30 days before the first dose. 
k 12-lead ECG will be done in triplicate (≥1 minute apart). 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. 
l A unilateral bone marrow aspiration and biopsy must be performed at screening if not performed within 60 days before the first dose for all patients, 
provided it is performed as part of their standard care and there has been no intervening therapy between the time of the biopsy and start of study drug. In 
those patients who had evidence of bone marrow disease at screening, upon achieving a possible CR (eg, physical exam or imagine indicating a possible 
CR), a bone marrow aspiration and biopsy should be obtained to confirm the CR. 
m Hematology assessments (which include hemoglobin, hematocrit, platelets, red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) are required to be performed at screening, every visit during the treatment phase and Safety follow-up visit (if necessary as 
defined in Section 5.11). 
n Serum chemistry assessments include sodium, potassium, chloride, urea or blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, 
AST, ALT, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate or phosphorus, uric acid, magnesium, and bicarbonate (or CO2 
combining performance, CO2CP). Chemistry assessments are required at screening, at Cycle 1, weekly on Day 1 of subsequent cycles and Safety follow-up 
visit (if necessary as defined in Section 5.11). 
o Coagulation assessments (PT, INR, aPTT) are required at screening, Day 1 of subsequent cycles and Safety follow-up visit (if necessary defined in 
Section 5.11). 
p Hepatitis serology (which includes hepatitis C antibody, HBsAg, HBsAb, and HBcAb) will be performed at screening. Patients who are HBcAb positive will 
undergo viral load measurement (HBV DNA by PCR) at screening and monthly during the study. Patients who are HCV antibody positive, will undergo 
viral load testing (HCV RNA by PCR) at screening and monthly during the study. 


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q Urinalysis (which includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose) will be performed at screening. 
r Two negative pregnancy tests (at least one blood test) must be obtained before initiating therapy. The first test must be performed within 10-14 days before 
lenalidomide therapy and the second test within 24 hours before lenalidomide therapy. Urine pregnancy tests will be performed weekly during the first 4 
weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the 
pregnancy testing should occur every 2 weeks. Pregnancy tests must be continued every 4 weeks (cycle) for at least 90 days after the last dose of 
zanubrutinib and lenalidomide, whichever comes last.  Pregnancy testing and counseling should be performed if a patient misses her period or if there is any 
abnormality in her menstrual bleeding. Lenalidomide treatment must be discontinued during this evaluation. If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. A patient who has a positive pregnancy test result at any time after the study drug administration will be immediately 
withdrawn from participation in the study. 
s Pharmacokinetic samples will be drawn according to the schedule in Table 2. Procedures for collection of samples are described in the Lab Manual. 
Additional PK samples may be taken if needed, to further evaluate zanubrutinib and lenalidomide exposure. The investigator will record the time of blood 
collection and the time of administration in the eCRF. 
t Pretreatment tumor assessment should be performed within 28 days before the first dose. A CT scan (with contrast unless contraindicated) of the neck, chest, 
abdomen, and pelvis, and any other disease sites and a PET or PET/CT scan are required for the pretreatment tumor assessment. During treatment, PET and 
contrast CT should be repeated every 12 weeks for the first 48 weeks, every 16 weeks for the next 48 weeks, and every 24 weeks thereafter until disease 
progression, use of alternative anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first. Disease 
assessment is performed on Cycle 4 Day 1 ± 3 days, Cycle 7 Day 1± 3 days, Cycle 10 Day 1 ± 3 days, Cycle 13 Day 1 ± 3 days, Cycle 17 Day 1± 3 days, 
Cycle 21 Day 1± 3 days, Cycle 25 Day 1± 3 days, Cycle 31± 3 days, etc. In the event that CT contrast is contraindicated, MRI may be performed as an 
alternative. Lesions in anatomical locations that are not well visualized by CT may be measured at baseline from MRI instead and should continue to be 
measured from MRI until disease progression. 
u 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. 
 
 


Signature Page 
Approval

SAP_001.pdf: 
BGB-3111-110 
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Statistical Analysis Plan 2.0 
3 August 2023 
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Page 1 of 33 
STATISTICAL ANALYSIS PLAN 
Study Protocol Number 
BGB-3111-110 
Study Protocol Title 
A Phase 1, Open Label, Multiple Dose, Dose 
Escalation and Expansion Study of Bruton’s Tyrosine 
Kinase (BTK) Inhibitor, Zanubrutinib, in 
Combination With Lenalidomide, With or Without 
Rituximab in Patients With Relapsed/Refractory 
Diffuse Large B-Cell Lymphoma 
Date 
August 3rd, 2023 
Version 
2.0 
NCT Number
NCT04436107


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SIGNATURE PAGE 
Author:  
 
      Principle Statistician, GSDS 
Approval 
 
Head of Global Statistics 
 
Chief Medical Officer 
 
Senior Physician, Clinical Development 


 
 
 
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Table of Contents 
List of Abbreviations and Terms .................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................................... 8 
2. 
STUDY OVERVIEW.............................................................................................................. 8 
2.1. Part 1 ........................................................................................................................................ 8 
2.2. Part 2 ........................................................................................................................................ 9 
3. 
STUDY OBJECTIVES ......................................................................................................... 10 
3.1. Part 1 ...................................................................................................................................... 10 
3.1.1. 
Primary Objectives ......................................................................................................... 10 
3.1.2. 
Secondary Objectives ..................................................................................................... 10 
3.1.3. 
Exploratory Objectives ................................................................................................... 10 
3.2. Part 2 ...................................................................................................................................... 11 
3.2.1. 
Primary Objectives ......................................................................................................... 11 
3.2.2. 
Secondary Objectives ..................................................................................................... 11 
3.2.3. 
Exploratory Objectives ................................................................................................... 11 
4. 
STUDY ENDPOINTS ........................................................................................................... 11 
4.1. Part 1 ...................................................................................................................................... 11 
4.1.1. 
Primary Endpoints .......................................................................................................... 11 
4.1.2. 
Secondary Endpoints ...................................................................................................... 12 
4.1.3. 
Exploratory Endpoints.................................................................................................... 12 
4.2. Part 2 ...................................................................................................................................... 13 
4.2.1. 
Primary Endpoints .......................................................................................................... 13 
4.2.2. 
Secondary Endpoints ...................................................................................................... 13 
4.2.3. 
Exploratory Endpoints.................................................................................................... 13 
5. 
SAMPLE SIZE CONSIDERATION..................................................................................... 13 
6. 
STATISTICAL METHODS.................................................................................................. 14 
6.1. Analysis Sets.......................................................................................................................... 14 
6.2. Data Analysis General Consideration .................................................................................... 14 
6.2.1. 
Definitions and Computations ........................................................................................ 14 
6.2.2. 
Conventions .................................................................................................................... 15 
6.2.3. 
Handling of Missing Data .............................................................................................. 15 


 
 
