Conditions: Relapsed/Refractory Follicular Non-Hodgkin Lymphoma
Keywords: Relapsed/Refractory Follicular non-Hodgkin Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 217
Healthy volunteers: no

Brief summary:
he purpose of the study is to evaluate the efficacy, safety, and tolerability BGB-3111 plus obinutuzumab versus obinutuzumab alone in participants with relapsed/refractory non-Hodgkin follicular lymphoma.

Detailed description:

Arms:
arm 1: Obinutuzumab 1000 milligrams (mg) intravenously on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2 to 6; and then every 8 weeks until unacceptable toxicity, withdrawal of consent, loss of clinical benefit, or disease progression; each cycle is 28 days arm 2: Zanubrutinib 160 mg twice a day orally with or without food; Obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2 to 6; and then every 8 weeks until unacceptable toxicity, withdrawal of consent, loss of clinical benefit, or disease progression; each cycle is 28 days

Interventions: intervention 1: Zanubrutinib intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: Oral administration as a capsule intervention 2: Intravenous administration

Protocol document:
Prot_000.pdf: 
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CLINICAL RESEARCH PROTOCOL 
 
 
Protocol Title:  
An International, Phase 2, Open-Label, Randomized Study of 
BGB-3111 Combined with Obinutuzumab Compared With 
Obinutuzumab Monotherapy in Relapsed/Refractory 
Follicular Lymphoma 
Protocol Identifier: 
BGB-3111-212 
Phase: 
2 
Investigational Product: 
Zanubrutinib (BGB-3111) 
Indication: 
Follicular Lymphoma 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA 94403 USA 
Reference Numbers: 
United States IND 125326 
EudraCT 2017-001552-54 
Sponsor Medical Monitor 
 
Telephone: 
 
Email: 
 
Original Protocol: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 3.0:  
Amendment 4.0: 
07 June 2017 
22 December 2017 
04 February 2019 
30 June 2019 
18 August 2021 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.  
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from the Sponsor. 
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SYNOPSIS 
Name of Sponsor/Company:  BeiGene, Ltd. 
Investigational Product:  zanubrutinib (BGB-3111) 
Title of Study:  An International, Phase 2, Open-Label, Randomized Study of BGB-3111 Combined 
with Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular 
Lymphoma 
Protocol Identifier:  BGB-3111-212 
Phase of Development:  2 
Number of Patients:  Approximately 210 
Study Centers:  Approximately 100 sites  
Study Objectives: 
All primary and secondary objectives will compare zanubrutinib (BGB-3111) plus obinutuzumab 
versus obinutuzumab monotherapy. 
Primary: 
• 
To evaluate efficacy, as measured by overall response rate determined by independent central 
review 
Secondary: 
• 
To evaluate efficacy, as measured by the following: 
o Overall response rate determined by investigator assessment 
o Duration of response determined by independent central review and by investigator 
assessment 
o Progression-free survival determined by independent central review and by 
investigator assessment 
o Overall survival 
o Rate of complete response or complete metabolic response determined by independent 
central review and by investigator assessment 
o Time to response determined by independent central review and by investigator 
assessment 
o Patient-reported outcomes 
• 
Safety and tolerability 
• 
Pharmacokinetics (zanubrutinib plus obinutuzumab arm only) 
Exploratory: 
• 
Overall response rate in obinutuzumab arm after crossover to receive zanubrutinib plus 
obinutuzumab 
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Study Design: 
This is an international (approximately 100 sites), phase 2, open-label, randomized, active-control 
study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in 210 patients with 
relapsed or refractory follicular lymphoma.  The primary efficacy endpoint is overall response rate 
(ORR) determined by independent central review.  Disease response will be assessed per the Lugano 
Classification for Non-Hodgkin Lymphoma (NHL) (Cheson et al, 2014) — hereafter referred to as 
Lugano Classification for NHL. 
Central randomization (2:1) will be used to assign patients to one of the following study drug 
treatments: 
Arm A: zanubrutinib plus obinutuzumab 
Arm B: obinutuzumab monotherapy 
Randomization will be stratified by the number of prior lines of therapy (2 to 3 versus ˃ 3), 
rituximab-refractory status (yes vs no), and geographic region (China vs ex-China).  Treatment with 
zanubrutinib plus obinutuzumab and treatment with obinutuzumab monotherapy will be open label.  
Study treatment must commence within 5 days after randomization.   
Study Schema 
Abbreviation: NHL, non-Hodgkin lymphoma. 
a Randomization stratified by the number of prior lines of therapy (2 to 3 vs > 3), rituximab-refractory status (yes 
vs no), and geographic region (China vs ex-China). 
b Option for addition of zanubrutinib following independent central confirmation of disease response status. 
Each cycle consists of 28 days.  Study drug treatments will be administered as follows, depending on 
cohort and treatment assignment: 
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a day) 
with or without food. 
Obinutuzumab will be administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, then 
1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 mg every 8 weeks.  (At the discretion of the 
investigator, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 
instead of 1,000 mg on Day 1 of Cycle 1.)  Responding patients may continue to receive maintenance 
obinutuzumab every 8 weeks for an additional 24 months (eg, maximum total duration of 
obinutuzumab of approximately 30 months [maximum 20 doses]). 
At the discretion of the investigator, patients in arm B will be eligible to receive crossover treatment 
with zanubrutinib plus obinutuzumab if they experience progressive disease or their disease does not 
respond to therapy with a complete response (CR) or partial response (PR) after 12 months.  This must 
be confirmed by independent central review.  For patients who initiate crossover treatment with 
zanubrutinib plus obinutuzumab, safety, laboratory, and response evaluation assessments will continue 
to be performed per the Schedule of Assessments. 
 
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Study Assessments 
Assessments of follicular lymphoma status during the study include: disease-related constitutional 
symptoms, physical examination of lymph nodes, liver, and spleen, complete blood count (CBC), bone 
marrow examination, positron emission tomography (PET)/computed tomography (CT) scan with 
contrast of neck, chest, abdomen, and pelvis, patient-reported outcomes (PROs; EQ-5D-5L and 
EORTC QLQ-C30 questionnaires).  
Tumor assessments, including imaging studies, will be performed at screening, every 12 weeks from 
Cycle 1 Day 1 for 24 months, then every 24 weeks for 24 months, and then yearly until disease 
progression.  All known sites of disease must be documented at screening and reassessed at each 
subsequent tumor evaluation. All patients must undergo PET-CT scan during screening.  Patients 
whose disease is not [18F]fluorodeoxyglucose (FDG)-avid at screening will be followed by CT-based 
assessments alone.  Patients whose disease is FDG-avid at screening will be followed by an integration 
of PET-CT and CT-based assessments as follows:   
• 
PET-CT scans are required at screening, end of Cycles 3, 6, and 12, and to confirm a result on CT 
scan (CR/PR or disease progression)  
• 
CT scans with contrast are required at all other tumor response assessments 
Patients receiving zanubrutinib should remain on study treatment until disease progression is confirmed 
by independent central review.  Patients receiving obinutuzumab should remain on study treatment 
until either disease progression is confirmed by independent central review or approximately 
30 months of treatment with obinutuzumab (maximum 20 doses), whichever occurs first.  
Assessments of safety will include adverse events (AEs), serious adverse events (SAEs), clinical 
laboratory tests, physical examinations, and vital signs.  AEs will be graded for severity per National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).  An independent 
data monitoring committee (DMC) will periodically monitor safety data. 
Key Eligibility Criteria: 
The patients to be included in this trial will have a histologically confirmed diagnosis of B-cell 
follicular lymphoma (Grade 1, 2 or 3a) based on the World Health Organization (WHO) 2008 
classification of tumors of hematopoietic and lymphoid tissue, the presence of measurable disease, and 
archival tissue available confirming diagnosis of B-cell follicular lymphoma.  Patients must have 
received ≥ 2 prior systemic treatments for follicular lymphoma (including an anti-CD20 antibody and 
an appropriate alkylator-based combination therapy).  Patients will have no currently active clinically 
significant cardiovascular disease, and no active infection with hepatitis B or C or HIV. 
Test Product, Dose, and Mode of Administration:   
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a day) 
with or without food.  Patients will take zanubrutinib with water at approximately the same time every 
day, with a minimum of 8 hours between consecutive doses.  Zanubrutinib capsules should not be 
opened, broken, or chewed at any time. 
Reference Therapy, Dose, and Mode of Administration:   
Obinutuzumab will be administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, then 
1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 mg every 8 weeks.  (At the discretion of the 
investigator, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 
instead of 1,000 mg on Day 1 of Cycle 1.)  Responding patients may continue to receive maintenance 
obinutuzumab every 8 weeks for an additional 24 months (eg, maximum total duration of 
obinutuzumab of approximately 30 months [maximum 20 doses]). 
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Obinutuzumab should be administered at a rate of 50 mg/hr.  The rate of the infusion can be escalated 
in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.  If no infusion reaction occurs 
during the Cycle 1 Day 1 infusion and the final infusion rate was 100 mg/hr or faster, infusions can be 
started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum 
of 400 mg/hr for all subsequent doses.  Patients should be premedicated with acetaminophen, 
antihistamine, and a glucocorticoid before each obinutuzumab infusion. 
Statistical Methods: 
All efficacy analyses will be performed using the Intent-to-Treat (ITT) analysis set (all patients who are 
randomized to a treatment group). 
Primary Efficacy Endpoint Analysis: 
Primary inference of comparing overall response rate by independent central review will be based on a 
Cochran-Mantel-Haenszel test adjusted for the randomization factors (number of prior lines of therapy 
[2 to 3 vs > 3] and rituximab-refractory status [yes vs no]) in the ITT analysis set. 
The null and alternative hypotheses for comparing overall response rate are as follows: 
 
H0: ORRA = ORRB 
 
Ha: ORRA > ORRB 
where ORRA is the overall response rate in arm A (zanubrutinib plus obinutuzumab) and ORRB is the 
overall response rate in arm B (obinutuzumab monotherapy).  If the obtained one-sided p-value is 
≤ 0.025, it will be concluded that the combination therapy of zanubrutinib plus obinutuzumab results in 
a statistically significantly increase in overall response rate versus obinutuzumab monotherapy; thereby 
demonstrating the superiority of arm A over arm B.  
Secondary Efficacy Endpoint Analyses: 
• 
Duration of response will be summarized only for patients who have achieved an objective 
response.  The distribution of duration of response will be summarized for each treatment 
group by the Kaplan-Meier method. 
• 
Progression-free survival (PFS) will be compared based on the log-rank test stratified by the 
randomization stratification factors (number of prior lines of therapy [2 to 3 vs > 3], rituximab 
refractory status [yes vs no], and geographic region [China vs ex-China]).  The distribution of 
progression-free survival, including median progression-free survival and progression-free 
survival rate at selected timepoints, will be estimated using the Kaplan-Meier method for each 
arm. 
• 
Overall survival between the 2 treatment groups will be compared using the same methods 
employed for the PFS comparison.  The distribution of overall survival (including median and 
other quartiles) and overall survival rate at selected timepoints will be estimated by the 
Kaplan-Meier method 
• 
Complete response rate and complete metabolic response rate will be calculated as the 
proportion of patients who reached best overall response of complete response (complete 
metabolic response) or higher.  The complete response and complete metabolic response rate 
will be compared between treatment groups using Fisher’s exact test. 
• 
Time-to-response will be summarized only for responders by sample mean, median and 
standard deviation for each treatment group. 
• 
The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be utilized.  The scores and their 
changes from baseline will be summarized and compared between two treatment groups  
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Exploratory Efficacy Endpoint Analysis: 
• 
Overall response rate in arm B after crossover to arm A will be summarized descriptively. 
Safety Analyses: 
The Safety analysis set (all patients who received any dose of study medication) will be used for all 
safety analyses.  
Drug exposure will be summarized by treatment group and study medication including duration, 
dosage, and dose intensity.   
All treatment-emergent AEs will be summarized.  SAEs, deaths, treatment-emergent AEs ≥ Grade 3, 
study drug-related treatment-emergent AEs, treatment-emergent AEs that led to treatment 
discontinuation, dose reduction or dose interruption will be summarized. 
Pharmacokinetic Analyses: 
Blood samples to assess plasma zanubrutinib concentrations will be collected in patients in arm A. 
Plasma zanubrutinib concentrations will be summarized by scheduled time of collection.  A population 
pharmacokinetics (PK) analysis may be performed to include plasma concentrations of zanubrutinib 
from this trial in an existing model.  PK parameters such as apparent clearance of the drug from plasma 
and AUC0-12 may be derived from the population PK analysis if supported by data. 
An exposure-response (efficacy or safety endpoints) analysis may be performed if supported by data.  
The results from the population PK and exposure-response analyses may be reported separately from 
the Clinical Study Report. 
Sample Size Considerations: 
The sample size calculation is based on the comparison of the primary endpoint of ORR in the ITT 
analysis set.  Assuming ORRA=0.55 and ORRB=0.30, 210 patients will be enrolled in a 2:1 ratio 
(140 patients in arm A and 70 patients in arm B) to provide a power of approximately 91% in testing 
ORRA versus ORRB using a normal approximation to binomial distribution with a 2-sided significance 
level of 0.05 with continuity correction.  The sample size calculation is based on methods in  
Hulley et al, 2013 and Fleiss et al, 1980. 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
LIST OF ABBREVIATIONS AND TERMS ................................................................................14 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Follicular Lymphoma .................................................................................................16 
1.2. 
Inhibition of Bruton Tyrosine Kinase in Follicular Lymphoma .................................17 
1.3. 
Zanubrutinib (BGB-3111) ..........................................................................................17 
1.3.1. 
Summary of Relevant Nonclinical Data with Zanubrutinib .......................................17 
1.3.2. 
Summary of Relevant Clinical Experience with Zanubrutinib ...................................18 
1.3.2.1. 
Dose Selection for Zanubrutinib .................................................................................18 
1.3.2.2. 
Preliminary Efficacy and Safety Data with Zanubrutinib ..........................................19 
1.3.2.3. 
Safety Pharmacology ..................................................................................................20 
1.3.2.4. 
Clinical Pharmacology ................................................................................................21 
1.4. 
Benefit-Risk Assessment ............................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................23 
3. 
STUDY DESIGN .......................................................................................................24 
3.1. 
Summary of Study Design ..........................................................................................24 
3.2. 
Study Schema .............................................................................................................26 
3.3. 
Blinding ......................................................................................................................26 
3.4. 
Duration of Study .......................................................................................................26 
3.5. 
Discussion of Study Design, Including Choice of Control Group .............................26 
4. 
SELECTION OF STUDY POPULATION ................................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................31 
5. 
ENROLLMENT AND STUDY PROCEDURES ......................................................33 
5.1. 
Enrollment and Randomization ..................................................................................33 
5.2. 
Electrocardiogram .......................................................................................................34 
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5.3. 
Zanubrutinib Dispensation ..........................................................................................35 
5.4. 
Pharmacokinetics ........................................................................................................35 
5.5. 
Safety Assessments .....................................................................................................35 
5.6. 
Efficacy Assessments .................................................................................................36 
5.7. 
Patient-Reported Outcomes ........................................................................................38 
5.8. 
Laboratory Assessments .............................................................................................38 
5.9. 
Unscheduled Visits .....................................................................................................41 
5.10. 
Arm B “Crossover” Treatment Adding Zanubrutinib ................................................41 
5.11. 
End of Treatment Period .............................................................................................42 
5.12. 
Safety Follow-Up ........................................................................................................42 
5.13. 
Long-Term Follow-Up ...............................................................................................43 
5.14. 
End of Study ...............................................................................................................43 
5.15. 
Lost to Follow-Up.......................................................................................................43 
6. 
STUDY TREATMENT ..............................................................................................44 
6.1. 
Study Treatment Preparation and Dispensation .........................................................44 
6.1.1. 
Packaging and Labeling ..............................................................................................44 
6.1.2. 
Handling and Storage .................................................................................................44 
6.1.3. 
Compliance and Accountability .................................................................................44 
6.1.4. 
Disposal and Destruction ............................................................................................45 
6.2. 
Dosage and Administration ........................................................................................45 
6.2.1. 
Zanubrutinib ...............................................................................................................45 
6.2.2. 
Obinutuzumab .............................................................................................................45 
6.3. 
Overdose .....................................................................................................................46 
6.4. 
Precautions ..................................................................................................................46 
6.4.1. 
Surgery and Procedures ..............................................................................................46 
6.5. 
Dose Interruption and Modification ...........................................................................46 
6.5.1. 
Zanubrutinib Dose Reductions for Hematologic Toxicity .........................................47 
6.5.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity ...................................47 
6.5.3. 
Dose Interruptions and Modifications for Obinutuzumab ..........................................47 
7. 
PRIOR AND CONCOMITANT THERAPY .............................................................49 
7.1. 
Prior Therapy ..............................................................................................................49 
7.2. 
Concomitant Therapy .................................................................................................49 
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7.2.1. 
Permitted Medications ................................................................................................49 
7.2.2. 
Prohibited Medications ...............................................................................................50 
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................50 
7.3.1. 
CYP-Inhibiting/Inducing Drugs .................................................................................50 
8. 
SAFETY MONITORING AND REPORTING .........................................................51 
8.1. 
Adverse Events ...........................................................................................................51 
8.1.1. 
Definitions and Reporting ...........................................................................................51 
8.1.1.1. 
Assessment of Severity ...............................................................................................51 
8.1.1.2. 
Assessment of Causality .............................................................................................52 
8.1.1.3. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................53 
8.1.2. 
Laboratory Test Abnormalities ...................................................................................53 
8.2. 
Definition of a Serious Adverse Event .......................................................................53 
8.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................54 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................54 
8.4.1. 
Adverse Event Reporting Period ................................................................................54 
8.4.2. 
Reporting Serious Adverse Events .............................................................................55 
8.4.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................55 
8.4.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................55 
8.4.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................56 
8.4.3. 
Eliciting Adverse Events ............................................................................................56 
8.4.4. 
Disease Progression ....................................................................................................56 
8.4.5. 
Deaths .........................................................................................................................57 
8.4.6. 
Pregnancies .................................................................................................................57 
8.5. 
Post-Study Adverse Event ..........................................................................................57 
8.6. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards and Ethics Committees ......................................................................57 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................58 
9.1. 
Study Endpoints ..........................................................................................................58 
9.1.1. 
Primary Endpoint ........................................................................................................58 
9.1.2. 
Secondary Endpoints ..................................................................................................58 
9.1.3. 
Exploratory Endpoint ..................................................................................................59 
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9.2. 
Statistical Analysis ......................................................................................................59 
9.2.1. 
Randomization Methods .............................................................................................59 
9.2.2. 
Analysis Sets ...............................................................................................................59 
9.2.3. 
Efficacy Analysis ........................................................................................................59 
9.2.3.1. 
Primary Efficacy Endpoint Analysis ..........................................................................59 
9.2.3.2. 
Secondary Efficacy Endpoint Analyses ......................................................................60 
9.2.3.3. 
Exploratory Efficacy Endpoint Analysis ....................................................................61 
9.2.3.4. 
Sensitivity Analysis ....................................................................................................61 
9.2.4. 
Pharmacokinetic Analyses ..........................................................................................61 
9.3. 
Safety Analyses ..........................................................................................................62 
9.3.1. 
Extent of Exposure .....................................................................................................62 
9.3.2. 
Adverse Events ...........................................................................................................62 
9.3.3. 
Laboratory Analyses ...................................................................................................63 
9.3.4. 
Vital Signs ..................................................................................................................63 
9.3.5. 
Electrocardiogram .......................................................................................................63 
9.3.6. 
Sample Size Considerations .......................................................................................63 
9.3.7. 
Interim Analysis ..........................................................................................................63 
9.3.8. 
Final Analysis .............................................................................................................63 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................64 
10.1. 
Steering Committee ....................................................................................................64 
10.2. 
Data Monitoring Committee .......................................................................................64 
10.3. 
Independent Central Review .......................................................................................64 
10.4. 
Provision of Study Results and Information to Investigators .....................................64 
11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ..........................65 
11.1. 
Regulatory Authority Approval ..................................................................................65 
11.2. 
Investigator Responsibilities .......................................................................................65 
11.2.1. 
Good Clinical Practice ................................................................................................65 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................65 
11.2.3. 
Informed Consent .......................................................................................................65 
11.2.4. 
Investigator Reporting Requirements .........................................................................66 
11.2.5. 
Confidentiality ............................................................................................................66 
11.2.6. 
Case Report Forms .....................................................................................................66 
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11.2.7. 
Drug Accountability ...................................................................................................67 
11.2.8. 
Inspections ..................................................................................................................67 
11.2.9. 
Protocol Adherence ....................................................................................................67 
11.3. 
Protocol Modifications ...............................................................................................67 
11.4. 
Study Report and Publications....................................................................................68 
11.5. 
Study and Study Center Closure .................................................................................68 
11.6. 
Records Retention and Study Files .............................................................................69 
11.7. 
Information Disclosure and Inventions ......................................................................70 
11.8. 
Joint Investigator/Sponsor Responsibilities ................................................................71 
11.8.1. 
Access to Information for Monitoring ........................................................................71 
11.8.2. 
Access to Information for Auditing or Inspections ....................................................71 
12. 
REFERENCES ...........................................................................................................72 
APPENDIX 1. SIGNATURE OF INVESTIGATOR .................................................................75 
APPENDIX 2. MODIFIED LUGANO CLASSIFICATION FOR NHL ...................................76 
APPENDIX 3. DIAGRAM FOR NODAL AREAS IN FLIPI SCORE .....................................80 
APPENDIX 4. NEW YORK HEART ASSOCIATION CLASSIFICATION ...........................81 
APPENDIX 5. ECOG PERFORMANCE STATUS...................................................................82 
APPENDIX 6. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-LEVELS 
HEALTH QUESTIONNAIRE ...................................................................................83 
APPENDIX 7. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 ...................................................................................85 
APPENDIX 8. DOSE MODIFICATION FOR ZANUBRUTINIB WHEN CO-
ADMINISTERED WITH STRONG/MODERATE CYP3A INHIBITORS 
OR INDUCERS ..........................................................................................................87 
APPENDIX 9. SCHEDULE OF ASSESSMENTS ....................................................................88 
 
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LIST OF TABLES 
Table 1: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection (Detected Positive 
by PCR) ......................................................................................................................40 
Table 2: 
Zanubrutinib Dose Reduction Steps ...........................................................................46 
Table 3: 
Timeframe and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................55 
 
LIST OF FIGURES 
Figure 1. 
Study Schema .............................................................................................................26 
 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BGB-3111 
zanubrutinib 
BTK 
Bruton tyrosine kinase 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DMC 
data monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
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IRT  
Interactive Response Technology 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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1. 
INTRODUCTION 
1.1. 
Follicular Lymphoma 
Follicular lymphoma is well characterized by its clinical presentation (primarily lymph node 
enlargement), its morphologic characteristics (preservation of follicular lymph node architecture 
despite infiltration with malignant lymphocytes), and its molecular features (over 90% of cases 
are associated with a specific translocation between the immunoglobulin heavy chain gene on 
chromosome 14 and the bcl-2 oncogene on chromosome 18).  While there is considerable 
heterogeneity in the clinical course of follicular lymphoma, it is generally an indolent 
malignancy, with a prolonged but incurable clinical course.  A cross-European registry study 
published in 2015, calculated a median age at onset of 62 years and an annual incidence of 
5 cases per 100,000 population (Mounier et al 2015).  Of note, the incidence of follicular 
lymphoma appears to be increasing significantly, from an estimated incidence of 2 to 
3 cases/100,000 population in the 1950s. 
Follicular lymphoma is classified by grade and stage.  The World Health Organization (WHO) 
classification (Swerdlow et al 2008; Jaffe 2009) grades follicular lymphoma based on the 
number of blasts per high powered field, where Grade 1 is up to 5 blasts per high power field, 
and Grade 3b is more than 15, or a pure sheet of blasts.  Grade 3b is considered to have a course 
identical to diffuse large B-cell lymphoma (DLBCL).  The Ann Arbor staging system method is 
also used (National Comprehensive Cancer Network 2017; Dreyling et al 2017) to characterize 
follicular lymphoma by stage: stage I and II disease is considered localized, and may be suitable 
for local therapies such as involved field radiation therapy; whereas stage III and IV disease is 
considered widespread, and is managed with systemic therapies. 
With modern chemoimmunotherapy for follicular lymphoma, median survival exceeds 10 years, 
except for the approximately 20% of patients with short remission duration following initial 
chemoimmunotherapy (Casulo et al 2015).  In fact, over the past several decades, the 
incorporation of novel active agents into treatment practices for follicular lymphoma have 
resulted in a decline in lymphoma subtype-specific mortality trends (Howlader et al 2016).  Yet, 
follicular lymphoma remains incurable, and the clinical history is typically one of multiple 
relapses, with successive treatment regimens resulting in progressively shorter disease-control 
intervals, until the emergence of fatal, resistant disease.  In addition to the morbidity and 
mortality associated with treatment resistance, cumulative treatment-related toxicity (especially 
immunosuppression, myelosuppression, and secondary leukemia related to alkylator exposure), 
and transformation to DLBCL, remain significant contributors to mortality in patients with 
follicular lymphoma. 
Therapeutic strategies in follicular lymphoma have been transformed in recent decades by the 
introduction of anti-CD20 monoclonal antibodies, used alone or as part of chemoimmunotherapy 
regimens.  For patients with a high tumor burden, the progression-free survival (PFS) benefit of 
adding rituximab to cytotoxic chemotherapy has been clearly demonstrated in randomized trials 
(Hiddemann et al 2005; Herold et al 2007; Schulz et al 2007; Marcus et al 2016; Bachy et al 
2013).  The chemoimmunotherapy regimens, rituximab, cyclophosphamide, doxorubicin, and 
prednisolone; rituximab, cyclophosphamide, vincristine, and prednisolone; and bendamustine 
plus rituximab are all considered as treatment standards.  Rituximab maintenance after initial 
chemoimmunotherapy has also been shown in phase 3 studies to improve PFS, but not overall 
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survival (OS; Sehn et al 2016).  More recently, a phase 3 study has demonstrated that the second 
generation anti-CD20 antibody, obinutuzumab, plus chemotherapy, prolongs PFS as compared 
with rituximab plus chemotherapy (Marcus et al 2016), and thus obinutuzumab is likely to be 
added soon to expert guidelines as appropriate for initial therapy.  
The treatment options are limited for patients with disease that has relapsed after or is refractory 
to chemoimmunotherapy.  In the rituximab-refractory setting, obinutuzumab plus bendamustine 
prolongs PFS as compared with bendamustine alone (Sehn et al 2016).  Idelalisib, a 
phosphoinositol-3-kinase inhibitor approved by the United States Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) for follicular lymphoma under their 
respective, accelerated and conditional approval mechanisms in 2013, is considered an 
appropriate treatment option for patients who have received at least 2 prior systemic therapies 
(Zydelig Prescribing Information 2016; Zydelig Summary of Product Characteristics 2016).  
However, late-stage trials intended to confirm the clinical benefit of idelalisib in follicular 
lymphoma were terminated early because of an imbalance in infectious deaths in the idelalisib 
arms of these studies (Zydelig FDA Alerts 2016).  
1.2. 
Inhibition of Bruton Tyrosine Kinase in Follicular Lymphoma 
Inhibitors of Bruton tyrosine kinase (BTK) have been evaluated in follicular lymphoma and have 
shown modest single agent activity.  The first generation BTK inhibitor ibrutinib was evaluated 
in a phase 2 trial in 110 patients with “chemoimmunotherapy-resistant” follicular lymphoma, 
defined as having received at least 2 prior lines of therapy and demonstrated progressive disease 
within 12 months of a chemoimmunotherapy regimen.  In this study, the overall response rate 
(ORR) was 21% and the median duration of response was 19.4 months (Gopal et al 2016).   
1.3. 
Zanubrutinib (BGB-3111) 
Zanubrutinib, formerly designated as BGB-3111, is a potent, specific, and irreversible BTK 
inhibitor with a favorable pharmacologic and toxicologic 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. This 
may reduce toxicities possibly due to off-target inhibition such as diarrhea, 
thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue;  
2. Zanubrutinib has improved oral bioavailability;  
3. Zanubrutinib displays significantly less inhibitory effect on rituximab-induced 
antibody-dependent cell-mediated cytotoxicity, and so is unlikely to adversely impact the 
antitumor effects of rituximab. 
1.3.1. 
Summary of Relevant Nonclinical Data with Zanubrutinib 
Summaries of nonclinical studies are provided below.  For more detailed information please refer 
to the zanubrutinib Investigator 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 
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B-cell receptor aggregation-triggered BTK autophosphorylation, and blocks downstream PLCγ2 
signaling in mantle cell lymphoma cell lines.  Zanubrutinib had an IC50 of 1.8 nM in a 
homogeneous time-resolved fluorescence-based BTKpY223 assay.  It potently and selectively 
inhibited cellular growth of several mantle cell lymphoma cell lines (REC-1, Mino and JeKo-1) 
and the activated B-cell type 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 induces dose-dependent antitumor effects 
against REC-1 mantle cell lymphoma xenografts engrafted either subcutaneously or systemically 
in mice which are significantly more effective than ibrutinib.  Zanubrutinib also demonstrated 
better antitumor activity than ibrutinib in TMD-8 DLBCL subcutaneous xenograft model.  In a 
pharmacokinetic (PK)/pharmacodynamic 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.  
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 vs EGFR, 
FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC.  Cellular assays also confirmed that 
zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR 
(> 6-fold).  Inhibition of ITK has been reported to reduce rituximab-induced antibody-dependent 
cell-mediated cytotoxicity.  Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib 
in inhibiting rituximab-induced antibody-dependent cell-mediated cytotoxicity, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity 
than ibrutinib in both biochemical and cellular assays. 
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 QTc changes were noted in the conscious 
telemetry-implanted dogs over 24 hours after dosing up to 100 mg/kg, or in the repeat dose 
toxicity studies in dogs over 91 days at doses up to 100 mg/kg/day.  No mortality or severe 
toxicity was noted in 91-day repeat dose toxicity studies in both rats and dogs at doses up to 
300 mg/kg and 100 mg/kg, respectively.  Test article-related reversible histopathology changes 
were mainly noted in rats, including pancreas, spleen, prostate gland, cecum, colon, rectum, skin 
(lip and/or nose), and uterus.  None of the above findings were considered to be adverse in the 
91-day repeated dosing studies.  No genotoxicity was noted in the genotoxicity core battery 
studies. 
1.3.2. 
Summary of Relevant Clinical Experience with Zanubrutinib 
1.3.2.1. 
Dose Selection for Zanubrutinib 
In the first-in-human, phase 1 study, zanubrutinib -AU-003, the PK of zanubrutinib was linear 
between 40 mg and 320 mg once a day administered orally (BeiGene Investigator Brochure).  
The absorption of zanubrutinib is rapid with median time to maximum plasma concentration 
(Cmax) of 2 hours.  The terminal elimination half-life is approximately 4 hours at 320 mg once a 
day.  Results from a food-effect study showed that zanubrutinib exposure was not altered by 
high-fat breakfast, and mean area under the plasma concentration-time curve (AUC) and Cmax 
were increased by 12% and 51%, respectively with standard breakfast when compared with 
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fasting.  The magnitude of increase in exposure with food was well within doubling of exposure 
associated with 320 mg administered once a day in the ongoing phase 1, and was not associated 
with any new safety findings.  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 a day and 320 mg once a day (Tam et al 2015).  At the 160 mg twice a day dose, full BTK 
occupancy was observed at trough, suggesting that sustained target occupancy could be achieved 
in disease-originating tissues, thus more efficiently inhibiting BTK on a continuous basis, further 
preventing breakthrough signaling despite cycles of new BTK synthesis.  Activity has been 
observed across various B-cell malignancies (including chronic lymphocytic leukemia [CLL], 
mantle cell lymphoma, Waldenstrom 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 a day and 320 mg once a day dose; both 
schedules show a high level of activity without compromising the tolerability profile as 
compared with lower doses of zanubrutinib.  Therefore, the dose of 160 mg administered orally 
twice a day has been selected as the recommended phase 2 and phase 3 dose based on sustained 
target occupancy, high rates of objective response in multiple types of B-cell malignancies, and a 
favorable safety and tolerability profile. 
1.3.2.2. 
Preliminary Efficacy and Safety Data with Zanubrutinib 
There are two relevant studies of zanubrutinib that provide efficacy and safety data, the 
first-in-human study, BGB-3111-AU-003, and the combination study, BGB-3111-GA101-001. 
The BGB-3111-AU-003 study is an open-label, dose-escalation and dose-expansion study of 
zanubrutinib monotherapy that was initiated in Australia in August 2014.  The study consists of 
two parts.  In part 1, the primary objectives are to determine the safety and tolerability of 
zanubrutinib in patients with various B-cell malignancies (CLL/small lymphocytic lymphoma 
[SLL], non-Hodgkin lymphoma [NHL], and Waldenstrom macroglobulinemia [WM]) and 
determine the recommended phase 2 dose.  In part 2, the primary objective is to further assess 
the safety and tolerability of zanubrutinib in patients with B-cell malignancies, while a secondary 
objective is to assess the anti-tumor activity of zanubrutinib at the recommended phase 2 dose.   
In the BGB-3111-AU-003 CLL/SLL cohort, as of 03 October 2016, 46 patients were followed 
up for at least 12 weeks.  Zanubrutinib was well tolerated, with 65% of patients reporting no 
drug-related adverse events (AEs) > Grade 2 severity.  The most frequent AEs of any attribution 
were petechiae or purpura or contusion (combined events, 22 patients; 48%), upper respiratory 
tract infection (33%; all Grade 1 or 2), fatigue (28%; all Grade 1 or 2), diarrhea, cough, and 
headache (all 20%; all Grade 1 or 2).  There were 3 serious adverse events (SAEs) assessed as 
possibly related to zanubrutinib (Grade 2 cardiac failure, Grade 2 pleural effusion and Grade 3 
purpura).  After a median follow-up of 8.6 months (range, 2.2 to 20.9 months), the ORR was 
96% (44/46), with a partial response (PR) rate of 67% (31/46), partial response with 
lymphocytosis rate of 28% (13/46), and stable disease (SD) rate of 2% (1/46).  Of the 8 patients 
with measurable disease at baseline, their tumor volume (sum of product diameters) decreased 
from 60% to 100% with a median decrease of 86%.  No instances of disease progression or 
Richter’s transformation have occurred.   
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In the BGB-3111-AU-003 Waldenstrom macroglobulinemia cohort, as of 31 December 2016, 
46 patients were enrolled.  The most frequent AEs reported (all were Grade 1 or 2) were: upper 
respiratory infection (33%), contusion (28%), and constipation (22%).  There were 3 treatment-
related SAEs (Grade 2 atrial fibrillation, Grade 2 headaches, Grade 3 cryptococcal meningitis); 
in all 3 cases, zanubrutinib was withheld and safely resumed.  Three patients developed atrial 
fibrillation (one Grade 1, two Grade 2, all events in patients without a previous history of atrial 
fibrillation), and 1 patient reported Grade 3 diarrhea.  No serious hemorrhage was reported.  
Two patients have discontinued zanubrutinib for AEs, 1 with an exacerbation of pre-existing 
bronchiectasis and 1 with prostate cancer.  The ORR was 93% (38/41); with a major response 
rate of 78% (32/41), including very good partial response rate of 39% (16/41) and PR rate of 
39% (16/41).  In patients with hemoglobin < 10 g/dL at baseline, hemoglobin increased from a 
median of 8.8 g/dL to 13.8 g/dL and serum immunoglobulin M decreased from a median of 
32.5 g/L at baseline to 5.4 g/L.  Of the 16 patients with lymphadenopathy at baseline, the median 
decrease in lymphadenopathy (measured as median reduction in sum of product diameters) was 
38% (9% to 81%). 
The BGB-3111-GA101-001 study is an ongoing, open-label, multicenter, phase 1b study of the 
combination of zanubrutinib and obinutuzumab in patients with various B-cell malignancies.  As 
of 15 December 2016, 40 patients with CLL/SLL (17 patients with previously untreated disease; 
23 patients with relapsed/refractory disease), and 13 patients with relapsed or refractory 
follicular lymphoma were enrolled. The median follow-up time was 4.1 months for CLL/SLL 
and 6.2 months for follicular lymphoma.  Zanubrutinib plus obinutuzumab was well tolerated.  
No fatal AEs occurred; only 1 AE led to treatment discontinuation (squamous cell carcinoma in a 
patient with prior squamous cell carcinoma).  SAEs were reported in 25.0% of the patients with 
CLL/SLL and 23.1% of the patients with follicular lymphoma; there was only 1 SAE related to 
obinutuzumab (infusion-related reaction) and 1 SAE related to zanubrutinib (pneumonia). There 
were no AEs of atrial fibrillation.  Patients were evaluable for response if they had completed 
baseline and ≥ 1 on-treatment response assessment.  ORRs were 88.9% in previously untreated 
CLL/SLL, 86.7% in relapsed/refractory CLL/SLL, and 81.8% in relapsed/refractory follicular 
lymphoma, including 3 complete responses (CRs) in CLL/SLL and 5 CRs in follicular 
lymphoma.  Two patients experienced disease progression (1 with relapsed/refractory CLL, 1 
with relapsed/refractory follicular lymphoma); no instances of disease transformation occurred.  
For more detailed information on the clinical experience for zanubrutinib please refer to the 
Investigator Brochure (BeiGene Investigator Brochure). 
1.3.2.3. 
Safety Pharmacology 
The potential risk of zanubrutinib on QT interval prolongation was assessed using a battery of 
preclinical studies and a clinical thorough QT study (BGB-3111-106).  A GLP-compliant hERG 
assay was conducted.  Based on the clinical steady-state, unbound Cmax of 0.042 μM (total Cmax 
346 ng/mL; plasma protein binding 94.2%) observed at the recommended Phase 2 dose (RP2D) 
of 160 mg BID, there is more than a 200-fold exposure margin compared with the hERG IC50 of 
9.11 μM. 
No effects on blood pressure, heart rate, or electrocardiogram (ECG) findings, including QT and 
QTc intervals, were noted in telemetry-instrumented conscious dogs following single doses of 
zanubrutinib up to 100 mg/kg.  In addition, no abnormal changes in ECG or cardiovascular 
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function were noted in 28- and 91-day repeat-dose toxicity studies in dogs at doses up to 
100 mg/kg.  In these studies, the systemic exposure of zanubrutinib was 10-fold higher than that 
observed at the human therapeutic dose. 
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 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. 
1.3.2.4. 
Clinical Pharmacology 
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicate 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 Cmax, 
in healthy subjects.  Co-administration of zanubrutinib with the 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.  Administration of zanubrutinib with 
strong/moderate CYP3A inhibitors or CYP3A inducers (refer to Appendix 8 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 8.  The medical monitor 
should be consulted in these situations.   
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 effectiveness 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) must be used.  The coadministration of oral P-glycoprotein (P-gp) substrates with 
a narrow therapeutic index (eg, digoxin) should be used with caution as zanubrutinib may 
increase their concentrations. 
1.4. 
Benefit-Risk Assessment 
A pooled safety analysis of ongoing zanubrutinib clinical trials using a data cutoff of September 
2017 provides data for 641 subjects receiving zanubrutinib either as monotherapy or in 
combination with other agents following a mean exposure time of 7.7 months.  Historically, the 
class of BTK inhibitors has raised some safety concern, particularly regarding the potential for 
serious hemorrhage and cardiac rhythm disturbance with atrial fibrillation or flutter being the 
most common events.  The pooled analysis of zanubrutinib safety data shows atrial fibrillation 
was 1.7% and serious hemorrhage was 1.9%; both of these values are close to expected 
background rates.  Concomitant use of vitamin K antagonists was, and continues to be, allowed 
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in zanubrutinib trials.  No new safety or tolerability signals have been observed and there have 
been few instances of drug discontinuation for any adverse event (Tam et al 2017).   
The current randomized Phase 2 study is based on results from a global Phase 1b, open-label, 
multicenter study of the combination of zanubrutinib and obinutuzumab in patients with B-cell 
malignancies—specifically, CLL/SLL, WM, follicular lymphoma, mantle cell lymphoma, 
marginal zone lymphoma, and DLBCL.  The primary objectives in this study were to evaluate 
the safety and tolerability for the combination of zanubrutinib and obinutuzumab.  The first 
patient was dosed on 13 January 2016 and, as of the 16 September 2018 data cutoff, a total of 
119 patients had been treated on study.  Adverse events ≥ Grade 3, regardless of attribution by 
the investigator, included: neutropenia in 28 subjects (23.5%), fatigue in 1 (0.8%), 
thrombocytopenia in 9 (7.6%), pyrexia in 3 (2.5%), back pain in 3 (2.5%), constipation in 1 
(0.8%), pneumonia in 6 (5.0%) and urinary tract infection in 3 subjects (2.5%).  Seven subjects 
(5.9%) had an adverse event leading to treatment discontinuation.  No new safety signals or 
trends have been observed with the combination therapy of zanubrutinib and obinutuzumab. 
Given the safety summary profile for zanubrutinib, either as monotherapy or in combination with 
obinutuzumab, BeiGene believes that the benefit-risk balance remains favorable for research 
subjects. 
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2. 
STUDY OBJECTIVES 
All primary and secondary objectives will compare zanubrutinib plus obinutuzumab versus 
obinutuzumab monotherapy. 
Primary: 
• To evaluate efficacy, as measured by overall response rate determined by independent 
central review 
Secondary: 
• To evaluate efficacy, as measured by the following: 
− Overall response rate determined by investigator assessment 
− Duration of response determined by independent central review and by 
investigator assessment 
− Progression-free survival determined by independent central review and by 
investigator assessment 
− Overall survival 
− Rate of complete response or complete metabolic response determined by 
independent central review and by investigator assessment 
− Time to response determined by independent central review and by investigator 
assessment 
− Patient-reported outcomes 
• Safety and tolerability 
• Pharmacokinetics (zanubrutinib plus obinutuzumab arm only) 
Exploratory: 
• Overall response rate in obinutuzumab arm after crossover to receive zanubrutinib 
plus obinutuzumab 
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is an international (approximately 100 sites), phase 2, open-label, randomized, 
active-control study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in 
210 patients with relapsed or refractory follicular lymphoma.  The primary efficacy endpoint is 
ORR determined by independent central review.  Disease response will be assessed per the 
Lugano Classification for Non-Hodgkin Lymphoma (NHL) (Cheson et al 2014; 
Appendix 2) - hereafter referred to as Lugano Classification for NHL. 
Central randomization (2:1) will be used to assign patients to one of the following study drug 
treatments: 
Arm A: zanubrutinib plus obinutuzumab 
Arm B: obinutuzumab monotherapy 
Randomization will be stratified by the number of prior lines of therapy (2 to 3 versus ˃ 3), 
rituximab-refractory status (yes vs no), and geographic region (China vs ex-China).  
Rituximab-refractory is defined as follows: “Failure to respond to, or progression during, any 
previous rituximab-containing regimen (monotherapy or combined with chemotherapy), or 
progression within 6 months of the last rituximab dose, in the induction or maintenance 
treatment settings.”  Rituximab-containing regimen is defined as those with at least four weekly 
doses of rituximab if administered as monotherapy, or at least four cycles if given as 
chemoimmunotherapy.  For induction therapy regimens during which a patient had disease 
progression, the minimum necessary rituximab dose is one full cycle (monotherapy or 
chemoimmunotherapy) or one dose of 375 mg/m2 (maintenance).  A patient who has not 
received any prior rituximab will have a rituximab-refractory status of “NO” for stratification. 
Treatment with zanubrutinib plus obinutuzumab and treatment with obinutuzumab monotherapy 
will be open label.  Study treatment must commence within 5 days after randomization.   
Each cycle consists of 28 days.  Study drug treatments will be administered as follows, 
depending on cohort and treatment assignment: 
• Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day 
(160 mg twice a day) with or without food. 
• Obinutuzumab will be administered 1,000 mg intravenously on days 1, 8, and 15 of 
Cycle 1, then 1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 mg every 8 weeks.  
(At the discretion of the investigator, obinutuzumab may be administered 100 mg on 
Day 1 and 900 mg on Day 2 of Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1.)  
Responding patients may continue to receive maintenance obinutuzumab every 
8 weeks for an additional 24 months (eg, maximum total duration of obinutuzumab of 
approximately 30 months [maximum 20 doses]). 
• At the discretion of the investigator, patients in arm B will be eligible to receive 
crossover treatment with zanubrutinib plus obinutuzumab if they experience 
progressive disease or their disease does not respond to therapy with a CR or PR after 
12 months.  This must be confirmed by independent central review.  For patients who 
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initiate crossover treatment with zanubrutinib plus obinutuzumab, safety, laboratory, 
and response evaluation assessments will continue to be performed per the Schedule 
of Assessments (Appendix 9). 
Study Assessments 
Assessments of follicular lymphoma status during the study include: disease-related 
constitutional symptoms, physical examination of lymph nodes, liver, and spleen, complete 
blood count (CBC), bone marrow examination, positron emission tomography (PET)/computed 
tomography (CT) scan with contrast of neck, chest, abdomen, and pelvis, patient-reported 
outcomes (PROs; EQ-5D-5L and EORTC QLQ-C30 questionnaires).  
Tumor assessments, including imaging studies, will be performed at screening, every 12 weeks 
from Cycle 1 Day 1 for 24 months, then every 24 weeks for 24 months, and then yearly until 
disease progression.  All known sites of disease must be documented at screening and reassessed 
at each subsequent tumor evaluation. All patients must undergo PET-CT scan during 
screening.  Patients whose disease is not FDG-avid at screening will be followed by CT-based 
assessments alone.  Patients whose disease is FDG-avid at screening, by either site assessment or 
the central imaging vendor, will be followed by an integration of PET-CT and CT-based 
assessments as follows:  
• PET-CT scans are required at screening, end of Cycles 3, 6, and 12, and to confirm a 
result on CT scan (CR/PR or disease progression)  
• CT scans with contrast are required at all other tumor response assessments 
Patients receiving zanubrutinib should remain on study treatment until disease progression is 
confirmed by independent central review.  Patients receiving obinutuzumab should remain on 
study treatment until either disease progression is confirmed by independent central review or 
approximately 30 months of treatment with obinutuzumab (maximum 20 doses), whichever 
occurs first. 
Assessments of safety will include AEs, SAEs, clinical laboratory tests, physical examinations, 
and vital signs.  AEs will be graded for severity per the current version of National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).  An independent 
data monitoring committee (DMC) will periodically monitor safety data. 
Components of the Follicular Lymphoma International Prognostic Index (FLIPI) score  
(Solal-Céligny et al 2004) at diagnosis and at screening will be collected: age, Ann Arbor stage, 
hemoglobin level, number of nodal areas (see Appendix 3), and serum LDH level, in addition to 
the following components of FLIPI 2 (Relander et al 2010): bone marrow involvement, nodes 
> 6 cm, and β2-microglobulin. 
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3.2. 
Study Schema 
The study schematic is provided in Figure 1. 
Figure 1. 
Study Schema 
 