 
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6.2.3.1. 
Handling of Missing Date in Prior/Concomitant Medications ................................. 15 
6.2.3.2. 
Handling of Missing Date in Adverse Events............ Error! Bookmark not defined. 
6.2.3.3. 
Handling of Missing Date in Death ........................... Error! Bookmark not defined. 
6.2.3.4. 
Handling of Missing Start Date in Subsequent Anticancer Therapy ................. Error! 
Bookmark not defined. 
6.2.3.5. 
Handling of Missing Date in Diagnosis ..................... Error! Bookmark not defined. 
6.2.3.6. 
Handling of Missing Date in Prior Therapy/Response to Prior Therapy ........... Error! 
Bookmark not defined. 
6.2.4. 
Adjustments for Covariates ............................................................................................ 18 
6.2.5. 
Multiple Comparisons/Multiplicity ................................................................................ 18 
6.2.6. 
Data Integrity.................................................................................................................. 18 
6.3. Subject Characteristics .......................................................................................................... 18 
6.3.1. 
Subject Disposition ........................................................................................................ 18 
6.3.2. 
Protocol Deviations ........................................................................................................ 19 
6.3.3. 
Demographic and Other Baseline Characteristics .......................................................... 19 
6.3.4. 
Disease History and Characteristics ............................................................................... 19 
6.3.5. 
Prior Anticancer Drug Therapies and Surgeries ............................................................ 19 
6.3.6. 
Prior and Concomitant Medications ............................................................................... 19 
6.3.7. 
Medical History .............................................................................................................. 20 
6.4. Safety Analyses ..................................................................................................................... 20 
6.4.1. 
Extent of Exposure ......................................................................................................... 20 
6.4.2. 
Adverse Events ............................................................................................................... 21 
6.4.3. 
Laboratory Analyses ...................................................................................................... 22 
6.4.4. 
Vital Signs ...................................................................................................................... 23 
6.4.5. 
ECOG performance status .............................................................................................. 24 
6.4.6. 
Electrocardiograms......................................................................................................... 24 
6.5. Efficacy Analyses .................................................................................................................. 24 
6.5.1. 
Hypothesis Test .............................................................................................................. 24 
6.5.2. 
Efficacy Analysis for Response Rates ........................................................................... 25 
6.5.3. 
Efficacy Analysis for Time to Event Endpoints............................................................. 25 
6.5.4. 
Subgroup Analyses ......................................................................................................... 26 


 
 
 
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6.5.5. 
Pharmacokinetic Analyses ............................................................................................. 26 
6.6. Biomarker Analyses .............................................................................................................. 31 
6.6.1. 
Predictive Biomarkers .................................................................................................... 31 
6.6.2. 
Other Biomarkers ........................................................................................................... 31 
7. 
INTERIM ANALYSIS .......................................................................................................... 32 
8. 
CHANGES IN THE PLANNED ANALYSIS ...................................................................... 32 
9. 
REFERENCES ...................................................................................................................... 32 
10. APPENDIX A: HANDELING OF CENSORING TIME TO EVENT DATA..................... 33 
 
 


 
 
 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation Definition 
ABC 
Activated B-cell like 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUC(0−t) 
Area under the plasma concentration-time curve from zero to the last 
measurable time points 
BID 
Twice daily 
BOR 
Best overall response 
BTK 
Bruton tyrosine kinase 
Cmax 
Maximum observed plasma concentration 
Cmax_ss 
Maximum observed plasma concentration at steady state 
Ctrough 
Minimal drug concentration at steady state 
CTCAE 
Common Terminology Criteria for Adverse Events 
CI 
Confidence interval 
CL/F 
Apparent clearance 
CR 
Complete response 
CRF 
Case report form 
CRR 
Complete response rate 
CT 
Computed tomography 
CV% 
Inter-subject variability 
DLBCL 
Diffuse large B cell lymphoma  
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
ECOG 
Eastern Cooperative Oncology Group 
GCB 
Germinal-center B-cell 
GEP 
Gene expression profiling  
IHC 
Immunohistochemistry 


 
 
 
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Abbreviation Definition 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PFS 
Progression-free survival  
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred terms 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Disease progression 
QD 
Once daily 
RAUC 
Accumulation ratio of AUC 
RCmax 
Accumulation ratio of Cmax 
RO 
Accumulation ratio 
RP2D 
Recommended Phase 2 dose 
R/R 
Relapsed/refractory 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SMC 
Safety Monitoring Committee 
SOC 
System organ class 
Tmax 
Time to maximum observed plasma concentration 
TEAE 
Treatment-emergent AE 
TTR 
Time to response 
WHO DD 
World Health Organization Drug Dictionary 
 


 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the detailed plan for analysis of data in evaluation 
of safety and efficacy for the BGB-3111-110. This document is based on Protocol Amendment 
Version 2.0 dated 01 December 2020. 
2. STUDY OVERVIEW 
This is a phase 1, open label, multiple doses, dose escalation and expansion study of Bruton’s 
Tyrosine Kinase (BTK) Inhibitor, zanubrutinib, in combination with lenalidomide in patients 
with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). This study consists of two 
parts. 
2.1. Part 1 
Part 1 is the dose escalation portion, consisting of lenalidomide dose escalation with zanubrutinib 
fixed dose as the table below:   
Table 1: Doses and schedules of interest in dose escalation 
Dose Level  
Zanubrutinib  Lenalidomide  
Dose Level -1  160 mg BID  
10 mg QD  
Dose Level 1   
(Starting dose)  160 mg BID  
15 mg QD  
Dose Level 2  160 mg BID  
20 mg QD  
Dose Level 3  160 mg BID  
25 mg QD  
BID=twice daily; QD=once daily  
For dose escalation, 3+3 principles will be followed for the maximum tolerated doses (MTD) 
determination. The dose of zanubrutinib will remain fixed with up to 3 dose levels of 
lenalidomide to be explored according to Table 1. Zanubrutinib will be administered orally at 
160 mg BID, while lenalidomide will be administered orally daily at the dose designated by dose 
levels in Table 1 on Days 1-21 of each 28-day cycle. Both zanubrutinib and lenalidomide will 
continue until disease progression (PD) or unacceptable toxicity.  
The starting dose of lenalidomide will be 15 mg/day. The dose limiting toxicity (DLT) 
observation period is 28 days (1 cycle) of therapy followed by evaluation for toxicity on Cycle 2 
Day 1, where the DLT is defined in Section 3.2.1.1 of the protocol. Further, define the MTD as 
the highest dose at which < 33 % of the patients enrolled at one dose level experience a DLT. 
Enrollment will proceed as follows. 
 If no DLT is observed during the DLT observation period in the initial three patients of a 
cohort (0/3), dose escalation to the next higher dose level cohort will occur.  