Abbreviation: NHL, non-Hodgkin lymphoma. 
a Randomization stratified by the number of prior lines of therapy (2 to 3 vs > 3), rituximab-refractory status 
(yes vs no), and geographic region (China vs ex-China). 
b Option for addition of zanubrutinib following independent central confirmation of disease response status. 
3.3. 
Blinding 
Treatment with zanubrutinib and obinutuzumab will be open label, however, the assessment of 
overall response rate by independent central review (primary endpoint) will be blinded.  
3.4. 
Duration of Study 
The total duration of this study is expected to be approximately 5 years, assuming an expected 
enrollment duration of 30 months and maximum duration of obinutuzumab of approximately 
30 months (maximum 20 doses) after the last enrolled patient.  Patients assigned to arm A 
(zanubrutinib plus obinutuzumab), who in the opinion of the investigator, continue to benefit 
from study treatment may continue treatment with zanubrutinib by enrolling on the zanubrutinib 
Long Term Extension Study; this is a rollover study for patients who wish to continue receiving 
zanubrutinib. 
3.5. 
Discussion of Study Design, Including Choice of Control Group 
The proposed study will be conducted in patients with histologically confirmed follicular 
lymphoma (Grade 1, 2, or 3a) who have received ≥ 2 prior systemic treatments for follicular 
lymphoma; have received an anti-CD20 antibody, and an appropriate alkylator-based 
combination therapy (eg, rituximab, cyclophosphamide, doxorubicin, and prednisolone; 
rituximab, cyclophosphamide, vincristine, and prednisolone; and/or bendamustine plus 
rituximab). 
The patient eligibility definition above is intended to define a patient population for whom new, 
effective treatments are needed.  While current expert guidelines specify the repeat use of 
chemoimmunotherapy for patients with a long (≥ 24 months) remission to their prior therapy, 
acceptable options for patients with a short remission to prior therapy are quite limited.  
Additionally, many treatments are not applicable to patients with follicular lymphoma in later 
relapse due to age, non-lymphoma comorbidity, limited bone marrow reserve due to prior 
cytotoxic therapy or stem cell transplantation, or radioimmunotherapy treatments 
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(National Comprehensive Cancer Network 2017; Dreyling et al 2017).  For many patients with 
follicular lymphoma in later relapse, and particularly those with short response duration to prior 
therapy, this leaves anti-CD20 antibody therapy or idelalisib as palliative options.  
According to the European Society for Medical Oncology Clinical Practice Guidelines for 
diagnosis, treatment and follow-up of newly diagnosed and relapsed follicular lymphoma 
(Dreyling et al 2017):  “the selection of salvage treatment depends on efficacy of prior 
regimens…obinutuzumab has recently received a positive recommendation for approval by the 
European Medicines Agency for rituximab-refractory cases based on an improved PFS in 
comparison with bendamustine only.”  In Europe, the anti-CD20 agent, obinutuzumab 
(Gazyvaro®) has gained approval in the rituximab-refractory setting (Gazyvaro Summary of 
Product Characteristics 2016), when added to bendamustine, based on demonstration of 
prolonging PFS compared with bendamustine-alone in patients who were refractory to their prior 
rituximab-containing treatment (Sehn et al 2016).  In the context of the proposed trial in the 
third-line and beyond setting, the use of obinutuzumab monotherapy as a comparator would be 
appropriate given the likelihood that prior bendamustine-based therapy will already have been 
administered or considered, and the ability to re-administer anti-CD20 monotherapy remains a 
palliative measure in the majority of patients with relapsed or refractory disease.  Furthermore, 
the use of obinutuzumab rather than rituximab would allow for a direct measure of the 
contribution of obinutuzumab to the safety and activity of the novel combination regimen under 
investigation (zanubrutinib plus obinutuzumab). 
Obinutuzumab has also been evaluated as a single-agent in relapsed or refractory follicular 
lymphoma/indolent lymphoma.  In a randomized phase 2 study of obinutuzumab versus 
rituximab in rituximab-sensitive, relapsed indolent lymphoma, defined as having a documented 
response lasting at least 6 months from the last rituximab dose, obinutuzumab was associated 
with a higher response rate (45% versus 27%) compared with rituximab, but there was no 
difference in median or 2-year PFS (Sehn et al 2015).  In a previous phase 1 study, 
obinutuzumab demonstrated a 23% ORR rate in 23 patients with relapsed or refractory indolent 
lymphoma, with a 15% response rate in a subset of 13 patients with rituximab-refractory disease, 
defined as progressive disease within 12 months of previous rituximab therapy (Sehn et al 2012).  
In the phase 3 GALLIUM study in patients with previously untreated follicular lymphoma, 
obinutuzumab-chemotherapy induction followed by obinutuzumab maintenance prolonged PFS 
as compared with rituximab-chemotherapy induction followed by rituximab maintenance 
(Marcus et al 2016). 
The phosphoinositol-3-kinase inhibitor idelalisib (Zydelig®) was approved by the EMA for use 
in patients with follicular lymphoma refractory to 2 prior lines of treatment, based on results 
from a single-arm, multicenter clinical study conducted in 125 patients with indolent lymphoma 
(Zydelig Summary of Product Characteristics 2016).  The study population included 72 patients 
with follicular lymphoma.  All patients were refractory to rituximab, defined per protocol as less 
than a PR or disease progression within 6 months after completion of a prior therapy.  The ORR 
was 57% (54% in follicular lymphoma), with 6 patients (8%; all with follicular lymphoma) 
achieving a CR.  The median duration of response was 12.5 months. 
Despite this initial promising data, three phase 3 trials of idelalisib in indolent lymphoma, in 
combination with anti-CD20 agents or chemoimmunotherapy, were prematurely terminated due 
to an imbalance in infectious deaths in the idelalisib arms of the studies (Zydelig FDA 
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Alerts 2016).  Thus, we believe that treatments capable of inducing a high rate of durable 
responses, with favorable safety profiles, in patients with follicular lymphoma or indolent 
lymphoma in second or greater relapse, are still needed; particularly those patients who are now 
treatment-refractory or have a short remission duration with prior therapy. 
The patient population selected for this phase 2 study will have received standard treatment 
options with chemoimmunotherapy approaches and will have failed their last therapy.  This 
represents a follicular lymphoma population with a high unmet medical need.  Patients who have 
failed, or who have been considered unsuitable for idelalisib, and who would be appropriate to 
receive palliative anti-CD20 therapy with obinutuzumab will be enrolled. 
The early results of the combination of zanubrutinib and obinutuzumab are promising with 
regard to the frequency of objective response, depth of response, lack of treatment failure due to 
progressive disease or toxicity, and tolerability/safety profile.  Though the incorporation of 
chemoimmunotherapy into the sequential treatment practice for follicular lymphoma has 
improved lymphoma-specific outcomes in this disease, follicular lymphoma remains incurable, 
and the incorporation of cytotoxic agents into the treatment sequence for follicular lymphoma, 
particularly alkylating agents, can result in cumulative myelotoxicity, immunosuppression, and 
risk for secondary leukemia; therefore, it is reasonable to evaluate regimens such as zanubrutinib 
plus obinutuzumab as potential alternatives to cytotoxic chemoimmunotherapy regimens. 
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4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all of the following criteria: 
1. ≥ 18 years of age at the time of informed consent 
2. Histologically confirmed diagnosis of B-cell follicular lymphoma (Grade 1, 2 or 3a) 
based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue 
3. ≥ 2 prior systemic treatments for follicular lymphoma 
4. Previously received an anti-CD20 antibody and an appropriate alkylator-based 
combination therapy, including: 
a. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone 
b. Rituximab, cyclophosphamide, vincristine, and prednisolone 
c. Bendamustine plus rituximab 
5. Disease progression after completion of most recent therapy or refractory disease, defined 
as failure to achieve CR or PR to most recent therapy, and most recent therapy was an 
appropriate second-line (or later) systemic therapy for follicular lymphoma 
6. Presence of measurable disease, defined as ≥ 1 nodal lesion that is > 2 cm in longest 
diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter 
7. Availability of archival tissue confirming diagnosis of B-cell follicular lymphoma (or if 
archival tissue is not available, a copy of the pathology report confirming diagnosis of 
B-cell follicular lymphoma is required) 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
9. Life expectancy ≥ 6 months 
10. Adequate organ function defined as: 
a. Absolute neutrophil count (ANC) ≥ 1000/mm3, except when neutropenia is assessed 
by the investigator to be directly due to active lymphoma, in which case ANC must 
be ≥ 750/mm3 
b. Platelet > 50,000/mm3 (without growth factor support or transfusion within 7 days) 
c. Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault or MDRD 
equation or as measured by nuclear medicine scan or 24-hour urine collection) 
d. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 x upper 
limit of normal (ULN) 
e. Serum total bilirubin < 2.0 x ULN (unless documented Gilbert’s syndrome) 
11. Female patients of childbearing potential, must practice highly effective methods of 
contraception initiated prior to first dose of study drug, for the duration of the study, and 
for ≥ 90 days after the last dose of zanubrutinib, or 18 months after the last dose of 
obinutuzumab, whichever is longer.  A woman is considered of childbearing potential 
(WOCBP), ie, fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
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salpingectomy and bilateral oophorectomy.  Highly effective contraceptive methods 
include the following: 
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal or transdermal 
b. Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
c. An intrauterine device  
d. Intrauterine hormone-releasing system  
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day prior to first 
dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose 
of zanubrutinib, or 18 months after the last dose of obinutuzumab, whichever is 
longer).  Total sexual abstinence should only be used as a contraceptive method if it is 
in line with the patients’ usual and preferred lifestyle.  Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to investigational medicinal product, and 
withdrawal are not acceptable methods of contraception.   
Of note, barrier contraception (including male and female condoms with or without 
spermicide) is not considered a highly effective method of contraception and if used, 
this method must be used in combination with another acceptable method listed 
above. 
For patients using hormonal contraceptives such as birth control pills or devices, a second 
barrier method of contraception (eg, condoms) must be used. 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone level in the post-menopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the absence of 12 months 
of amenorrhea, a single follicle-stimulating hormone measurement is insufficient. 
12. Male patients are eligible if abstinent (as defined above), vasectomized, or if they agree 
to the use of barrier contraception in combination with other methods described above 
during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib, or 
18 months after the last dose of obinutuzumab, whichever is longer. 
13. Ability to provide written informed consent and can understand and comply with the 
requirements of the study. 
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4.2. 
Exclusion Criteria 
Each patient eligible to participate in this study must NOT meet any of the following exclusion 
criteria: 
1. Known central nervous system involvement by leukemia or lymphoma 
2. Evidence of transformation from follicular lymphoma to DLBCL or other aggressive 
histology (such as large cells seen on biopsy or high PET avidity in a single node seen on 
PET scan) 
3. Allogeneic hematopoietic stem cell transplantation within 12 months of study enrollment 
4. Prior exposure to a BTK inhibitor   
5. Prior malignancy within the past 2 years, except for curatively treated basal or squamous 
cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or 
localized Gleason score 6 prostate cancer 
6. Clinically significant cardiovascular disease including the following: 
a. Myocardial infarction within 6 months before screening 
b. Unstable angina within 3 months before screening 
c. New York Heart Association Class III or IV congestive heart failure (see Appendix 4) 
d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, 
ventricular fibrillation, torsades de pointes) 
e. QTcF > 480 milliseconds based on Fridericia’s formula 
f. History of Mobitz II second-degree or third degree heart block without a permanent 
pacemaker in place 
g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure > 170 mmHg and diastolic 
blood pressure > 105 mmHg at screening 
7. 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 
8. History of stroke or intracranial hemorrhage within 6 months before first dose of study 
drug  
9. Severe or debilitating pulmonary disease 
10. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, bariatric 
surgery procedures, symptomatic inflammatory bowel disease, or partial or complete 
bowel obstruction 
11. Active fungal, bacterial and/or viral infection requiring systemic therapy 
12. Underlying medical conditions that, in the investigator’s opinion, will render the 
administration of study drug hazardous or obscure the interpretation of safety or efficacy 
results 
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13. Known infection with 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 (<15 IU/mL).  
14. Major surgery within 4 weeks of the first dose of study drug 
15. Pregnant or lactating women 
16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug 
17. Ongoing alcohol or drug addiction 
18. Hypersensitivity to zanubrutinib or obinutuzumab or any of the other ingredients of the 
study drugs 
19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer 
20. Concurrent participation in another therapeutic clinical trial. 
21. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids 
must be fully tapered off/stopped at least 5 days before the day of first study drug. 
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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 9). 
Visit Windows 
A study visit may be scheduled on any day within a specified study week.  For any given day 
within the study week, the visit window is ± 7 days (ie, 7 days before or after the given day) 
unless otherwise stated.  Study drug supplies must be considered when scheduling visits during 
windows.  Procedures for a given visit may be split across the window to allow for drug resupply 
and completion of study procedures.   
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.  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 35-day 
screening period.  Consent must be obtained using the most current version of the form approved 
by the ethics committee. 
Repeating the screening procedures or tests is allowed if the patient did not previously meet the 
inclusion and exclusion criteria or if needed in order 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 randomization, study site personnel should document the screen failure 
in the patient’s source documents.  The documentation should include demographics and medical 
history, the reason for screen failure, the eligibility criteria reviewed, procedures performed, etc.   
5.1. 
Enrollment and Randomization 
All screening procedures must be performed up to 35 days before the first administration of 
study drug, unless noted otherwise; assessments not completed within this interval must be 
repeated.  The site investigator is responsible for maintaining a record of all patients screened 
and those who are enrolled in the study. 
Patient Numbering 
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant.  
Patient numbers will be assigned in chronological order starting with the lowest number.  Once a 
patient number has been assigned to a patient, it cannot be reassigned to any other patient.  
Medical and Cancer History 
Review any medical and cancer history any time after obtaining informed consent; includes 
presence or absence of disease-related constitutional symptoms.  Clinically significant medical 
history findings (ie, previous diagnoses, diseases or surgeries) not pertaining to the study 
indication, started before signing the informed consent, and considered relevant for the patient’s 
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study eligibility will be collected and captured in the electronic case report form (eCRF).  
Clinically significant is defined as any events, diagnoses or laboratory values requiring 
treatment, follow-up or the presence of signs or symptoms that require medical intervention.  
Concurrent medical signs and symptoms must be documented to establish baseline severities. 
Other background information to be collected 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, date of birth [or age] and race/ethnicity) will also be collected. 
Components of the Follicular Lymphoma International Prognostic Index (FLIPI) score  
(Solal-Céligny et al 2004) at diagnosis and at screening will be collected: age, Ann Arbor stage, 
hemoglobin level, number of nodal areas (see Appendix 3), and serum LDH level, in addition to 
the following components of FLIPI 2 (Relander et al 2010): bone marrow involvement, nodes 
> 6 cm, and β2-microglobulin. 
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 may apply.  No eligibility 
waivers will be granted.   
After a patient is screened and the investigator determines the patient is eligible for 
randomization, study site personnel will complete an Eligibility Authorization Packet and email 
it to the medical monitor or designee to approve the 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.  
The archival tissue sample used for follicular lymphoma diagnosis or the associated pathology 
report from diagnosis will be sent to the central pathology laboratory for confirmation of tissue 
diagnosis.  It is not required that the archival tissue sample or pathology report be sent before 
randomization/treatment assignment, but documentation must be provided as part of the 
eligibility package. 
Enrollment/Randomization 
Access the IRT system to assign study drugs.  This may occur up to 5 days before the day of first 
dose of study drug.   
5.2. 
Electrocardiogram 
Obtain per local practice and read locally to confirm eligibility.  A 12-lead electrocardiogram 
will be performed in triplicate at screening.  Patients should be in the semi-recumbent or supine 
position. 
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5.3. 
Zanubrutinib Dispensation 
Zanubrutinib will be dispensed by the study center personnel to patients at scheduled study visits 
to ensure adequate drug supply for administration at home throughout the treatment phase as 
detailed in the Pharmacy Manual.  Instructions are to be provided for dosing, storage, and the 
return of all bottles (used and unused) at future visits. 
5.4. 
Pharmacokinetics 
Blood samples to assess plasma zanubrutinib concentrations will be collected in patients in arm 
A.  Sparse PK samples will be collected from patients randomized to arm A (zanubrutinib plus 
obinutuzumab) at the following time points: predose (within 30 min prior to zanubrutinib dose), 
and 2 hours (± 30 min) post zanubrutinib dose on Cycle 1 Day 1 and Cycle 2 Day 1.  No sparse 
PK samples are required during crossover treatment.  On the days PK samples are to be 
collected, study drug administration must occur under the supervision of the investigator (or 
designee) after the predose PK sample is obtained.  The actual time (to the nearest minute) of 
zanubrutinib administration on the day prior to Cycle 1 Day 1 and Cycle 2 Day 1 must be 
recorded on the eCRF.  Should a drug-drug interaction between zanubrutinib and a concomitant 
medication be suspected, further blood samples for PK analyses may be taken to characterize the 
extent of the interaction. 
Blood samples (2 mL) for PK analysis will be collected into EDTA collection tubes.  Details 
concerning handling of the PK plasma samples, including labeling and shipping instructions will 
be provided in the laboratory manual for this study.  PK samples will only be collected from sites 
that are able to adequately follow the sampling, handling and processing procedures outlined in 
the laboratory manual. 
Samples will be shipped to the designated bioanalytical lab for quantification of plasma 
zanubrutinib concentrations using a validated method. 
5.5. 
Safety Assessments 
Physical Examination and Vital Signs 
Physical examination, vital signs (sitting blood pressure, heart rate, and body temperature), and 
weight will be performed at each study visit.  Height (cm) is determined at screening only.   
A complete physical exam includes an assessment of systems per standard of care at the study 
site and as clinically indicated by symptoms. 
Assessment of vital signs and a focused physical examination on Cycle 1 Day 1 may be skipped 
if performed within 7 prior days. 
ECOG Performance Status 
ECOG performance status will be assessed at the screening visit, each visit during study 
treatment, and at the safety follow-up visit.  Appendix 4 will be used to assess performance 
status. 
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Concomitant Medications Review 
Record any new medications, changes in ongoing medications or procedures, and medications 
discontinued within 35 days before the first visit in Cycle 1 and since the prior study visit, 
thereafter. 
Adverse Events Review 
Record AEs that occurred during screening on the medical history case report form and in the 
patient’s clinical record. 
Collect non-serious AE information from the time of first dose of study drug through safety 
follow-up.  Information on all SAEs (regardless of relatedness) will be collected from the time of 
signed informed consent through screen failure or safety follow-up.  The AE reporting period is 
defined in Section 8.4.1. 
All treatment-related AEs and SAEs will be followed until resolution or stabilization.  The 
accepted regulatory definition for an AE is provided in Section 8.1.1.  Important additional 
requirements for reporting SAEs are explained in Section 8.4.2.  
5.6. 
Efficacy Assessments 
Response will be assessed by independent central review and categorized per the Lugano 
Classification for NHL (Cheson et al 2014).  The primary endpoint will be ORR based on 
independent central review.  Investigators will assess response without knowledge of 
independent central review results.  Response parameters will include assessment of 
lymphadenopathy, hepatomegaly and splenomegaly, blood lymphocyte count, bone marrow 
aspirate/biopsy, platelet count, hemoglobin level, and neutrophil count.  In the event of a 
treatment delay, disease assessments are to continue per the Schedule of Assessments 
(Appendix 9). 
For patients receiving zanubrutinib, refer to Appendix 2 regarding the assessment of disease 
progression during study drug holds. 
Disease-Related Constitutional Symptoms 
Disease-related constitutional symptoms (or B-symptoms) (unexplained fever of ≥ 101°F 
[or 38.3°C], drenching night sweats; or unexplained loss of > 10% body weight within the 
previous 6 months) will be evaluated at screening, every 12 weeks from Cycle 1 Day 1 for 
24 months, then every 24 weeks for 24 months, and then yearly until disease progression. 
Exam of Liver, Spleen and Lymph Nodes 
Enlargement of liver, spleen, and lymph nodes is included in the physical examination at 
screening, every 12 weeks from Cycle 1 Day 1 for 24 months, then every 24 weeks for 
24 months, and then yearly until disease progression. 
Imaging Assessments 
All patients must have baseline (within 35 days of randomization) PET/CT scan with contrast of 
neck, chest, abdomen, and pelvis and any other disease sites. 
Patients with suspected transformation of disease (eg, a PET/CT with high standardized uptake 
value-avidity or new onset symptoms) should be fully evaluated prior to enrollment on study.   
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Screening findings will determine whether patients are followed with contrast-enhanced PET/CT 
or contrast-enhanced CT only.  Patients with disease that is FDG-avid by either site assessment 
or the central imaging vendor must be followed by PET/CT. 
Ideally, and depending on the imaging equipment available, contrast-enhanced CT should occur 
combined with PET on a single visit. Combined PET/CT may be used in lieu of a CT with 
contrast only if the CT of the combined PET/CT has been performed with diagnostic quality and 
contrast is administered.   
PET/CT scans are required at screening and after Cycles 3, 6, and 12.  A PET/CT scan is 
required to confirm a result on CT scan (CR/PR or disease progression). 
CT with contrast will be performed at all other tumor assessment timepoints (see Appendix 9, 
Schedule of Assessments).  
For patients with a contraindication to receiving CT scan IV-contrast (eg, contrast allergy, or 
other medical contraindication such as renal insufficiency), magnetic resonance imaging (MRI) 
may be used in place of CT scans.  For patients being assessed via MRI, a non-contrast chest CT 
scan is acceptable, and preferred, in place of a chest MRI to evaluate the lung parenchyma.  The 
same imaging technique (ie, CT, MRI) should be used consistently throughout a patient’s time 
on the study.  All efforts will be made to ensure that the imaging equipment, contrast agent, and 
person (investigator or radiologist) performing the evaluation is kept constant throughout a 
patient’s remaining course on study.  
All PET/CT scans, CT scans, and MRIs obtained during the study will be collected and reviewed 
by a central imaging vendor identified to this trial.  De-identified copies of all scans and 
radiology reports (including those from screening) must be provided to the sponsor or designee 
(eg, central imaging vendor). 
Modification from Lugano Classification for NHL (Cheson et al 2014): 
Pseudoprogression is defined as an objective tumor response occurring after initial 
documentation of apparent radiological progressive disease and has been observed in patients 
receiving a BTK inhibitor for treatment of follicular lymphoma (Salles et al 2016).  For patients 
in either arm, a timepoint finding of “disease progression” will require a confirmatory scan at 
least 4 weeks after the scan that initially demonstrated possible progression.  An exception to the 
confirmatory scan requirement exists if one or more of the following clear, clinical signs of 
progression is present and the investigator believes the progression is unequivocal: 
a. Clinical symptoms and signs of disease progression (including worsening laboratory 
values)  
b. Deterioration of ECOG performance status  
c. Rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) that necessitates urgent medical intervention.  
Note: If any of the conditions above are present, no confirmatory scan is required to confirm the 
disease progression. 
Due to the potential for pseudoprogression cases in this study, patients in both Arms A and B 
should remain on study treatment while the patient waits for the confirmation scan results. 
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Bone Marrow Examination 
Bone marrow biopsy is required under the following conditions during the treatment period: 
during screening to assess bone marrow involvement of lymphoma; and if clinical and laboratory 
results demonstrate that a CR has been achieved, in order to confirm a CR – only applicable to 
patients whose bone marrow was positive for lymphoma involvement at screening.   
Bone marrow biopsies will be reviewed by local laboratory and results will be entered into the 
CRF.  In addition, all of the bone marrow samples from screening to end of study will be 
collected to be reviewed by a pathologist from central pathology laboratory. 
5.7. 
Patient-Reported Outcomes 
PROs will continue to be assessed until disease progression, death, or withdrawal of consent, 
regardless of study treatment discontinuation.  Patients should complete the EQ-5D-5L and 
EORTC QLQ-C30 questionnaires per the Schedule of Assessments (Appendix 9) before study 
drug is administered, and when possible before performing any other procedures.  No PRO 
questionnaires are required during crossover treatment.   
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome (EuroQol 
Group 1990; Herdman et al, 2011).  Patients will self-rate their current state of mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 possible 
responses that record the level of severity (no problems, slight problems, moderate problems, 
severe problems, or extreme problems) within each dimension.  The questionnaire also includes 
a visual analog scale to self-rate general health state on a scale from “the worst health you can 
imagine” to “the best health you can imagine.”  A sample questionnaire is provided in 
Appendix 6 as an example only. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients.  It is a copyrighted instrument, which has been translated and validated in over 
100 languages and is used in more than 3,000 studies worldwide.  The EORTC QLQ-C30 
includes 30 separate questions (items) resulting in 5 functional scales (Physical Functioning, 
Role Functioning, Emotional Functioning, Cognitive Functioning, and Social Functioning), 
1 Global Health Status scale, 3 symptom scales (Fatigue, Nausea and Vomiting, and Pain), and 
6 single items (Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, and Financial 
Difficulties) (Fayers et al, 2001).  The recall period is 1 week (the past week).  The EORTC 
QLQ-C30 has been widely used among cancer patients in general, and specifically in 
non-Hodgkin lymphoma patients.  It is a reliable and valid measure of PRO in cancer patients 
and takes about 11 minutes to administer.  A sample questionnaire is provided in Appendix 7 as 
an example only. 
5.8. 
Laboratory Assessments 
Samples for protocol-specified CBC, chemistry and coagulation profiles will be evaluated by a 
central laboratory.  Additional laboratory assessments, including lab values required within a 
short timeframe on dosing days to determine drug dosage, and unscheduled laboratory tests 
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ordered by the investigator as necessary for patient monitoring, will be performed locally and 
entered into the eCRF.  Samples for serum immunoglobulins, β2-microglobulin, pregnancy 
testing, and hepatitis B and C testing will be performed locally.  These tests may be performed 
centrally in certain countries. 
A detailed description of the procedures for sample collection, handling, storage, and shipment 
of the laboratory samples and all material such as test tubes and labels is provided in the 
laboratory manual. 
Chemistry, CBC with differential, coagulation, serum immunoglobulin, and β2-microglobulin, 
will be performed at the timepoints specified in the Schedule of Assessment (Appendix 9), and 
may also be performed as medically necessary.  On Cycle 1 Day 1, laboratory assessments 
should be done before the study drug administration.  Screening blood and tests performed 
within 72 hours of the first study drug administration do not need to be repeated on Cycle 1 Day 
1.   
Hematology 
CBC with differential is required to be performed at every visit during the treatment phase and 
during safety follow-up and long-term follow-up.  CBC includes hemoglobin, hematocrit, 
platelet count, red blood cell count, white blood cell count with differential including neutrophils 
(including bands), lymphocytes, monocytes, eosinophils, and basophils.  
Chemistry 
Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphate/phosphorus, magnesium, total bilirubin, total protein, 
albumin, ALT, AST, lactate dehydrogenase, and alkaline phosphatase.    
Serum Immunoglobulins 
Quantitative serum immunoglobulins (IgG, IgM, IgA) will be measured at screening; on Day 1 
of Cycle 3, Cycle 6, Cycle 9, and Cycle 12; and then every 24 weeks thereafter until disease 
progression.    
Coagulation 
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 only.   
Hepatitis B and C testing 
Hepatitis B/C serologic markers and/or viral load will be tested at screening.  The hepatitis B 
testing includes HBsAg, HBcAb, and hepatitis B surface antibody (HBsAb) as well as HBV 
DNA by 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, during monthly 
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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, 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, physicians with expertise in 
managing hepatitis C. 
The medical monitor should be informed of any suspected hepatitis B or hepatitis C reactivation.   
Table 1 below, shows how the results for, HBV/HCV, and HBV/HCV testing at screening relate 
to inclusion and exclusion criteria. 
Table 1: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection (Detected Positive 
by PCR) 
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
 