 
 
 
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 If one DLT is observed, three additional patients will be enrolled at the same dose level for a 
total of at least six patients. If no further DLTs are observed (1/6), escalation to the next 
higher dose level cohort will occur.  
 If two or more DLTs ( ≥2/6) are observed in patients, the MTD is considered to have been 
exceeded and no further patients will be enrolled at that dose.  
 If there are two or more DLTs in Dose Level 1, Dose Level -1 will be enrolled.  
 If all evaluated dose levels demonstrate an observed incidence of DLT in < 33% of patients, 
the MTD of lenalidomide in the combination has not been reached. At least six patients 
should be treated at the MTD or highest tested dose. 
 If a patient experiences a DLT during the DLT observation period, the patient will 
discontinue treatment.  
 The decision to proceed to the next dose level or an interim dose level will be made in a Dose 
Level Review Meeting by the Sponsor in conjunction with the investigators after careful 
consideration of all available safety and laboratory information. Safety data from patients on 
preceding cohorts that remain on continuous dosing will also be considered. 
 According to study results and other relevant information, more additional patients, up to 12 
patients, may be allowed to enroll to tested doses at or below MTD by Safety Monitoring 
Committee (SMC) to collect more safety data. 
In the Dose Escalation Phase, if a patient is non-compliant with the prescribed therapy or ends 
treatment within the first cycle for reasons other than study drug(s) related toxicity, ie, withdraws 
consent, they will be replaced. Any patient that missed >4 doses of zanubrutinib or lenalidomide 
for reasons other than toxicity will be replaced. 
Pharmacokinetics (PK) blood sampling will be performed at predose (0 hr), 0.5, 1, 2, 3, 4, 8hr on 
Cycle 1 Day 1 and Cycle 1 Day 21 for measurement of plasma zanubrutinib and lenalidomide 
concentration. 
After the PR2D of lenalidomide is defined, further enrollment into Part 2 will commence. 
2.2. Part 2 
Part 2 will be conducted as an open label, single arm, multicenter, expansion study with Simon’s 
two-stage design (Simon, 1989). Eligible R/R DLBCL patients will receive zanubrutinib 
combined with lenalidomide. The dose of lenalidomide will be based upon the recommended the 
RP2D identified in Part 1. Both treatment medications will continue until PD or unacceptable 
toxicity.  


 
 
 
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PK blood sampling will be performed for 12 patients from the first stage enrollment at predose (0 
hr), 0.5, 1, 2, 3, 4, 8 hr on Cycle 1 Day 1 and Cycle 1 Day 21 for measurement of plasma 
zanubrutinib and lenalidomide concentration. 
During both parts, immunohistochemistry (IHC) and gene expression profiling (GEP) will be 
used to assess enrolled patients’ status with respect to subtype of DLBCL. Subjects can be 
classified into germinal-center B-cell (GCB) or non-GCB like phenotype by IHC, and into the 
three subtypes: activated B-cell like (ABC), GCB and unclassified, by GEP. 
 
3. STUDY OBJECTIVES 
3.1. Part 1 
3.1.1. Primary Objectives  
 To determine the MTD and the RP2D of zanubrutinib in combination with lenalidomide, by 
dose escalation of lenalidomide in patients with R/R DLBCL. 
 To determine the safety and tolerability of zanubrutinib in combination with lenalidomide, in 
patients with R/R DLBCL by dose escalating lenalidomide. 
3.1.2. Secondary Objectives 
 To evaluate the efficacy of zanubrutinib in combination with lenalidomide in patients with 
R/R DLBCL as measured by overall response rate (ORR) assessed by investigator. 
 To characterize the PK profiles of zanubrutinib and lenalidomide after single dose and at 
steady state when given in combination. 
 To evaluate the efficacy, as measured by ORR, of zanubrutinib in combination with 
lenalidomide in different DLBCL subtypes. 
3.1.3. Exploratory Objectives 
 To evaluate the efficacy of zanubrutinib in combination with lenalidomide as measured by 
complete response rate (CRR), time to response (TTR), duration of response (DOR), 
progression-free survival (PFS) and overall survival (OS), in patients with R/R DLBCL as 
well as in patients within different subtypes of R/R DLBCL. 
 To evaluate the correlation of clinical/genetic risk factors and clinical outcomes. 
 To explore mechanisms of disease resistance. 


 
 
 
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3.2. Part 2 
3.2.1. Primary Objectives 
To evaluate the efficacy of zanubrutinib combined with lenalidomide in patients with R/R 
DLBCL as measured by ORR. 
3.2.2. Secondary Objectives  
 To evaluate the efficacy of zanubrutinib combined with lenalidomide, as measured by CRR, 
PFS, TTR and DOR. 
 To determine the safety and tolerability of zanubrutinib combined with lenalidomide in 
patients with R/R DLBCL. 
 To further characterize the PK profiles of zanubrutinib and lenalidomide after single dose 
and at steady state when given in combination. 
 To evaluate the efficacy (ORR, CRR, TTR, PFS, and DOR) based on the DLBCL subtypes. 
3.2.3. Exploratory Objectives 
 To evaluate OS. 
 To evaluate the correlation of clinical/genetic risk factors and clinical outcomes (eg, ORR, 
CRR, PFS, TTR, DOR and OS). 
 To explore mechanisms of disease resistance. 
4. STUDY ENDPOINTS 
4.1. Part 1 
4.1.1. Primary Endpoints 
The primary endpoint is the safety of zanubrutinib combined with lenalidomide which will be 
assessed throughout the study by monitoring adverse events (AE) and serious AEs (SAE), per 
the NCI-CTCAE Version 5.0, physical examination and laboratory measurements, within the 
safety analysis set.  
The RP2D of lenalidomide will be determined based on safety data. 


 
 
 
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4.1.2. Secondary Endpoints 
Define the best overall response (BOR) as the best response recorded from the start of the 
combination therapy until data cut or start of new anticancer treatment.  
The secondary endpoints are described as follows. 
 ORR, defined as the proportion of patients whose BORs are either PR or CR based on the 
Lugano classification (Cheson, et al., 2014)  
 PK evaluations, for zanubrutinib and lenalidomide, as appropriate and allowed by the data. 
For a single dose profile, the evaluations include but not limited to AUC(0−t), Cmax, Tmax and 
CL/F. Furthermore, for a steady state profile, the evaluations include but not limited to 
AUC(0−t), Cmax_ss , Tmax, Ctrough, CL/F and Ro.  
 Clinical outcomes, as measured by ORR, based on different subtypes (GCB and non-GCB 
classified by IHC, and ABC and GCB by GEP).  
4.1.3. Exploratory Endpoints 
The exploratory endpoints are the clinical outcomes and then by clinical/genetic risk factors and 
potential resistance biomarkers and mechanisms of resistance.  
The clinical outcomes of interest are listed as follows. 
 CRR, defined as the proportion of patients whose BORs are CR based on the Lugano 
classification (Cheson, et al., 2014). 
 PFS, defined as the time from the documented date of treatment initiation to the documented 
date of PD, assessed based on the Lugano classification (Cheson, et al., 2014), or the date of 
death, whichever occurs earlier. 
 DOR, defined as the time from the documented date of first response to the documented date 
of PD, assessed based on the Lugano classification (Cheson, et al., 2014), or the date of 
death, whichever occurs earlier. 
 TTR, defined as the time from the documented date of treatment initiation to the documented 
date of first response. 
 OS, defined as the time from the documented date of treatment initiation to the date of death 
from any cause. 