HBsAg (-) and HBcAb (+) 
HBV DNA “Not detected”  
 
*Perform monthly monitoring of HBV DNA  
 
 
HBsAg (-) and HBcAb (+) 
HBV DNA detected 
HCV 
 
Antibody (-) or Antibody (+) 
HCV RNA “Not detected”   
 
*Perform monthly monitoring of HCV RNA  
 
 
Antibody (+) 
HCV RNA Detected  
Abbreviations: HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; HBV, hepatitis B virus; 
HCV, hepatitis C virus. 
Pregnancy Test 
A serum pregnancy test will be performed at screening, within 7 days of randomization, and at 
the end of treatment in women of childbearing potential.  During treatment, laboratory-based, 
highly-sensitive pregnancy tests (urine or serum) will be performed within 4 weeks after Cycle 1, 
Day 1, then every 4 weeks even if the timing falls outside of the normally scheduled visits.  
Pregnancy tests must be continued every 4 weeks for at least 90 days after the last dose of study 
drug (even if the timing falls outside of the normally scheduled visits).  If a urine pregnancy test 
is positive, it must be confirmed by a serum pregnancy test.  A patient who has a positive 
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pregnancy test result at any time after the study drug administration will be immediately 
withdrawn from treatment in the study. 
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 of liver, spleen, and lymph nodes; disease-related constitutional symptoms; 
hematology and chemistry laboratory assessments; serum immunoglobulins; and pregnancy tests.  
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. 
Arm B “Crossover” Treatment Adding Zanubrutinib 
At investigator discretion, and with medical monitor approval, patients in Arm B may 
“crossover” to add zanubrutinib following disease progression confirmed by independent central 
review.  To initiate crossover therapy with zanubrutinib, a patient must meet the safety and 
laboratory test requirements documented below.  Once approved for crossover, these patients 
will continue to follow the required safety and laboratory procedures in the Schedule of 
Assessments (Appendix 9) while receiving zanubrutinib and obinutuzumab.  No sparse PK 
samples or PRO questionnaires are required during crossover treatment.  The total duration of 
obinutuzumab treatment (ie, total of monotherapy plus combination therapy) will be 
approximately 30 months (maximum 20 doses).  Following completion of 20 doses of 
obinutuzumab treatment, patients receiving crossover therapy will continue to receive 
zanubrutinib until disease progression.  Tumor response will be evaluated by the investigator. 
To request crossover treatment adding zanubrutinib, site staff will complete the Request for 
Crossover Treatment form and submit it to the medical monitor for approval following 
independent central review confirmation of disease progression.  Documentation must be 
provided showing that the patient meets the following requirements within 15 days before date of 
submission of the form: 
• ANC ≥ 1000/mm3, except when neutropenia is assessed by the investigator to be 
directly due to active lymphoma, in which case ANC must be ≥ 750/mm3 
• Platelet > 50,000/mm3 (without growth factor support or transfusion within 7 days) 
• Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault or MDRD 
equation or as measured by nuclear medicine scan or 24‑hour urine collection) 
• AST/serum glutamic oxaloacetic transaminase, and (ALT)/serum glutamic pyruvic 
transaminase ≤ 3.0 x ULN 
• Serum total bilirubin < 2.0 x ULN (unless documented Gilbert’s syndrome) 
• No known New York Heart Association Class III or IV congestive heart failure 
(see Appendix 4) 
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• QTcF ≤ 480 milliseconds based on Fridericia’s formula 
The investigator will confirm that the above crossover requirements are met and that the patient 
qualifies to add full dose zanubrutinib at 160 mg twice daily.  Contact the medical monitor for 
any patient being considered for crossover who, based on the protocol dose modification section, 
would be required to implement a dose modification or a delay in the initial dosing of 
zanubrutinib. 
Patients approved to receive crossover treatment with combination zanubrutinib plus 
obinutuzumab should begin zanubrutinib as soon as possible after crossover approval.  If the 
timing of the crossover approval does not align with a visit for obinutuzumab administration, the 
patient should come to clinic for an unscheduled visit.  The first crossover visit should include 
education about the combination therapy and the dose, route, and frequency of zanubrutinib 
administration; the patient should initiate zanubrutinib therapy on the date of the first crossover 
visit. 
5.11. 
End of Treatment Period 
The treatment period starts with the first day of assigned study treatment and includes ongoing 
assessments for safety and efficacy per the Schedule of Assessments following completion of 
protocol-specified treatment.  The treatment period ends on the first day of next-line therapy or 
on the day of confirmed disease progression, whichever occurs first. 
Patients may discontinue study drug for any one of the following reasons: 
• Disease progression 
• Any intolerable adverse event that cannot be improved with standard medical 
intervention or would lead to undue risk to the patient  
• Patient withdrew consent 
• Patient pregnancy  
• Investigator decision  
• Other 
Patients may voluntarily withdraw consent from treatment at any time.   
5.12. 
Safety Follow-Up 
All patients who permanently discontinue zanubrutinib will have a safety follow-up visit 
30 (± 7) days after the last dose of study drug to collect AEs, including AEs that may have 
occurred or been ongoing after the patient discontinued study treatment.  For the obinutuzumab 
monotherapy arm (Arm B), the safety follow-up visit will occur 90 days after the last dose of 
study drug.  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 
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patient or guardian to collect this information.  Refer to the Schedule of Assessments 
(Appendix 9) for the assessments to be performed at the safety follow-up visit.   
5.13. 
Long-Term Follow-Up 
All patients who discontinue study drug treatment will remain in the study, complete safety 
follow-up, and subsequently commence long-term follow-up, which includes monitoring 
survival status and subsequent therapies for follicular lymphoma, and which may also include 
imaging and tumor response assessments for patients who have not yet had confirmed 
radiographic progression.  Visits repeat every 12 weeks (± 14 days) until study end.  For patients 
who permanently discontinue study drug treatment before radiographic progression is 
documented and confirmed by independent central review, tumor assessments (including 
radiographic imaging) will continue until radiographic progression is identified and confirmed 
by independent central review or start of next-line therapy, whichever comes first.  Patients with 
centrally confirmed disease progression will be followed up only for survival status and 
information about their next-line therapy. 
If the patient refuses to return for these visits or is unable to do so, every effort should be made 
to contact them or patient’s guardian by telephone to determine the patient’s disease status and 
survival.  
5.14. 
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.  
5.15. 
Lost to Follow-Up 
Every reasonable effort should be made to contact any patient apparently lost to follow up during 
the study to complete study related assessments, record outstanding data, and retrieve study drug.   
Following 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, relatives).  Such efforts 
should be documented in the patient’s source documents.   
If all efforts fail to establish contact, the patient will be considered lost to follow up.   
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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Preparation and Dispensation 
6.1.1. 
Packaging and Labeling 
Zanubrutinib capsules will be provided in a child-resistant high-density polyethylene bottle with 
an induction seal and bottle label.  Obinutuzumab will be provided in vials containing solution 
for infusion.   
The contents of the label will be in accordance with all applicable local regulatory requirements. 
6.1.2. 
Handling and Storage 
The IRT system will be used for drug supply management.  The study drugs will be dispatched 
to a study center only after receipt of the required documents in accordance with applicable 
regulatory requirements and the sponsor’s procedures.  The investigator or 
pharmacist/designated personnel is responsible for maintaining the drug supply inventory and 
acknowledgment 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 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.  
Zanubrutinib bottles must be stored at room temperature 15ºC to 30ºC.  
Obinutuzumab must be stored at 2°C to 8°C (36°F to 46°F), protected from light and should not 
be frozen or shaken.  For the diluted product, chemical and physical stability have been 
demonstrated in 0.9% NaCl at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 
8°C (36°F to 46°F) followed by 48 hours (including infusion time) at room temperature 
(≤ 30°C/86°F).  The solution for infusion should be used immediately.  If not used immediately, 
the prepared solution may be stored up to 24 hours at 2°C to 8°C.   
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 administered to and returned by patients, 
if applicable. 
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6.1.4. 
Disposal and Destruction 
After completion of the study, and following final drug inventory reconciliation by the monitor, 
the study site will destroy or return all unused study drug supplies.  The inventoried supplies can 
be destroyed on site or at the depot according to institutional policies, after receiving written 
sponsor approval. 
6.2. 
Dosage and Administration 
6.2.1. 
Zanubrutinib 
Zanubrutinib will be dispensed by the study center personnel to patients at scheduled study visits 
to ensure adequate drug supply for administration at home throughout the treatment phase as 
detailed in the Pharmacy Manual.  The investigator is to instruct the patient to take the study 
drug exactly as prescribed and at the same time each day of dosing.  Patients will be requested to 
bring their unused medication and all empty bottles to the center at each visit.  All dosages 
prescribed and dispensed to the patient and all dose changes including reason for dose changes 
during the study must be recorded on the appropriate eCRF. 
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a 
day) with or without food.  Patients will take zanubrutinib with water at approximately the same 
time every day, with a minimum of 8 hours between consecutive doses.  Zanubrutinib capsules 
should not be opened, broken, or chewed at any time. 
Patients receiving zanubrutinib should be instructed that if a dose of the study drug is not taken 
at the scheduled time, they 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. 
On the days of PK blood sampling, study drug administration for patients assigned to arm A 
(zanubrutinib plus obinutuzumab) will occur at the center after the predose blood sampling has 
occurred under the supervision of the investigator or his/her designee.  The investigator or 
his/her designee must instruct the patient not to self-administer the study drug prior to the office 
visit on those days.   
6.2.2. 
Obinutuzumab 
Patients will receive obinutuzumab 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, then 
1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 mg every 8 weeks.  (At the discretion of the 
investigator, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of 
Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1.)  Responding patients may continue to receive 
maintenance obinutuzumab every 8 weeks for an additional 24 months (eg, maximum total 
duration of obinutuzumab of approximately 30 months [maximum 20 doses]). 
Obinutuzumab should be administered at a rate of 50 mg/hr.  The rate of the infusion can be 
escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.  If no infusion 
reaction occurs during the Cycle 1 Day 1 infusion and the final infusion rate was 100 mg/hr or 
faster, infusions can be started at a rate of 100 mg/hr and increased in 100 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr for all subsequent doses.  Patients should be 
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premedicated with acetaminophen, antihistamine, and a glucocorticoid before each 
obinutuzumab infusion. 
6.3. 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any AE or SAE criterion must be 
reported in the appropriate timeframe as an AE or SAE.  There is no specific antidote for 
zanubrutinib.  In the event of an overdose, patients should be closely monitored and given 
appropriate supportive treatment.  
There has been no experience with overdose in obinutuzumab.  Doses ranging from 50 mg up to 
and including 2000 mg per infusion have been administered in clinical trials.  For patients who 
experience overdose, treatment should consist of immediate interruption or reduction of 
obinutuzumab and supportive therapy. 
6.4. 
Precautions 
6.4.1. 
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.  Obinutuzumab should also be interrupted, if applicable.   
6.5. 
Dose Interruption and Modification 
The guidelines set forth in Table 2 should be followed for dose interruption or modification of 
zanubrutinib for hematologic (Section 6.5.1) or nonhematologic (Section 6.5.2) toxicities.  No 
dose modifications for obinutuzumab are allowed. 
Temporary drug holds may cause short term worsening of disease.  Please review note at the end 
of Appendix 2 when assessing disease after a drug hold. 
Table 2: 
Zanubrutinib Dose Reduction Steps 
Dose Level 
Zanubrutinib Dose (Arm A) 
0 = starting dose 
160 mg twice a day 
-1 dose level 
80 mg twice a day 
-2 dose level 
80 mg once a day 
Zanubrutinib may be restarted upon resolution of toxicity and per investigator discretion if held 
for ≤ 28 consecutive days.  If, in the investigator’s opinion, it is in the patient’s best interest to 
restart treatment after > 28 days, then written approval must be obtained from the sponsor’s 
medical monitor.  
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6.5.1. 
Zanubrutinib Dose Reductions for Hematologic Toxicity 
Dosing will be held for individual patients under any of the following conditions, based on 
investigator assessment of study drug relatedness: 
• Grade 4 neutropenia (lasting > 10 days)  
• Grade 4 thrombocytopenia (lasting > 10 days) 
• Grade 3 thrombocytopenia associated with significant bleeding 
• ≥ Grade 3 febrile neutropenia 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery 
of the toxicity to ≤ Grade 1 or baseline.   
If the same event reoccurs, subjects will restart at one dose level lower upon recovery of the 
toxicity to ≤ Grade 1 or baseline.  
A maximum of 2 dose reductions will be allowed.  
Subjects with Grade ≥ 3 thrombocytopenia associated with significant bleeding requiring 
medical intervention should be discussed with the medical monitor. 
6.5.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity 
For nonhematological toxicities ≥ Grade 3 (other than atrial fibrillation, or hypertension 
adequately controlled with oral medication) or asymptomatic laboratory events (laboratory 
events indicating liver or renal dysfunction will not be considered asymptomatic laboratory 
events), suspected to be related to study drug treatment, study drug will be held until recovery to 
≤ Grade 1, and then restarted at original dose level.  If the event recurs at ≥ Grade 3, drug will be 
held until recovery to ≤ Grade 1 and restarted at level -2.  If the event recurs at ≥ Grade 3 at level 
-2, the patient will be discontinued from study treatment.   
For patients experiencing atrial fibrillation that is symptomatic and/or incompletely controlled: 
after the atrial fibrillation is adequately controlled study drug may be restarted at either the 
original dose or dose level -1, per 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 5.8. 
6.5.3. 
Dose Interruptions and Modifications for Obinutuzumab 
There are no dose modifications of obinutuzumab. 
Obinutuzumab can cause severe and life-threatening infusion reactions.  Stop obinutuzumab 
infusion immediately and permanently discontinue for Grade 4 infusion reactions.  Interrupt 
obinutuzumab infusion and manage symptoms for Grade 3 infusion reactions; upon resolution of 
symptoms, consider restarting obinutuzumab infusion at no more than half the previous rate 
(the rate being used at the time that the infusion reaction occurred) and, if the patient does not 
experience any further infusion reaction symptoms, the infusion rate escalation may resume at 
the increments and intervals as appropriate for the treatment cycle dose.  Permanently 
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discontinue obinutuzumab treatment if patients experience a Grade 3 infusion-related symptom 
at rechallenge.  For Grade 1 or 2 infusion reactions, reduce infusion rate or interrupt infusion and 
treat symptoms; upon resolution of symptoms, continue or resume infusion and, if the patient 
does not experience any further infusion reaction symptoms, the infusion rate escalation may be 
resumed at the increments and intervals as appropriate for the treatment cycle dose.   
Consider obinutuzumab treatment interruption if patients experience an infection, Grade 3 or 4 
cytopenia, or a ≥ Grade 2 nonhematologic toxicity.  Refer to the obinutuzumab Investigator 
Brochure or local prescribing information (if available), for guidance regarding infusion 
reactions, as well as for dose withholding or discontinuation in response to specific toxicities 
associated with obinutuzumab. 
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7. 
PRIOR AND CONCOMITANT THERAPY 
7.1. 
Prior Therapy 
Medications taken within 4 weeks before randomization 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 follicular lymphoma, 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 prior certain medications and therapies for 
follicular lymphoma (including allogeneic hematopoietic stem cell transplantation within 
12 months of study enrollment and prior exposure to a BTK inhibitor) are excluded from study 
participation.   
7.2. 
Concomitant Therapy 
All concomitant medications taken during the study will be recorded in the eCRF with 
indication, dose information, and dates of administration.   
Patients with high tumor burden should be monitored closely and prophylactic measures, 
including allopurinol or rasburicase, may be instituted per institutional standards. 
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. 
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. 
7.2.1. 
Permitted Medications 
The following treatments are allowed:   
• Blood transfusions and growth factor support per standard of care and institutional 
guidelines 
• Corticosteroids for non-follicular lymphoma indications 
Patients should not receive treatment with systemic corticosteroids other than 
intermittently to control or prevent infusion reactions, or for short durations 
(< 2 weeks) to treat non-follicular lymphoma-related conditions (eg, to treat a flare of 
chronic obstructive pulmonary disease), or at doses less than 20 mg/day of prednisone 
or prednisone-equivalent given daily to treat non-follicular lymphoma-related 
conditions 
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• Therapy to reduce symptoms of disease per standard of care and institutional 
guidelines 
Tumor lysis syndrome has not been currently reported with zanubrutinib treatment, but has been 
reported rarely with obinutuzumab.  Patients with high tumor burden should be monitored 
closely and prophylactic measures, including allopurinol, may be instituted per institutional 
standards.   
7.2.2. 
Prohibited Medications 
Patients should not receive other anticancer therapy (cytotoxic, biologic, or immunotherapy) 
while on treatment in this study.  Other anticancer therapy should not be administered until 
disease progression (as per clinical practice standards at the study center), unmanageable 
toxicity, or no further clinical benefit occurs which requires permanent discontinuation of the 
study drug.   
7.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications 
7.3.1. 
CYP-Inhibiting/Inducing Drugs 
When administering zanubrutinib, caution should be used with the any of the following, because 
they may affect the metabolism of zanubrutinib: 
• Strong/moderate CYP3A inhibitors 
• CYP3A inducers 
• Grapefruit juice 
• Seville oranges 
If at all possible, patients are encouraged not to use strong/moderate CYP3A inhibitors and 
inducers and consider using alternative agents.  However, if CYP3A inhibitors or inducers will 
be used, follow the dose modification table in Appendix 8.  The medical monitor should be 
consulted in these situations. Please refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
for a more complete list. 
A 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 effectiveness 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) must 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. 
No formal drug interaction studies have been conducted with obinutuzumab (GAZYVA package 
insert). 
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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 and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of 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 these instances, all patient identifiers will be blinded on 
the copies of the medical records prior to submission to the sponsor. 
8.1.1.1. 
Assessment of Severity 
The investigator will make an assessment of 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 v4.03.   
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living 
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• 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 8.4.2. 
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 prior to transmission of the 
SAE report to the sponsor since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements.  The investigator may change his/her opinion of 
causality in light of 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 
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 
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• 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 and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent.  Any changes in the severity of AEs/SAEs, must be recorded in the 
appropriate AE or SAE eCRF page(s); both increases in grade and decreases in grade will be 
recorded with updated start and stop dates.  The investigator will ensure that follow-up includes 
any supplemental investigations as may be indicated to elucidate the nature and/or causality of 
the AE or SAE.  This may include additional laboratory tests or investigations, histopathological 
examinations, radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any post-mortem findings, including histopathology. 
New or updated information will be recorded on the originally completed SAE report, with all 
changes signed and dated by the investigator.  The updated SAE report should be resent to the 
sponsor within the timeframes outlined in Section 8.4.2. 
8.1.2. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, CBC, or coagulation) or other abnormal 
assessments (eg, ECGs, X-rays, or vital signs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs.  This includes clinically significant abnormal 
laboratory findings or other abnormal assessments that are present at baseline and significantly 
worsen during the study.  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 that require 
active medical intervention, or lead to dose interruption or discontinuation. 
8.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
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NOTE: the term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE.  It does not refer to an 
AE, which hypothetically might have caused death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere 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 
8.3. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the Investigator’s Brochure. 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.4.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
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For patients receiving zanubrutinib plus obinutuzumab: all AEs and SAEs, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of zanubrutinib, 
90 days after the last dose of obinutuzumab. 
For patients receiving obinutuzumab monotherapy: all AEs and SAEs, regardless of relationship 
to study drug, will be reported until 90 days after the last dose of obinutuzumab. 
For patients who have the addition of zanubrutinib to obinutuzumab at 12 months, AEs will 
continue to be reported until 30 days after the last dose of zanubrutinib, 90 days after the last 
dose of obinutuzumab. 
After this period, the investigator should report any SAEs that are believed to be related to prior 
study drug treatment. 
8.4.2. 
Reporting Serious Adverse Events 
8.4.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be be reported promptly to the sponsor or designee as described in Table 3. 
Table 3: 
Timeframe and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
Type 
Timeframe 
for Making 
Initial Report 
Documentation 
Method 
Timeframe 
for Making 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All 
SAEs 
Within 24 
hours of first 
knowledge of 
the SAE 
SAE report 
form 
As 
expeditiously 
as possible 
SAE report 
form 
Email or 
fax SAE 
report form 
Abbreviation: SAE, serious adverse event. 
8.4.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the sponsor within 24 hours as outlined above in Section 8.4.2.1.  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 timeframes. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying the sponsor of the event and completing the form.  
The form will be updated when additional information is received. 
The investigator will 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. 
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8.4.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.4.2.1.  The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  Prompt notification of SAEs by the investigator to the appropriate project 
contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards 
the safety of other patients are met. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
This protocol is being filed under an Investigational New Drug (IND) protocol amendment with 
the United States FDA.  Once active, a given SAE may qualify as an IND safety report if the 
SAE is both attributable to the study drug and unexpected.  In this case, all investigators filed to 
the IND (and associated INDs for the same compound) will receive an expedited investigator 
safety report, identical in content to the IND safety report submitted to the FDA. 
Expedited investigator safety reports are prepared according to the sponsor’s policy and are 
forwarded to investigators as necessary.  The purpose of the report is to fulfill specific regulatory 
and Good Clinical Practice (GCP) requirements regarding the product under investigation. 
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. 
8.4.3. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.4.4. 
Disease Progression 
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term.  Instead, 
the symptoms, signs or clinical sequelae 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 due to disease 
progression” instead of “disease progression”.  If a patient experienced a fatal multi-organ failure 
due to disease progression, the term “multi-organ failure due to disease progression” should be 
reported as the SAE with death as outcome instead of reporting “fatal disease progression” or 
“death due to disease progression.” 
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8.4.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg “death”, 
“death of unknown cause”, or “death unexplained.” 
8.4.6. 
Pregnancies 
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 study drug, 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 following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
8.5. 
Post-Study Adverse Event 
A post-study AE or SAE is defined as any adverse event that occurs after the AE/SAE reporting 
period, defined in Section 8.4.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients.  However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will 
notify the sponsor. 
8.6. 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards and 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 serious adverse events, the sponsor will 
assess the expectedness of the SAEs using the following reference documents: 
• BeiGene Investigator Brochure BGB-3111 
• Obinutuzumab Investigator Brochure and/or Prescribing Information (for marketed 
products) 
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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 (SAP). 
9.1. 
Study Endpoints 
9.1.1. 
Primary Endpoint 
The primary endpoint is overall response rate determined by independent central review using 
Lugano Classification for NHL (modified from Cheson et al, 2014).  The overall response rate is 
defined as the proportion of patients who achieve either complete response or partial response as 
best overall response.  Best overall response is defined as best response achieved during the 
entire follow-up period.  However, for the patients in arm B who cross over to arm A, the disease 
assessment after the crossover will not be included in the derivation of best overall response. 
9.1.2. 
Secondary Endpoints 
• Overall response rate determined by investigator assessment 
• Duration of response determined by independent central review and by investigator 
assessment, defined as the time from the date that response criteria are first met to the 
date that disease progression is objectively documented or death, whichever occurs 
first 
• Progression-free survival determined by independent central review and by 
investigator assessment, defined as the time from randomization to the date of first 
documentation of disease progression or death, whichever occurs first 
• Overall survival defined as the time from randomization to the date of death due to 
any reason. 
• Rate of complete response or complete metabolic rate determined by independent 
central review and by investigator assessment, defined as the proportion of patients 
who achieve complete response or complete metabolic rate as best overall response 
• Time-to-response determined by independent central review and by investigator 
assessment, defined as the time from randomization to the time the response criteria 
are first met 
• Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L 
questionnaires 
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, 
and vital signs 
• PK parameters such as apparent clearance of the drug from plasma (CL/F) and 
AUC0-12 
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9.1.3. 
Exploratory Endpoint 
• Overall response rate in arm B after crossover to arm A. 
9.2. 
Statistical Analysis 
9.2.1. 
Randomization Methods 
As discussed in Section 5.1, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization using the number of prior lines of therapy (2 to 3 vs 
> 3), rituximab-refractory status (yes vs no), and geographic region (China vs ex-China) as 
strata. 
9.2.2. 
Analysis Sets 
The Intent-to-Treat (ITT) analysis set includes all enrolled patients who are randomized.  The 
ITT analysis set will be the primary population used for efficacy analyses.   
The Safety analysis set includes all patients who received any dose of study drug.  Patients will 
be included in the treatment groups corresponding to the actual treatment received.  The Safety 
analysis set will be used for all safety analyses. 
The Per-Protocol analysis set includes patients who received any dose of study drug and had no 
major protocol deviations.  Criteria for exclusion from the Per-Protocol analysis set will be 
determined and documented before the database lock for the primary analysis.  
The PK analysis set includes all zanubrutinib-treated patients who have at least one measurable 
PK concentration. 
9.2.3. 
Efficacy Analysis 
9.2.3.1. 
Primary Efficacy Endpoint Analysis 
Primary inference of comparing overall response rate by independent central review will be 
based on a Cochran-Mantel-Haenszel test adjusted for the randomization factors (number of 
prior lines of therapy [2 to 3 vs > 3], rituximab-refractory status [yes vs no]), and geographic 
region (China vs ex-China) in the ITT analysis set. 
The null and alternative hypotheses for comparing overall response rate are as follows: 
 