 
 
 
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4.2. Part 2 
4.2.1. Primary Endpoints 
ORR, defined as the proportion of patients whose BORs are either PR or CR based on the 
Lugano classification (Cheson, et al., 2014). 
4.2.2. Secondary Endpoints 
 Clinical outcomes of zanubrutinib combined with lenalidomide, including CRR, PFS, TTR 
and DOR, in the efficacy analysis set as well as the subgroups classified by IHC and by GEP. 
 Safety and tolerability of zanubrutinib combined with lenalidomide will be assessed 
throughout the study by monitoring AEs and SAEs, per the NCI-CTCAE Version 5.0, 
physical examination and laboratory measurements.  
 PK evaluations, for zanubrutinib and lenalidomide, as appropriate and allowed by the data, 
including but not limited to AUC(0−t), Cmax, Tmax and CL/F for a single dose profile and 
AUC(0−t), Cmax_ss , Tmax, Ctrough, CL/F and Ro for a steady state profile.  
 Clinical outcomes (eg, ORR, CRR, DOR, PFS, TTR) based on the GCB and non-GCB 
identified by IHC and ABC and GCB subtype identified by GEP.  
4.2.3. Exploratory Endpoints 
 OS. 
 Clinical outcomes (ORR, CRR, PFS, TTR and DOR) by clinical/genetic risk factors. 
 Potential resistance biomarkers and mechanisms of resistance. 
5. SAMPLE SIZE CONSIDERATION 
The number of dose levels to examine and the emerging toxicities of the combination therapy 
will determine the sample size. It is anticipated that approximately 27 patients in Part 1 and 
approximately 36 patients in Part 2 will be required. Under 10% dropout rate in Part2 by 
assumption, approximately 67 patients will be enrolled in total. 
Sample size in Part 1 will depend on the number of dose levels to examine and the emerging 
toxicities of the combination therapy.  
For Part 2, Simon's two-stage design will be used. The null hypothesis that the true response rate 
is 0.25 will be tested against a one-sided alternative. In the first stage, if there are 4 or fewer 
responses in the first 18 patients, the study will be terminated. The null hypothesis will be 


 
 
 
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rejected if 15 or more response are observed in 36 patients. This design yields a type I error rate 
of 0.025 and power of 96% when the true response rate is 0.55.  
6. STATISTICAL METHODS 
6.1. Analysis Sets 
Safety analysis set is defined as all patients who are exposed to at least one dose of any 
medication within the combination therapy.  
Efficacy analysis set is defined as all patients who are exposed to at least one dose medication 
with confirmed R/R DLBCL. Patients with no post-baseline response assessments will be treated 
as non-responders. It will be used as the primary analysis set for all the efficacy analyses. 
Efficacy evaluable analysis set is defined as all patients who are exposed to at least one 
medication with confirmed R/R DLBCL and have at least one post-baseline response assessment 
unless discontinued treatment due to clinical progression or death prior to response assessment in 
the efficacy analysis set. It will be used for sensitivity analyses.  
PK analysis set is defined as all patients who have at least one post dose plasma concentration 
collected without major protocol deviation affecting PK. It will be used for PK analysis. 
Biomarker analysis set is defined as all the patients who is in a valid subtype of DLBCL 
classified by IHC or GEP and has at least one disease assessment after the initiation of treatment. 
It will be used for biomarker analysis. 
6.2. Data Analysis General Consideration 
6.2.1. Definitions and Computations 
Definitions are described as follows. 
 Study drugs are zanubrutinib, in combination with lenalidomide. 
 Date of treatment initiation =
Date of the first dose of  any study drug in the treatment phase.  
 Study days = Assessment date −Date of treatment initiation + 1 in days, if assessment 
conducted on or after the date of the treatment initiation; and Study days =
Assessment date −Date of treatment initiation in days, if assessment conducted before 
the date of the treatment initiation. Note that there is no study day 0. 
 Baseline = The last nonmissing value collected on or before the treatment initiation. 


 
 
 
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All calculations and analyses will be conducted using SAS® Enterprise Guide Version 7.15 or 
higher. 
6.2.2. Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses.  
 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up to 1 
significant digit. 
 P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be presented 
as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’. 
 Missing efficacy or safety data will not be imputed unless otherwise specified. 
 For by-visit observed data analyses, percentages will be calculated based on the number of 
patients with non-missing data as the denominator, unless otherwise specified. 
 For continuous endpoints, descriptive statistics will include sample size, mean, standard 
deviation, median, 1st and 3rd quartiles and range (minimum and maximum). 
 For discrete endpoints, summary statistics will include frequencies and percentages 
 
6.2.3. Handling of Missing Data 
 
Missing data will not be imputed unless otherwise specified elsewhere in this SAP. Missing 
dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures. Specific rules for the handling of missing or partially 
missing dates for adverse events and prior/concomitant medications/procedures are described as 
follows. 
By-visit endpoints will be analyzed using observed data unless otherwise specified. For observed 
data analyses, missing data will not be imputed, and only the observed records will be included. 
6.2.3.1. Impute partial dates for prior/concomitant 
medication/therapy/procedure 
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   


 
 
 
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If start date of a medication/therapy/procedure is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed end date > death date/end of study, then set to death date/end of study, 
whichever occurs first. 
 For records with CM.CMCAT='PREVIOUS SYSTEMIC THERAPY', if the imputed 
end date is on or after ADSL.TRTSDT then derive it as ADSL.TRTSDT - 1. 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
 
6.2.3.2. Impute partial dates for adverse events 
If year of the start date is missing or start date is completely missing, do not impute. Impute AE end date 
first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
 
If both month and day are missing, then set to December 31 
 
If only day is missing, then set to last day of the month 
 
If the imputed end date > death date, then set to death date 
    If year of the end date is missing or end date is completely missing, do not impute. 
 
If start date of an adverse event is partially missing, impute as follows: 
 
If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
 
If both month and day are missing and year ≠ year of treatment start date, then set to January 
01 
 
If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date 
 
If day is missing and month and year ≠ month and year of treatment start date, the set to first 
of the month 
 
If the imputed AE start date is after AE end date (maybe imputed), then update AE start date  


 
 
 
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with AE end date as final imputed AE start date 
 
If the imputed start date > death date, then set to death date 
 
6.2.3.3. Impute partial dates related to disease history and prior therapy 
(drug, surgery/procedure, radiotherapy) 
The following rules will be applied to impute partial dates such as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
 
If start date of a disease history or prior therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed start date > first dose date then set to first dose date – 1 
 
If end date of a disease history or prior therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed end date > first dose date, then set to first dose date -1 
 
6.2.3.4. Impute partial dates for subsequent anti-cancer therapy (same rule 
applies to safety and efficacy flag) 
If start date of subsequent anti-cancer therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to January 1st  
 If only day is missing, then set to first day of the month 
 If the subsequent anti-cancer therapy is collected from CRF “post-treatment 
discontinuation anti-cancer systemic therapy” or “post-treatment discontinuation anti-
cancer procedure” page, and the imputed date is prior to the last dosing date, then set 
to last dosing date + 1 
If stop date of is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 


 
 
 
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 If the imputed stop date > min (death date, study discontinuation date, data cutoff 
date), then set to min (death date, study discontinuation date, data cutoff date) 
 The imputed stop date must be after or equal to the end date 
If year of the start date/stop date is missing, do not impute.  
 
6.2.4. Adjustments for Covariates 
No adjustments for covariates are planned for primary and secondary analyses in this study, 
while baseline covariates may be included in the statistical models for exploratory analysis. 
6.2.5. Multiple Comparisons/Multiplicity 
Not applicable. 
6.2.6. Data Integrity 
Before pre-specified statistical analysis begins, the integrity of the data will be reviewed to 
assure fit-for-purpose. The data set for analysis should be an accurate and complete 
representation of the patients’ relevant outcomes from the clinical database. All data should be 
complete and reviewed up to a pre-specified cutoff date. Consistency checks and appropriate 
source data verification should be complete.  
6.3. Subject Characteristics 
Subject characteristics will be performed to the safety analysis sets of cohorts at each dose level 
in Part 1, the cohort in Part 2, and the pooling of cohorts at RP2D in Part 1 and Part 2 separately. 
6.3.1. Subject Disposition  
Number and percentage of enrolled patients will be summarized by categories, including treated, 
discontinued from treatment, remained on treatment, discontinued from study and remained in 
study. Primary reasons for discontinuation of each study drug and discontinuation of study will 
also be summarized in the same table. Moreover, study follow-up time (months) will be 
summarized by descriptive statistics. Lastly, survival status (alive, death, or lost to follow-up) at 
the cutoff date will be summarized using the data from the survival follow-ups.  
Study follow-up is defined as the time from first dose date to the death date or end of study date 
(whichever occurs earlier) for patients discontinued from study, or the data cutoff date for 
ongoing patients. 


 
 
 
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6.3.2. Protocol Deviations  
Important protocol deviation criteria will be established and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be summarized 
for all enrolled patients and will also be listed by each category.  
6.3.3. Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized using descriptive statistics. 
Continuous variables include age (years), height (cm), weight (kg), body mass index (kg/m2) and 
vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, and temperature); 
categorical variables include sex, race, age group (< 60 vs. ≥60 years), Eastern Cooperative 
Oncology Group performance status, hepatitis B core antibody and hepatitis C virus antibody. A 
listing of demographic and other baseline characteristics will be provided.  
6.3.4. Disease History and Characteristics  
History of disease and characteristic, as recorded on the case report form (CRF), will be 
summarized using descriptive statistics. Continuous variables for disease history and 
characteristics include time from initial diagnosis of DLBCL to study entry (days); categorical 
variables include with or without prior transplantation (including autologous and allogeneic stem 
cell transplantation), with or without prior radiotherapy, IHC subtype obtained from central lab, 
GEP subtype obtained from central lab, EBER ISH, c-MYC/BCL2/BCL6 rearrangement or 
expression status, Epstein-Barr virus in situ hybridization, disease stage at entry, disease status 
(relapsed or refractory), bulky disease (> 7.5 cm vs. ≤7.5 cm), extra-nodal disease and bone 
marrow involvement. A listing of disease history will be provided.  
6.3.5. Prior Anticancer Drug Therapies and Surgeries  
Prior anti-cancer drug therapies, prior anti-cancer radiotherapy, and prior anti-cancer surgeries 
will be summarized in the safety analysis set. The variables include number of patients with any 
prior anti-cancer therapy, number of prior regimens, duration of last therapy for prior anti-cancer 
drug therapies and curative intent, time from the end of last surgery to study entry for prior 
surgeries. The therapies and surgeries with the same sequence/regimen number are counted as 
one prior therapy/surgery.  
 
6.3.6. Prior and Concomitant Medications 
Prior medications are defined as medications that started before the first dose date. Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug and 


 
 
 
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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, lenalidomide, 
whichever occurs later.  
They will be coded using the World Health Organization Drug Dictionary (WHO DD) drug 
codes and will further be classified to the appropriate Anatomical Therapeutic Chemical (ATC) 
code.  
The number and percentage of patients in safety analysis set reporting prior/concomitant 
medications will be summarized by the ATC medication class and the WHO DD preferred term 
(PT) by phase. A listing of prior and concomitant medications will be provided.  
6.3.7. Medical History  
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.0 or higher. The number and percentage of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by MedDRA system organ class (SOC) 
and PT. A listing of medical history will be provided. 
6.4. Safety Analyses 
The sponsor, leading investigator and maybe other investigators will establish a SMC for 
ongoing safety assessment throughout the study. The SMC charter will define the organization 
members and procedures. The SMC will evaluate safety data from Part 1 and decide the dose 
level for next group or if enroll more eligible patients, based on the safety data from the former 
dose level. The SMC will continue monitoring safety data during Part 2 periodically as needed. 
Patients will be evaluated for AEs (all grades, according to NCI-CTCAE Version 5.0) and 
serious adverse events (defined in the protocol). Patients who have an AE leading to treatment 
discontinuation will be followed until the event resolves, the investigator assesses the event as 
stable, the patient is lost to follow-up, or the patient starts a different antitumor therapy. 
All safety analysis will be performed to the safety analysis sets of cohorts at each dose level in 
Part 1, the cohort in Part 2, and the pooling of cohorts at RP2D in Part 1 and Part 2 separately, 
except for DLT, which will be performed to the safety analysis sets of cohorts in Part 1. 
6.4.1. Extent of Exposure 
The following measures of the extent of exposure will be summarized: 
 
Duration of treatment of zanubrutinib = End date of zanubrutinib −
Start date of zanubrutinib + 1 in days. 


 
 
 
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 
Duration of treatment of lenalidomide = End date of lenalidomide −
Start date of lenalidomide + 1 in days, where the end date of lenalidomide is the latter one 
of the last dose date of lenalidomide and the Day 28 of the last cycle of lenalidomide, or 
death date, whichever occurs earlier. 
 
Total dose received per patient (mg): defined as the cumulative dose of the study drug 
during the treatment period of the study. 
 
Actual dose intensity (mg/day): defined as the total dose of a study drug received by a 
patient divided by the duration of treatment of the study drug. 
 
Relative dose intensity (%): defined as the ratio of the actual dose intensity and the planned 
dose intensity. Planned dose intensity is defined as the planned dose on study day 1 by a 
patient divided by the duration of exposure. 
 
Number (%) of patients with dose reductions 
 
Number (%) of patients with dose interruptions 
 
Number (%) of patients with dose modifications 
 
Reasons for dose reductions 
 
Reasons for dose interruptions 
6.4.2. Adverse Events 
AEs will be graded by the investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology 
using MedDRA. Adverse events will be coded to the MedDRA (Version 20.0 or higher) lowest 
level term closest to the verbatim term, along with the linked MedDRA preferred term (PT) and 
primary system organ class (SOC). 
A treatment-emergent AE (TEAE) is defined as an AE that had an onset date on or after the first 
dose of study drug and up to 30 days after the last dose of zanubrutinib or lenalidomide 
(whichever comes later), or the start of a new anticancer therapy, whichever comes first. 
Worsening of an event to Grade 5 beyond day 30 after last dose of study drug is also considered 
a TEAE (if it is prior to new anticancer therapy start). Only those AEs that were treatment 
emergent will be included in summary tables. All AEs, treatment-emergent or otherwise, will be 
presented in patient data listings. 
DLT events will be summarized by dose level in the dose escalation phase. 
An AE overview table, including the number and percentage of patients with TEAEs, treatment-
emergent serious adverse events (SAEs), TEAEs with Grade 3 or above, TEAEs that led to 


 
 
 
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death, TEAEs that led to treatment discontinuation, TEAEs that led to dose reduction, TEAEs 
that led to dose interruption, zanubrutinib-related TEAEs, lenalidomide-related TEAEs will be 
provided. Treatment-related AEs include those events considered by the investigator to be 
probably related to study drug or with a missing assessment of the causal relationship.  
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC, PT and the worst grade. A patient will be counted only once by the highest severity grade 
within an SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC 
and PT. The number (percentage) of patients with treatment-emergent SAEs, zanubrutinib-
related TEAEs, lenalidomide-related TEAEs, TEAEs with grade 3 or above, TEAEs that led to 
death, and TEAEs that led to treatment discontinuation, dose reduction or dose interruption will 
be summarized by SOC and PT. TEAEs with grade 3 or above will also be summarized by PT in 
descending order. 
Patient data listings of TEAE, treatment-emergent SAEs, zanubrutinib-related TEAEs, 
lenalidomide-related TEAEs, TEAEs with grade 3 or above, TEAEs that led to death, and 
TEAEs that led to treatment discontinuation, dose reduction or dose interruption will be 
provided. 
 