H0: ORRA = ORRB 
 
Ha: ORRA > ORRB 
where ORRA is the overall response rate in arm A (zanubrutinib plus obinutuzumab) and ORRB 
is the overall response rate in arm B (obinutuzumab monotherapy).  If the obtained one-sided 
p-value is ≤ 0.025, it will be concluded that the combination therapy of zanubrutinib plus 
obinutuzumab results in a statistically significantly increase in ORR versus obinutuzumab 
monotherapy; thereby demonstrating the superiority of arm A over arm B.  
A common response rate difference (ORRA - ORRB) will be estimated using Cochran-
Mantel-Haenszel weights based on the number of patients in each stratum with 95% stratified 
confidence interval (CI). The common odds ratio of overall response rate and its 2-sided 95% 
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CIs will be calculated.  A Clopper-Pearson 95% CI of overall response rate will be constructed 
per each arm. 
Best overall response will be defined as the best response recorded from randomization till data 
cut or start of new anticancer treatment.  The disease assessments after crossover for patients in 
arm B who cross over to arm A will not be included in the determination of best overall 
response.  Patients with no post-baseline response assessment (due to whatever reason) will be 
considered as non-responders.  The proportion for each of the best response categories, complete 
response and partial response, will be presented by treatment group. 
The data cutoff for the primary efficacy analysis will be approximately 3 months after 
randomization of the last patient.  Study follow-up will continue as described in Section 3.4, 
Section 5.13, and Section 8.4. 
Additional analysis details will be provided in the SAP. 
9.2.3.2. 
Secondary Efficacy Endpoint Analyses 
Duration of Response 
Duration of response will be summarized only for patients who have achieved an objective 
response.  The distribution of duration of response will be summarized for each treatment group 
by the Kaplan-Meier method. 
Progression-free Survival 
PFS will be compared based on the log-rank test stratified by the randomization stratification 
factors (number of prior lines of therapy [2 to 3 vs > 3], rituximab-refractory status [yes vs no], 
and geographic region [China vs ex-China]).  The distribution of PFS, including median PFS and 
PFS rate at selected timepoints, will be estimated using the Kaplan-Meier method for each arm. 
The censoring rules for PFS will follow United States FDA Guidance for Industry, Clinical Trial 
Endpoints for Approval of Cancer Drugs and Biologics (2007) as follows.   
• PFS for patients without any post-baseline disease assessment will be censored at the 
time of randomization 
• PFS for patients without disease progression or death at the time of analysis will be 
censored at the time of the last disease assessment   
• PFS for patients who are lost to follow-up prior to documented disease progression 
will be censored at the last disease assessment date 
• PFS for patients who start to receive new anticancer therapy will be censored at the 
last tumor assessment date prior to the introduction of new therapy 
• PFS for patients with disease progression or death occurring immediately after two or 
more missed consecutive disease assessments will be censored at the last assessment 
tumor assessment before the missed consecutive disease assessments 
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Overall Survival 
OS between the 2 treatment groups will be compared using the same methods employed for the 
PFS comparison.  The distribution of OS (including median and other quartiles) and OS rate at 
selected timepoints will be estimated by the Kaplan-Meier method. 
Complete Response/Complete Metabolic Response 
CR rate and complete metabolic response rate will be calculated as the proportion of patients 
who reached best overall response of CR (complete metabolic response) or higher.  The CR and 
complete metabolic response rate will be compared between treatment groups using Fisher’s 
exact test.  A Clopper-Pearson 95% CI of complete response rate and complete metabolic 
response rate will be constructed per each arm. 
Time-to-Response 
Time-to-response will be summarized only for responders by sample mean, median and standard 
deviation for each treatment group. 
Patient-Reported Outcomes 
The EORTC QLQ-C30 questionnaire will be summarized for each assessment timepoint.  The 
percentage of patients with a clinically meaningful change from baseline in ‘global health 
status/QOL’ and functional domains will be summarized as “improved”, “stable” or “worsened” 
and compared between arms A and B.  The data will also be analyzed using repeated measure 
mixed model to account for missing data under missing at random assumption.  
Change of EQ-5D-5L score will be summarized descriptively.  
9.2.3.3. 
Exploratory Efficacy Endpoint Analysis 
The overall response rate in arm B after crossover to arm A will be summarized descriptively.  
An exact 95% CI will be provided. 
9.2.3.4. 
Sensitivity Analysis 
A subgroup analysis for ORR by independent central review and selected secondary endpoints 
will be performed.   
Primary and selected secondary endpoints may be analyzed using the Per-Protocol analysis set as 
sensitivity analyses. 
Time to event analysis for duration of response and time to response, which includes all patients, 
may be performed.  
A multiple logistic regression will be performed in order to explore the relationship between the 
baseline prognostic factors and ORR, as well as to estimate the treatment effect adjusted for the 
imbalances in those factors.  
9.2.4. 
Pharmacokinetic Analyses 
Plasma zanubrutinib concentrations will be summarized by scheduled time of collection.  A 
population PK analysis may be performed to include plasma concentrations of zanubrutinib from 
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this trial in an existing model.  PK parameters such as apparent clearance of the drug from 
plasma and AUC0-12 may be derived from the population PK analysis if supported by data. 
An exposure-response (efficacy or safety endpoints) analysis may be performed if supported by 
data.  The results from the population PK and exposure-response analyses may be reported 
separately from the Clinical Study Report. 
9.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v4.03.  
Laboratory values (CBC, clinical chemistry, coagulation), vital signs, physical exams and 
electrocardiogram findings will also be used in determining the safety.  Descriptive statistics will 
be used to analyze all safety data by treatment group. 
9.3.1. 
Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity (mg/day) and relative dose intensity. 
The number (percentage) of patients requiring dose reductions, dose interruption, dose delay, 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 by categories.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events 
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified 
into standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA®).  AEs will be coded to MedDRA (Version 18.1 or higher) lower level term closest 
to the verbatim term.  The linked MedDRA preferred term and primary system organ class are 
also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug 
up to 30 days following study drug discontinuation (Safety Follow-up visit) or initiation of new 
anticancer therapy, whichever comes first.  Only those AEs that were treatment-emergent will be 
included in summary tables.  All AEs, treatment-emergent or otherwise, will be presented in 
patient data listings. 
The incidence of treatment-emergent AEs will be reported as the number (percentage) of patients 
with treatment-emergent AEs by system organ class and preferred term.  A patient will be 
counted only once by the highest severity grade according to NCI-CTCAE v.4.03 within a 
system organ class and preferred term, even if the patient experienced more than 1 
treatment-emergent AE within a specific system organ class and preferred term.  The number 
(percentage) of patients with treatment-emergent AEs 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.  SAEs, deaths, 
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treatment-emergent AEs ≥ Grade 3, related treatment-emergent AEs, and treatment-emergent 
AEs that led to treatment discontinuation, dose reduction or dose interruption will be 
summarized.  
Incidence and time to diarrhea (≥ Grade 3), severe bleeding (defined as ≥ Grade 3 bleeding of 
any site or central nervous system bleeding of any grade), and atrial fibrillation will be 
summarized.  
9.3.3. 
Laboratory Analyses 
CBC and serum chemistry values will be evaluated for each laboratory parameter by treatment 
group. Abnormal laboratory values will be flagged and identified as those outside (above or 
below) the normal range.  Reference (normal) ranges for laboratory parameters will be included 
in the Clinical Study Report.  Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, maximum for continuous variables; n [%] for categorical variables) for 
laboratory parameters and their changes from baseline will be calculated.  Laboratory values will 
be summarized by visit and by worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE (v.4.03) will be summarized by CTCAE 
grade.  In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) 
will be summarized separately. 
9.3.4. 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
temperature, and weight) and changes from baseline will be presented by visit and treatment 
group for all visits.  Vital signs will be listed by patient and visit. 
9.3.5. 
Electrocardiogram 
ECG assessments will be performed at the screening visit.  Descriptive statistics for baseline 
ECG parameters will be presented.  
9.3.6. 
Sample Size Considerations 
The sample size calculation is based on the comparison of the primary endpoint of ORR in the 
ITT analysis set.  Assuming ORRA = 0.55 and ORRB = 0.30, 210 patients will be enrolled in a 
2:1 ratio (140 patients in arm A and 70 patients in arm B) to provide a power of approximately 
91% in testing ORRA versus ORRB using a normal approximation to binomial distribution with a 
2-sided significance level of 0.05 with continuity correction. The sample size calculation is based 
on methods in Hulley et al, 2013 and Fleiss et al, 1980. 
9.3.7. 
Interim Analysis 
There is no interim analysis planned for this study.  
9.3.8. 
Final Analysis 
A final analysis prior to study termination will be performed.  The time and scope of the final 
analysis will be included in the SAP.  
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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Steering Committee 
This study will be overseen by a Steering Committee consisting of experts in follicular 
lymphoma and members of the sponsor’s staff.  The Steering Committee plays a central role in 
the design of the study, oversees the conduct of the study, and is to agree on a plan for 
communication of the results. 
10.2. 
Data Monitoring Committee 
An independent DMC consisting of experts in follicular lymphoma, clinical trial safety 
monitoring, and statistics will evaluate safety data periodically for this study.  Approximately 
every 6 months after the first 50 patients are enrolled and have 3 months’ follow-up, the DMC 
will review all available safety data.  A separate charter will outline the details for the 
composition and responsibility of the DMC. 
10.3. 
Independent Central Review 
The sponsor will contract with an independent central review facility to provide an independent 
and blinded review of imaging and clinical data necessary to assess tumor response in the BGB-
3111-212 study.  This will be conducted by qualified, board-certified radiologists and 
hematologists assigned to the BGB-3111-212 study.  An independent central review charter will 
describe the independent review and define the processes, roles, and responsibilities of the 
sponsor, the sites, the independent central review facility, and the reviewers. 
10.4. 
Provision of Study Results and Information to Investigators 
When the clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigator.  
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s). 
The sponsor will not routinely inform the investigator or patient of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will 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 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2. 
Investigator Responsibilities 
11.2.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” International Conference for Harmonisation (ICH) guidelines, and that 
the basic principles of “Good Clinical Practice,” as outlined in 21 Code of Federal Regulations 
(CFR) 312, Subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, Part 50, and 
21 CFR, Part 56, are adhered to. 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP 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 IEC/IRB.  The IEC/IRB 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 IEC/IRB 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 IEC/IRB approval, the approved informed 
consent form, and any other information that the IEC/IRB has approved for presentation to 
potential patients. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has 
approved for presentation to potential patients is amended during the study, the investigator is 
responsible for ensuring the IEC/IRB 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 IEC/IRB 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 IEC/IRB 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. 
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 
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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 8.4.2.3, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs to the IEC/IRB, 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 IEC/IRB.  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 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 ICF or as a separate signed document (for example, in 
the US, a site-specific HIPAA 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 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 
trial. 
The investigator agrees that all information received from BeiGene, including but not limited to 
the IB, this protocol, CRFs, 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. 
11.2.6. 
Case Report Forms 
For each patient randomized/assigned to treatment, an eCRF must be completed and signed by 
the principal investigator or subinvestigator within a reasonable time period after data collection.  
If a patient withdraws from the study, the reason must be noted in the appropriate eCRF.  If a 
patient is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome. 
The eCRF exists within an electronic data capture (EDC) system with controlled access managed 
by BeiGene or its authorized representative for this study.  Study staff will be appropriately 
trained in the use of eCRFs and applications of electronic signatures before being given access to 
the EDC system.  Original data and any changes of data will be recorded using the EDC system, 
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with all changes tracked by the system and recorded in an electronic audit trail.  The investigator 
attests that the information contained in the eCRF is true by providing an electronic signature 
within the EDC system.  After final database lock, the investigator will receive a copy of the 
patient data from that site (eg, paper, CD, or other appropriate media) for archiving the data at 
the study site.  
11.2.7. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records and returned or 
destroyed study product.  Dispensation records will document quantities received from BeiGene 
and quantities dispensed to patients, including lot number, date dispensed, patient identifier 
number, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements.  At the end of 
the study, following final drug inventory reconciliation by the monitor, the study site will dispose 
of and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet BeiGene’s requirements for disposal, arrangements will be 
made between the site and BeiGene or its representative for destruction or return of unused study 
drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
11.2.8. 
Inspections 
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, or to 
regulatory authority or health authority inspectors. 
11.2.9. 
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. 
11.3. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene.  All protocol modifications must be submitted to competent 
authorities according to local requirements and to the IRB/IEC together with, if applicable, a 
revised model ICF in accordance with local requirements.  Written documentation from 
competent authorities (according to local requirements) and from the IRB/IEC and required site 
approval must be obtained by the sponsor before changes can be implemented. 
Information on any change in risk and /or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming willingness to remain in the trial. 
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11.4. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the trial.  The data generated in this clinical trial are the exclusive 
property of the sponsor and are confidential.  Because 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 prior to submission or presentation in 
accordance with the clinical study agreement.  This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy.  Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings in advance 
of the publication/presentation. 
11.5. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolve and close all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Return of treatment codes to the sponsor 
• Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend or prematurely discontinue this study either 
at a single study center or at all study centers at any time for reasons including, but not limited 
to, safety or ethical issues or severe noncompliance.  If the sponsor determines such action is 
needed, the sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time.  When feasible, the sponsor will provide advance notification to the 
investigator of the impending action prior to it taking effect. 
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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 IEC/IRB promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor.  In 
addition, arrangements will be made for all unused study drug(s) in accordance with the 
applicable sponsor procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
11.6. 
Records Retention and Study Files 
The investigator must maintain adequate and accurate records 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, CRF 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 CRFs) would include (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, electrocardiogram, electroencephalogram, X-ray, pathology and 
special assessment reports, consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location.  The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel.  Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken.  The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable 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 the 
records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples remaining after this study may be retained in storage by the sponsor for a 
period up to 2 years. 
11.7. 
Information Disclosure and Inventions 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) is the sole property of the 
sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study are the sole property of the sponsor, and are hereby 
assigned to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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 which becomes publicly available through no fault of the investigator or 
study center personnel 
• Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information which is necessary to disclose in order to provide appropriate medical 
care to a patient 
• Study results which may be published as described in Section 11.4. 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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11.8. 
Joint Investigator/Sponsor Responsibilities 
11.8.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the CRFs for 
consistency. 
The monitor is responsible for routine review of the CRFs 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 CRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
11.8.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study.  If the investigator is notified of an 
inspection by a regulatory authority the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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12. 
REFERENCES 
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BeiGene Investigator Brochure, BGB-3111. Edition 4, February 2017. 
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Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the new 
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Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the 
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Howlader N, Morton LM, Feuer EJ, et al.  Contributions of Subtypes of Non-Hodgkin 
Lymphoma to Mortality Trends.  Cancer Epidemiol Biomarkers Prev. 2016;25(1):174-9.  
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Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and 
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Marcus RE, Davies AJ, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs 
progression-free survival (PFS) in patients with previously untreated follicular lymphoma: 
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Meeting, December 4, 2016; San Diego, California. Abstract 6. 
Mounier M, Bossard N, Remontet L, et al. Changes in dynamics of excess mortality rates and net 
survival after diagnosis of follicular lymphoma or diffuse large B-cell lymphoma: comparison 
between European population-based data (EUROCARE-5). Lancet Haematol. 
2015;2(11):e481-91. 
National Comprehensive Cancer Network Treatment Practice Guidelines B-cell Lymphoma 
Version 3.2017: March 27, 2017. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55. 
Relander T, Johnson NA, Farinha P, et al.  Prognostic factors in follicular lymphoma.  J Clin 
Oncol. 2010;28(17):2902-13. 
Salles GA, Trotman J, Lill M, et al. Pseudo-progression among patients with follicular 
lymphoma treated with ibrutinib in the phase 2 DAWN study. Blood. 2016;128:2980. 
Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy with rituximab and overall survival 
in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl 
Cancer Inst. 2007;99(9):706-14. 
Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed 
by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood. 
2012;119(22):5118-25.  
Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) 
with rituximab in patients with relapsed CD20 indolent B-cell non-Hodgkin lymphoma: final 
analysis of the GAUSS study. J Clin Oncol. 2015;33(30):3467-74.  
Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine 
monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma 
(GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 
2016;17(8):1081-93.  
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Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. 
Blood. 2004;104:1258-65. 
Swerdlow S, Campo E, Harris NL, et al. WHO classification of tumors of hematopoetic and 
lymphoid tissues. IARC, Lyon. 2008. 
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. 
Tam CS, Simpson D, Opat S, et al. Safety and activity of the highly specific BTK inhibitor 
BGB-3111 in patients with indolent and aggressive non Hodgkin’s lymphoma (59th ASH 
Annual Meeting & Exposition oral presentation, Abstract #152). Blood 2017;130:152. 
Zydelig FDA Alerts. March 14, 2016. https://www.fda.gov/drugs/drug-safety-and-
availability/fda-alerts-healthcare-professionals-about-clinical-trials-zydelig-idelalisib-
combination-other. Accessed 11 August 2021. 
Zydelig [prescribing information]. Foster City, CA: Gliead Sciences, Inc; 2016. 
Zydelig [summary of product characteristics]. Foster City, CA: Gliead Sciences, Inc; 2016. 
 
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APPENDIX 1. SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
An International, Phase 2, Open-Label, Randomized Study of 
BGB-3111 Combined with Obinutuzumab Compared With 
Obinutuzumab Monotherapy in Relapsed/Refractory Follicular 
Lymphoma 
PROTOCOL NO: 
BGB-3111-212 
This protocol is a confidential communication of BeiGene, Ltd.  I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol.  I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with good clinical practices and the applicable laws and regulations.  Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will 
be published or disclosed without prior written approval from BeiGene, Ltd. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, 
and the name of the center in which the study will be conducted.  Return the signed copy to PRA. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: _______________________________   Date:  _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 
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APPENDIX 2. MODIFIED LUGANO CLASSIFICATION FOR NHL 
Response and Site 
PET-CT-Based Response  
(Patients with FDG-Avid Disease at Screening) 
CT-Based Response 
(Patients Without FDG-Avid Disease at Screening) 
Complete     
Lymph nodes and 
extralymphatic sites 
Complete metabolic response 
Score 1, 2, 3* with or without a residual mass on 5-point scale 
It is recognized that in Waldeyer’s ring or extranodal sites with 
physiologic uptake or with activation within spleen or 
marrow (e.g., 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 
Complete radiologic response (all of the following): 
• Target nodes/nodal masses must regress to ≤ 1.5 cm in longest 
transverse diameter of a lesion 
• No extralymphatic sites of disease 
 
     Non-measured lesion Not applicable 
Absent 
     Organ enlargement 
Not applicable 
Regress to normal 
     New lesions 
None 
None 
     Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology, if indeterminate, immunohistochemistry 
negative 
Partial 
     Lymph nodes and 
extralymphatic sites 
Partial metabolic response 
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 
Partial remission (all of the following): 
• 
≥ 50% decrease in sum of the product of the perpendicular 
diameters for multiple lesions of up to 6 target measurable 
nodes and extranodal sites 
• When a lesion is too small to measure on CT, assign 5 mm x 5 
mm as the default value 
• When no longer visible, 0 x 0 mm 
• For a node > 5 mm x 5 mm, but smaller than normal, use actual 
measurement for calculation 
     Non-measured lesions Not applicable 
Absent/normal, regressed, but no increase 
     Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond normal 
     New lesions 
None 
None 
     Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in the context of a 
nodal response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan 
Not applicable 
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Response and Site 
PET-CT-Based Response  
(Patients with FDG-Avid Disease at Screening) 
CT-Based Response 
(Patients Without FDG-Avid Disease at Screening) 
No response or stable 
disease 
Target nodes/nodal 
masses, extranodal 
lesions 
No metabolic response 
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment 
Stable disease 
< 50% decrease from baseline in sum of the product of the 
perpendicular diameters for multiple lesions of up to 6 dominant, 
measurable nodes and extranodal 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** 
Individual target 
nodes/nodal masses 
 
Progressive metabolic disease 
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 
 
Progressive disease requires at least 1 of the following cross product 
of the longest transverse diameter of a lesion and perpendicular 
diameter progression: 
 