All deaths and causes of death will be summarized by cohorts and by total including those 
occurred during the study treatment period and those reported during the survival follow-up 
period after treatment completion/discontinuation. 
Summaries including all TEAEs, AEs worsened after the treatment-emergent (TE) period and/or 
AE started after the TE period but determined to be treatment-related will also be provided. 
6.4.3. Laboratory Analyses 
Clinical laboratory (ie, hematology, serum chemistry, coagulation, urinalysis, serum 
immunoglobins, hepatitis serologies, and thyroid function) values will be evaluated for each 
laboratory parameter by patient. The laboratory parameters of interest are summarized in Table 
2. Abnormal laboratory values will be flagged and identified as those outside the normal range. 
Reference ranges for laboratory parameters will be included in the clinical study report for the 
protocol.  
Laboratory parameters and their changes from baseline will be summarized using descriptive 
statistics by visit. Laboratory parameters that are graded in NCI-CTCAE Version 5.0 will be 
summarized by shifts from baseline CTCAE grades to worst post-baseline grades in both high 
and low directions. 


 
 
 
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A summary of patients with a change of 2 or more toxicity grade compared to baseline and 
patients with postbaseline toxicity grade of 3 or more in both high and low directions will be 
provided for laboratory parameters of interest. Listings of selected laboratory parameters will be 
provided. 
Table 2: Laboratory parameters of interest (including but not limited to) 
Hematology 
Serum Chemistry 
Coagulatio
n 
Serum 
Immunoglobuli
ns 
hemoglobi
n 
lymphocyt
es 
alanine 
aminotransfera
se 
albumin 
PT 
IgG 
neutrophil
s 
platelets 
alkaline 
phosphatase 
aspartate 
aminotransfera
se 
aPTT 
IgM 
white 
blood cells 
Hematocrit 
calcium 
creatinine 
 
IgA 
Red Blood 
Cell  
Basophils 
glucose 
potassium 
 
 
Monocyte
s 
Eosinophil
s 
sodium 
total bilirubin 
 
 
 
 
uric acid 
lactate 
dehydrogenase 
 
 
6.4.4. Vital Signs 
Vital sign parameters, including systolic and diastolic blood pressure, pulse rate, temperature, 
and weight, and their change from baseline will be summarized using descriptive statistics by 
visit. Patient data listings of vital signs will be provided. 


 
 
 
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6.4.5. ECOG performance status 
A shift table from baseline to worst post-baseline in eastern cooperative oncology group 
performance score will be summarized. Eastern cooperative oncology group status will be 
summarized by visit. 
 
6.4.6. Electrocardiograms 
Actual value and change from baseline for the electrocardiogram parameters (including heart 
rate, QT interval and QTcF interval) will be summarized. If triplicate readings are recorded, the 
average of the readings for the visit will be used for the summary. 
The number and percentage of patients satisfying the following QTcF conditions at any time 
postbaseline will be summarized: 
 
> 480 and ≤ 500, or > 500 msec 
 
≤ 30 msec maximum increase from baseline, > 30 and ≤ 60 msec maximum 
increase from baseline, or > 60 msec maximum increase from baseline 
Patient data listings of electrocardiogram will be provided. 
 
6.5. Efficacy Analyses 
The efficacy analysis will be performed on the efficacy analysis set of cohorts at each dose level 
in Part 1, the cohort in Part 2, and the pooling of cohorts at RP2D in Part 1 and Part 2 separately 
unless otherwise specified in this section. 
6.5.1. Hypothesis Test 
No hypothesis testing will be performed for Part 1. 
For Part 2, the ORR with the combination therapy is estimated as 55% in the overall R/R 
DLBCL population, which is deemed a clinical meaningful improvement. Simon's two-stage 
design (Simon, 1989) is based on the following hypothesis testing problem  
H0: ORR = 25%      vs.      Ha: ORR ≥25% 
in the efficacy analysis set of the cohort in Part 2. If the obtained one-sided p-value is less than 
0.025, it will be concluded that the combination therapy statistically significantly increases ORR 
compared to the historical control.  


 
 
 
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As stated in Section 2.2, if no more than 4 responses are observed within the first 18 patients in 
Part 2, the study will be stopped.  
6.5.2. Efficacy Analysis for Response Rates 
The response rates of interest are calculated as follows. 
ORR = Number of patients whose BORs are PR or CR/
 Number of patinets in the efficacy analysis set . 
 CRR = Number of patients whose BORs are CR/
Number of patinets in the efficacy analysis set . 
ORR will be directly estimated by the proportion of patients whose BORs are either PR or CR 
based on the Lugano classification (Cheson, et al., 2014). CRR will be estimated in a similar way 
by replace the patients whose BORs are either PR or CR by those whose BORs are CR. The 
precision of the estimators will be assessed by two-sides Clopper-Pearson 95% confidence 
intervals (CI).  
For analysis of disease response, BOR will be summarized as a categorical variable (CR, PR, 
stable disease, PD, not evaluable and not accessed), while study follow-up time as a continuous 
variable using descriptive statistics. Furthermore, ORR and CRR and their 95% CIs will also be 
presented in the table. A listing of BOR will be provided. 
Same analysis will be performed on the efficacy evaluable analysis set for sensitivity analysis. 
6.5.3. Efficacy Analysis for Time to Event Endpoints 
PFS is defined as the time from the starting date of the combination 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 tumor assessment.  
Kaplan-Meier method will be used to estimate progression event-free curves and corresponding 
quantiles (including the median). A two-sided 95% CIs of median, if estimable, will be 
constructed with a generalized Brookmeyer and Crowley method. The PFS 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.  
The PFS censoring rule will follow FDA Guidance for Industry Clinical Study Endpoints for the 
Approval of Cancer Drugs and Biologics (2018) in Appendix A.  
TTR is defined as time from the starting date of combination therapy to the date the response 
criteria are first met and will be summarized among responders.  


 
 
 
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DOR 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. Patients who do not have disease 
progression will be censored at their last valid assessment.  
OS is defined as the time from the starting date of the combination 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.  
Time to event endpoints (DOR, TTR and OS) will be similarly analyzed using the Kaplan-Meier 
method as described above for PFS. The Kaplan-Meier estimates of TTR, DOR and OS will be 
plotted over time. 
6.5.4. Subgroup Analyses  
Overall response of patients in RP2Dwill be summarized descriptively in the specified 
subgroups: sex, age group (<60 vs ≥=60), disease stage, disease status (relapsed vs. refractory), 
ECOG-PS (0 vs. ≥1), number of prior lines of therapy (1, 2, >=3), , bulky disease (>7.5 cm), 
extra nodal site (<=1 vs >1). Within group values (rates or means/medians) will be presented in 
forest plots. 
6.6. Pharmacokinetic Analyses 
 
The following analysis plan provides the framework for the summarization of the PK data from 
study BGB-3111-110. The objective is to assess plasma zanubrutinib and lenalidomide PK 
profile in different parts. The PK analyses will be performed on PK analysis set. Plasma 
zanubrutinib and lenalidomide concentration time data will be summarized and displayed in both 
tabular and graphical form. Individual and mean plasma concentration versus time data will be 
tabulated and plotted by dose level. Additional PK analyses may be conducted if deemed 
necessary and will be described in a separate analysis plan. 
6.6.1. Calculation of Pharmacokinetic Parameters  
Actual dose and blood draw times will be used to calculate the PK parameters. Parameters will 
be listed individually and summarized by treatment and part using descriptive statistics. PK 
parameters will be estimated based on non-compartmental analysis methods and will be 
computed using Phoenix WinNonlin® Version 8.0. or higher.  
Calculation and presentation of PK parameters will be based on the Work Instruction: Best 
Practice Guidance: Non-Compartmental Pharmacokinetic Data Analysis for Clinical Studies. 
Version 1.0, Document Number VV-QDOC-13140. 


 
 
 
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The PK parameter estimates for a single dose (Cycle 1 Day 1) profile includes but is not limited 
to the following. 
Parameter 
(Units) 
Definition 
Method of Determination 
AUClast  
(ng*h/mL)  
Area under the concentration-time 
curve from time zero to time of last 
quantifiable concentration  
Calculated using the linear up/log down 
variant of the trapezoidal rule 
AUCt  
(ng*h/mL) 
Area under the concentration-time 
curve from time zero to time t (8 hour) 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
AUCinf  
(ng*h/mL) 
Area under the concentration-time 
curve from time zero to infinite time 
with extrapolation of the terminal phase 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
Cmax  
(ng/mL) 
Maximum observed concentration  
Reported value 
Tmax (h) 
Time of the maximum observed 
concentration  
Actual elapsed time for observed Cmax 
Tlast (h) 
Time of the last quantifiable 
concentration 
Actual elapsed time for observed the last 
quantifiable concentration 
t1/2 (h) 
Apparent terminal elimination half-life  
ln(2)/λz, where λz is the first-order rate 
constant of drug associated with the 
terminal portion of the curve 
CL/F (L/h) 
Apparent drug clearance 
Calculated as Dose/(AUCinf*F), where F is 
the fraction of dose absorbed 
Vz/F (L) 
Apparent volume 
Calculated as CL/F/λz, where λz is the first-
order rate constant of drug associated with 
the terminal portion of the curve 
%AUCextrap 
(%) 
 
Percentage of AUC due to extrapolation 
from the last quantifiable concentration 
to infinity 
Calculated as (AUCinf-AUClast)/AUCinf*100 
The PK parameter estimates at steady state (Cycle 1 Day 21) included but not limited to the 
following. 
Parameter 
(Units) 
Definition 
Method of Determination 
AUClast  
(ng*h/mL)  
Area under the concentration-time 
curve from time zero to time of last 
quantifiable concentration  
Calculated using the linear up/log down 
variant of the trapezoidal rule 


 
 
 
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AUCt  
(ng*h/mL) 
Area under the concentration-time 
curve from time zero to time t (8 hour) 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
AUCtau 
(ng*h/mL) 
Area under the concentration-time 
curve during a dosing interval (tau) 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
Cmax (ng/mL) 
Maximum observed concentration 
Reported value 
Ctrough 
(ng/mL) 
Observed concentration at the end of 
dosing interval 
Reported value 
Tmax (h) 
Time of the maximum observed 
concentration  
Actual elapsed time for observed Cmax 
Tlast (h) 
Time of the last quantifiable 
concentration 
Actual elapsed time for observed the last 
quantifiable concentration 
t1/2 (h) 
Apparent terminal elimination half-life  
ln(2)/λz, where λz is the first-order rate 
constant of drug associated with the 
terminal portion of the curve 
CLss/F (L/h) 
Apparent drug clearance 
Calculated as Dose/(AUCtau*F), where F is 
the fraction of dose absorbed 
Vz/F (L) 
Apparent volume 
Calculated as CLss/F/λz, where λz is the 
first-order rate constant of drug associated 
with the terminal portion of the curve 
ARAUC 
Accumulation ratio of AUC 
AUCt on Day 21 of Cycle 1/AUCt on Day 
1 of Cycle 1 
ARCmax 
Accumulation ratio of Cmax 
Cmax on Day 21 of Cycle 1/Cmax on Day 1 
of Cycle 1 
The parameters Cmax, Tmax and Tlast will be obtained directly from the concentration-time profiles. 
If Cmax occurs at more than 1 timepoint, Tmax will be assigned to the first occurrence of Cmax. 
6.6.2. Reporting of Pharmacokinetic Concentrations for Descriptive Statistics 
The PK analyst will appropriately flag and annotate treatment of any anomalous concentrations, 
exclusions and any special treatment for descriptive statistics and plots. The concentration and 
time data of zanubrutinib and lenalidomide will be listed individually and summarized by part 
and dose level using descriptive statistics.  
The following conventions will be used for reporting descriptive statistics for concentration data.  
 
PK concentrations should be reported in listings at the same level of precision as that in the 
source data. 
 
If a concentration at a given time point is below the assay quantification limit (BLQ), the 
concentration shall be reported as the term “BLQ” with the lower limit of quantitation 
(LLOQ) defined in the footnotes. BLQ values shall be treated as zero for computation of 


 
 
 
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descriptive statistics. BLQ values will not be included for calculations of geometric mean 
and geometric coefficient of variation (CV%). 
 
If a concentration at a given time point is missing, it shall be reported as a missing value. If 
missing data are not identified in the bioanalytical source (i.e., the record is missing), the 
reporting convention of “NS" shall be utilized. 
 
If the calculated mean concentration is BLQ, the mean value shall be reported in outputs 
(such as tables) as BLQ and SD and geometric CV% shall be reported as ND (not 
determined). Minimum, median, and maximum may be reported. 
6.6.3. Plots of Pharmacokinetic Plasma Concentrations  
For zanubrutinib and lenalidomide, plasma concentration versus time data will be plotted 
individually and summarized graphically using arithmetic mean (±SD) plots by treatment group, 
respectively. Arithmetic mean concentrations that are BLQ shall be set to zero for plotting on 
linear scale but not shown on log-linear scale.  
 
6.6.4. Reporting of PK Parameters for Descriptive Statistics 
The PK analyst will appropriately flag and annotate treatment of any anomalous PK parameters, 
exclusions and any special treatment for descriptive statistics. 
 
All the PK parameters except tmax and t1/2 should have at least the following summary 
statistics: sample size (n), mean, standard deviation (SD), coefficient of variance (CV%), 
median, minimum, maximum, geometric mean, geometric CV%. 
 
For in-text tables, geometric mean (geometric CV%) will be the default method of reporting 
PK parameters. tmax should be presented as median, range (minimum, maximum), when 
presenting the summary statistics. t1/2 should be presented as geometric mean, range 
(minimum, maximum). 
 
For any parameters that n ≤ 2, SD should not be presented. 
 
The units for all PK parameters will be provided. 
 
It is recognized that the number of decimals in reported concentrations, for example: 
“9632.94401 ng/mL” or “9.963294401 ug/mL" are highly improbable and will be queried 
(since bioanalytical assays generally do not have this level of precision). Usually the first-in-
human dose escalation trial will provide the numerical range of PK parameters e.g. AUC 
range from 10 to 10,000 ng.hr/mL and Cmax range from 1 to 1000 ng/mL. 
 
In this scenario, for reporting PK parameters such as AUC and Cmax, the following guidance 
is provided for rounding: 
- If the numerical value is below 100 then one decimal place may be used e.g. 0.1 or 99.9. 
- For values ranging from >100, whole numbers should be used e.g. 100 or 9999. 


 
 
 
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- If > 10,000 the clinical pharmacologist may decide on changing units e.g. from ng/ml to μg 
/ml. 
- For reporting times e.g. for tmax or t1/2, if <1 hour use 2 decimals; time up to 24 hour should 
be reported to one decimal place e.g. 23.5 hour, time >24 hour should be rounded to nearest 
whole number e.g. 105 hr. 
6.6.5. Accumulation Ratio Analysis 
Accumulation ratio is defined as the ratio of plasma exposure (AUC, Cmax) at steady state (Day 
21) to the plasma exposure after the first dose (Day 1) of lenalidomide. Accumulation ratio can be 
presented in the subject level by 
Plasma Exposure𝐷𝑎𝑦 21
Plasma Exposure𝐷𝑎𝑦 1
 
Accumulation ratio for lenalidomide of Cmax and AUCt may be assessed using linear mixed 
effects models, including dose, day, and dose-day interaction as the fixed effect and a subject-
level random effect.  
log(PK parameter) = β0 + β1 × dose + β2 × day + β3 × dose ∗day + β4 × subject + ε 
where subject is a subject-level random effect. The categorical variable, day, distinguishes daily 
plasma exposure on day 1 and plasma exposure on Day 21. 
For each dose, the estimate of accumulation ratio will be obtained by applying an exponential 
function on the difference of least square (LS) means of log(PKDay 21) and log(PKDay 1). 
Similarly, a 95% CI for the accumulation ratio will be obtained by applying the exponential 
function on the 95% CI for the mean of log(PKDay 21) - log(PKDay 1). Provided below is the 
pseudo SAS code for running the model: 
proc mixed data= pkdata; 
    class dose day (ref=day1) subject; 
model logpk = dose day dose*day / solution; 
random subject; 
lsmeans dose*day/slice=dose diff cl; 
ods output lsmeans=lsmeans diffs=diffs;; 
run; 
 


 
 
 
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6.7. Biomarker Analyses 
Biomarker analysis will be performed on the biomarker analysis sets of cohorts at each dose 
level in Part 1, the cohort in Part 2, and the pooling of cohorts at RP2D in Part 1 and Part 2 
separately. 
6.7.1. Predictive Biomarkers 
Clinical outcomes (ORR, CRR, PFS, TTR, OS or DOR) will be analyzed in subgroups 
identified by these biomarker subtypes (ie, GCB and non-GCB classified by IHC, and GCB and 
ABC by GEP) using the same methods described in Section 6.5. 
 
A supportive analysis is based on patients with a valid subtype classification measurement, 
irrespective of the availability of post-treatment disease assessments. In this analysis, those 
without post-treatment disease assessments will be imputed with the worst outcome in tumor 
response. Similar analyses described above will also be used. 
Other statistical models (ie, logistic model for ORR, or Cox proportional hazards model for time 
to event endpoints) may be fitted with biomarker subtype index as covariate to explore its 
correlation with the clinical outcomes. 
Exploratory analyses of other predictive biomarkers or clinical/genetic risk factors such as Ki67, 
Epstein-Barr virus infection status, MYC/BCL2/BCL6 rearrangement status, genomic alteration 
status, tumor infiltrating lymphocytes levels, International Prognostic Index, etc. will be 
conducted similarly if data is available. 
6.7.2. Other Biomarkers 
For patients with paired tumor biopsies or blood, correlation between changes in the tumor 
tissues or peripheral blood, including but not limited to BTK pathway gene expression, tumor 
infiltrating lymphocytes levels, RNA expression and DNA mutational profiling, immune cell and 
cytokine profiling, ctDNA levels, and tumor response will be analyzed to identify potential 
pharmacodynamics and monitoring biomarkers.  
When deemed necessary, correlation analyses described for the predictive biomarkers will also 
be performed for these pharmacodynamic and monitoring biomarkers vs. clinical outcomes 
(ORR, CRR, PFS, TTR and DOR). These biomarkers may be treated as continuous and/or 
categorical variables (if suitable threshold can be identified) in these analyses. 
Tumor biopsy and blood samples taken at PD or response during the study will be used to 
identify potential resistance biomarkers and mechanisms. Similar analyses described for above 


 
 
 
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monitoring biomarker will also be performed for these resistance biomarkers, by replacing the 
efficacy endpoint of the response status with progression status. 
 
7. INTERIM ANALYSIS 
The interim analysis will be built based on the Simon’s two-stage design for the cohort in Part 2; 
see Section 6.5.1 for details.  
 
8. CHANGES IN THE PLANNED ANALYSIS 
Not applicable. 
 
9. REFERENCES 
Brookmeyer, R., & Crowley, J. (1982). A confidence interval for the median survival time. 
Biometrics(38), 29-41. 
Cheson, B. D., Richard, F. I., Sally, B. F., Franco, C., Lawrence, S. H., Emanuele, Z., & Lister, 
A. T. (2014). Recommendations for initial evaluation, staging, and response assessment 
of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical 
Oncology, 32, 3059-3067. 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research. (2018). FDA Guidance for Industry Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics.  
Greenwood, M. (1926). The natural duration of cancer. Public health and medical patients, 33, 
1-26. 
Schemper, M., & Smith, T. L. (1996). A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials, 17(4), 343-346. 
Simon, R. (1989). Optimal Two-stage Design for Phase II Clinical Trials. Controlled Clinical 
Trials, 10, 1-10. 


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10. APPENDIX A: HANDELING OF CENSORING TIME TO EVENT DATA 
The censoring rule for PFS will follow FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (Food and Drug Administration Center for Drug Evaluation Research CDER and Center for Biologics Evaluation and 
Research, 2018); see the following table. And this censoring rule will also apply to the other time to event data (DOR). 
Table 4: Censoring rules for PFS 
 
No. 
Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline and/or post-baseline disease 
assessment 
Date of treatment initiation 
Censored 
2 
Progression documented on scheduled visit or 
between scheduled visit 
Date of first disease assessment showing with documented 
PD 
Progressed 
3 
Alive without documented PD at the time of data 
cut-off or withdrawal from the study (including 
lost-to-follow-up without PD) 
Date of last disease assessment 
Censored 
4 
New anticancer treatment started before 
documented PD or death 
Date of last disease assessment prior to or on date of new 
anticancer treatment 
Censored 
5 
Death before first disease assessment 
Date of death 
Progressed 
6 
Death or progression after more than one missed 
scheduled disease assessment 
Date of last disease assessment without documented PD 
before missed disease assessment 
Censored