An individual node/lesion must be abnormal with: 
• longest transverse diameter of a lesion > 1.5 cm and 
• Increase by ≥ 50% from cross product of the longest transverse 
diameter of a lesion and perpendicular diameter nadir and 
• An increase in longest transverse diameter of a lesion or shortest 
axis perpendicular to the longest transverse diameter of a lesion 
from nadir 
o 
0.5 cm for lesions ≤ 2 cm 
o 
1.0 cm for lesions > 2 cm 
• In the setting of splenomegaly, the splenic length must increase 
by > 50% of the extent of its prior increase beyond baseline (e.g., 
a 15-cm spleen must increase to > 16 cm).  If no prior 
splenomegaly, must increase by at least 2 cm from baseline 
• New or recurrent splenomegaly 
     Non-measured lesions None 
New or clear progression of pre-existing non-measured lesions 
     New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered 
• Regrowth of previously resolved lesions 
• A new node > 1.5 cm in any axis 
• A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be attributable to 
lymphoma 
• Assessable disease of any size unequivocally attributable to 
lymphoma 
     Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
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Abbreviations: CT, computed tomography; FDG, [18F]fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography. 
Modified from Cheson BD, Fisher RJ, Barrington SF, et al.  J Clin Oncol 2014;32(27):3059-67. 
*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).  Measured dominant lesions: 
Up to six of the largest dominant nodes, nodal masses, and extranodal 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 
(e.g., liver, spleen, kidneys, lungs), gastrointestinal involvement, cutaneous lesions, or those noted on palpation.  Non-measured lesions: Any disease not selected 
as measured, dominant disease and truly assessable disease should be considered not measured.  These sites include any nodes, nodal masses, and extranodal 
sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal 
sites (e.g., gastrointestinal tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no 
higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
 
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 
Modification from Lugano Classification for NHL (Cheson et al, 2014): 
**Pseudoprogression has been observed in patients receiving a BTK inhibitor.  For patients in either arm, a timepoint finding of 
“disease progression” will require a confirmatory scan at least 4 weeks after the scan that demonstrated possible progression.  An 
exception to the confirmatory scan requirement exists if one or more of the clear, clinical signs of progression detailed in Section 5.6 
is present and the investigator believes the progression is unequivocal.  Patients may continue study treatment while they wait for the 
confirmation imaging. 
Note:  Temporary withholding of study drug (eg, for drug-related toxicity, surgery, or intercurrent illness) for as little as 7 days can 
cause a transient worsening of disease and/or of constitutional symptoms.  In such circumstances, and if medically appropriate, 
patients may resume therapy and relevant clinical, laboratory, and/or radiologic assessments should be performed to document 
whether tumor control can be maintained or whether actual disease progression has occurred.   
Isolated increase in lymph nodes and/or splenomegaly during periods of zanubrutinib hold will not be considered as progressive 
disease unless confirmed by a repeat imaging studies at least 6 weeks after restarting study drug administration.  The response 
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category “indeterminate due to zanubrutinib hold” should be selected for such instances.  Following the repeat imaging 6 weeks after 
restarting study drug, response should be in comparison to the imaging at baseline. 
 
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APPENDIX 3. DIAGRAM FOR NODAL AREAS IN FLIPI SCORE 
This diagram is to be used for counting the number of nodal areas involved.  Each rectangle 
corresponds to a nodal area.  Nodal areas considered were cervical, axillary, inguino-crural, para 
aortic and/or iliac, celiac and/or mesenteric, and other ancillary nodal sites. Involved area (or 
areas) either clinically or on CT scan (or scans) was quoted as 1 (2 if bilateral) and each patient 
had between 0 and 8 or more involved areas. 
 
Source:  Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 
2004;104:1258-65.  
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APPENDIX 4. NEW YORK HEART ASSOCIATION CLASSIFICATION 
NYHA Class 
Symptoms 
• I 
• Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g. 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, e.g. walking short distances (20-100 m). Comfortable 
only at rest. 
• IV 
• Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound subjects. 
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APPENDIX 5. ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
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APPENDIX 6. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 
5-LEVELS HEALTH QUESTIONNAIRE 
 
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APPENDIX 7. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 
 
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APPENDIX 8. DOSE MODIFICATION FOR ZANUBRUTINIB WHEN 
CO-ADMINISTERED WITH STRONG/MODERATE 
CYP3A INHIBITORS OR INDUCERS 
CYP3A 
Co-administered Drug 
Recommended use 
Inhibition 
Strong CYP3A inhibitor (eg, ketoconazole, 
conivaptan, clarithromycin, indinavir, 
itraconazole, lopinavir, ritonavir, telaprevir, 
posaconazole, voriconazole) 
80 mg once daily 
Moderate CYP3A inhibitor (eg, erythromycin, 
ciprofloxacin, diltiazem, dronedarone, 
fluconazole, verapamil, aprepitant, imatinib, 
grapefruit products) 
80 mg twice daily 
Induction 
Strong CYP3A inducer (eg, carbamazepine, 
phenytoin, rifampin, St. John’s wort) 
Avoid concomitant use; Consider alternative 
agents with less induction potential. 
Moderate CYP3A inducer (eg, bosentan, 
efavirenz, etravirine, modafinil, nafcillin) 
160 mg twice daily, use with caution; Monitor 
for potential lack of efficacy. 
 
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a. 
Note that there is no required visit for Cycle 7. 
b. Efficacy assessments are performed every 12 weeks after day of first dose for 96 weeks (approximately 24 months), then every 24 weeks for the next 
24 months and then yearly until disease progression.  To avoid duplication of physical examinations and examination of liver and spleen to fulfill the 
separate Safety and Efficacy requirements, the following guideline may be used: It is not necessary to perform duplicate assessments so long as each 
Cycle Visit and Response Evaluation Visit window is met. 
c. 
To occur 30 (± 7) days after permanent discontinuation of zanubrutinib and also 90 days after the permanent discontinuation of obinutuzumab (note: the 
obinituzumab safety follow-up visit may be performed as part of a required visit for patients continuing on zanubrutinib).  Patients must continue with the 
Response Evaluation schedule until date of centrally confirmed disease progression. 
d. Response assessments repeat every 12 weeks until centrally-confirmed disease progression, withdrawal of consent, death, or lost to follow-up, whichever 
occurs first.  If a patient has already transitioned to response assessments every 24 weeks or yearly, they may continue to follow the same visit frequency in 
Long-Term Follow-Up. Patients with centrally confirmed disease progression will be followed up only for survival status and information about their 
next-line therapy. Survival and next-line therapy follow-up will continue until withdrawal of consent, death, or lost to follow-up, whichever occurs first 
(contact to collect data will be in person or via phone [with the patient’s guardian, if applicable]). 
e. 
This must occur before any study-specific procedures, and may be obtained before the 35-day screening window.  Consent must be obtained using the 
current version of the form approved by the ethics committee. 
f. 
After a patient is screened and the investigator determines the patient is eligible for randomization, study site personnel will complete an Eligibility 
Authorization Packet and email it to the medical monitor or designee to approve the 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.   
g. Eligible patients will be randomized based on number of prior lines of therapy (2 to 3 vs ˃ 3), rituximab-refractory status (yes vs no), and geographic region 
(China vs ex-China).  Central randomization (2:1) will be used to assign patients to 1 of the following 2 arms: zanubrutinib plus obinutuzumab or 
obinutuzumab monotherapy. Study treatment must commence within 5 days after randomization. 
h. If an archival tissue sample is available, it should be sent to the central pathology laboratory for confirmation of tissue diagnosis.  It is not required that the 
archival tissue sample be sent before randomization/treatment assignment 
i. 
Obinutuzumab (arms A and B) will be administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, then 1,000 mg on Day 1 of Cycles 2 to 6, then 
1,000 mg every 8 weeks.  (At the discretion of the investigator, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 
instead of 1,000 mg on Day 1 of Cycle 1.)  Responding patients may continue to receive maintenance obinutuzumab every 8 weeks for an additional 24 
months (eg, maximum total duration of obinutuzumab of approximately 30 months [maximum 20 doses]). 
j. 
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a day) with or without food.  Patients who progress on 
obinutuzumab monotherapy are able to crossover to receive obinutuzumab plus zanubrutinib with confirmation of PD and discussion with medical monitor.  
At the end of Cycle 12, patients in the obinutuzumab arm without a PR or CR have the option to crossover to receive obinutuzumab plus zanubrutinib. 
k. Sparse PK samples will be collected from patients randomized to arm A (zanubrutinib plus obinutuzumab) at the following time points: predose (within 
30 min prior to zanubrutinib dosing) and 2 hours (± 30 min) post zanubrutinib dose on Day 1 of Cycle 1 and Day 1 of Cycle 2.  No sparse PK samples are 
required during crossover treatment.  The times of zanubrutinib administration and PK collection will be recorded. 
l. 
Safety assessments will be conducted on Day 1 of every cycle, unless otherwise specified. 
m. Assess systems per standard of care at the study site and as clinically indicated by symptoms.  Includes weight (height at screening only).   
n. A 12-lead electrocardiogram (ECG) will be performed in triplicate at screening.   
o. Collect non-serious AE information from the time of first dose of study drug through safety follow-up.  Collect SAE information from the time of signed 
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informed consent through screen failure or safety follow-up.   
p. Tumor assessments, including imaging studies, will be performed at screening, every 12 weeks from Cycle 1 Day 1 for 24 months, then every 24 weeks for 
24 months, and then yearly until disease progression.  Due to the potential for pseudoprogression cases in this study, patients in both Arms A and B should 
remain on study treatment while the patient waits for the confirmation scan results.  All known sites of disease must be documented at screening and 
reassessed at each subsequent tumor evaluation. All patients must undergo PET/CT scan during screening.  Patients whose disease is not FDG-avid at 
screening will be followed by CT-based assessments alone.  Patients whose disease is FDG-avid at screening will be followed by an integration of PET-CT 
and CT-based assessments as follows:  PET-CT scans are required at screening, end of Cycles 3, 6, and 12, and to confirm a result on CT scan (CR/PR or 
disease progression); CT scans with contrast are required at all other tumor response assessments.  For patients with a contraindication to receiving CT scan 
IV-contrast (eg, contrast allergy, or other medical contraindication such as renal insufficiency), MRI may be used in place of CT scans.  For patients being 
assessed via MRI, a non-contrast chest CT scan is acceptable, and preferred, in place of a chest MRI to evaluate the lung parenchyma.  The same imaging 
technique (ie, CT, MRI) should be used consistently throughout a patient’s time on the study.  Copies of all scans will be sent for independent central review 
for response assessment.  
q. Bone marrow biopsy is required under the following conditions during the treatment period: during screening to assess bone marrow involvement of 
lymphoma; and if clinical and laboratory results demonstrate that a CR has been achieved, in order to confirm a CR.  All of the pathology samples will be 
collected and reviewed by a pathologist from central pathology laboratory. 
r. 
Patients should complete the EQ-5D-5L and EORTC QLQ-C30 questionnaires before the first dose of study drug, and when possible before performing any 
other procedures.  No PRO questionnaires are required during crossover treatment.   
s. 
Complete blood count and differential will be evaluated by a central laboratory.  CBC includes hemoglobin, hematocrit, platelet count, red blood cell count, 
white blood cell count with differential including neutrophils (including bands), lymphocytes, monocytes, eosinophils, and basophils. 
t. 
Serum chemistry will be evaluated by a central laboratory and includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, 
calcium, phosphate/phosphorus, magnesium, total bilirubin, total protein, albumin, ALT, AST, lactate dehydrogenase, and alkaline phosphatase. 
u. Quantitative serum immunoglobulins (IgG, IgM, IgA) will be measured at screening; on Day 1 of Cycle 3, Cycle 6, Cycle 9, and Cycle 12; and then every 
24 weeks thereafter until disease progression, withdrawal of consent, death, or lost to follow up, whichever occurs first. 
v. β2-Microglobulin will be assessed by a local laboratory either during screening or predose on Day 1 of Cycle 1 (central lab services may be used in some 
countries).  β2-Microglobulin may be tested postdose as medically necessary. 
w. Prothrombin time, which will also be reported as international normalized ratio, and activated partial thromboplastin time will be evaluated by a central 
laboratory. 
x. Patients who are at risk for HBV reactivation as defined in Section 5.8 will undergo viral load testing at least monthly.  Patients who are HCV 
antibody-positive, but negative for HCV RNA, will undergo viral load testing at least monthly.  Hepatitis B and hepatitis C testing will be by local 
laboratories, but central lab services may be used in some countries – for example if required to achieve the needed sensitivity. 
y. For all women of childbearing potential (including those who have had a tubal ligation), a serum pregnancy test will be performed at screening, within 
7 days of randomization, and at end of treatment.  During treatment, laboratory-based, highly-sensitive pregnancy tests (urine or serum) will be performed 
within 4 weeks after Cycle 1, Day 1 and then every 4 weeks even if the timing falls outside of the normally scheduled visits.  Pregnancy tests must be 
continued every 4 weeks for at least 90 days after the last dose of study drug (even if the timing falls outside of the normally scheduled visits).  Pregnancy 
tests will be evaluated by local or central laboratories.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
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BGB-3111-212                                                                                   
Statistical Analysis Plan Version 1.0                                                            
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-212 
Study Protocol 
Title: 
An International, Phase 2, Open-Label, Randomized Study of BGB-3111 
Combined with Obinutuzumab Compared With Obinutuzumab Monotherapy 
in Relapsed/Refractory Follicular Lymphoma 
Date: 
12 November, 2021 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
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SIGNATURE PAGE 
Author:  
 
 
 
                
 
 
 
 
 
Signature 
Date:  ______________ 
 
 
 
 
 
 
 
 
 
Approval: 
 
 
 
 
 
 
Signature 
Date: ________________ 
 
 
 
 
 
 
 
 
 
Signature 
Date: ________________ 
 
 
 
 
 
 
 
 
 
 
Signature 
Date: ________________ 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
8 
2 
STUDY OVERVIEW 
8 
3 
STUDY OBJECTIVES 
10 
3.1 
Primary Objectives: 
10 
3.2 
Secondary Objectives: 
10 
3.3 
Exploratory Objectives: 
10 
4 
STUDY ENDPOINTS 
11 
4.1 
Primary Endpoints 
11 
4.2 
Secondary Endpoints 
11 
4.3 
Exploratory Endpoint 
12 
5 
SAMPLE SIZE CONSIDERATIONS 
12 
6 
STATISTICAL METHODS 
12 
6.1 
Analysis sets 
12 
6.2 
Data Analysis General Considerations 
13 
6.2.1 
Definitions and Computations 
13 
6.2.2 
Handling of Missing Data 
14 
6.2.3 
Adjustment for Covariates 
14 
6.2.4 
Multiplicity Adjustment 
14 
6.2.5 
Data Integrity 
14 
6.3 
Patient Characteristics 
15 
6.3.1 
Patient Disposition 
15 
6.3.2 
Protocol Deviations 
15 
6.3.3 
Randomization Stratification Factors 
16 
6.3.4 
Demographic and Other Baseline Characteristics 
16 
6.3.5 
Disease History 
16 
6.3.6 
Medical History 
17 
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6.3.7 
Prior Anticancer Therapies and Surgeries 
17 
6.3.8 
Prior and Concomitant Medications 
18 
6.4 
Efficacy Analysis 
19 
6.4.1 
Primary Efficacy Endpoint 
19 
6.4.2 
Secondary Efficacy Endpoints 
20 
6.4.2.1 
ORR by Investigator Assessment 
20 
6.4.2.2 
Progression-Free Survival 
20 
6.4.2.3 
Duration of Response 
22 
6.4.2.4 
Overall Survival 
22 
6.4.2.5 
Complete Response Rate 
22 
6.4.2.6 
Time to Response 
23 
6.4.2.7 
Patient-Reported Outcomes 
23 
6.4.3 
Sensitivity Analysis 
24 
6.4.4 
Subgroup Analyses 
25 
6.4.5 
Exploratory Efficacy Endpoints 
26 
6.5 
Safety Analyses 
26 
6.5.1 
Extent of Exposure 
26 
6.5.2 
Adverse Events 
27 
6.5.3 
Laboratory Values 
29 
6.5.4 
Vital Signs 
31 
6.5.5 
Electrocardiograms (ECG) 
31 
6.5.6 
ECOG 
31 
6.6 
PK Analyses 
31 
7 
INTERIM ANALYSIS 
31 
8 
CHANGES IN THE PLANNED ANALYSIS 
31 
9 
REFERENCES 
31 
APPENDIX A. 
IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES 
 
33 
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APPENDIX B. 
ADVERSE EVENTS OF SPECIAL INTEREST 
CATEGORIES AND SEARCH CRITERIA 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AEs 
Adverse events 
ADI 
Actual dose intensity 
AUC 
Area under the plasma concentration-time curve 
BID 
Bis in die (twice a day) 
BMI 
Body mass index 
BTK 
Bruton tyrosine kinase 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CR 
Complete response 
CT 
Computed tomography 
DIPP 
Data integrity protection plan 
DOR 
Duration of response 
eCRF 
Electronic case report form 
EAIR 
Exposure-Adjusted Incidence Rate 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
FL 
Follicular lymphoma 
GHS/QoL 
Global health status/Quality of life 
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ICR 
Independent central review 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NHL 
Non-Hodgkin’s lymphoma 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
QD 
Quaque die (once a day) 
RDI 
Relative dose intensity 
SAEs 
Serious adverse events 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO DD 
World Health Organization Drug Dictionary 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report the results for BGB-3111-212: An International, 
Phase 2, Open-Label, Randomized Study of BGB-3111 Combined with Obinutuzumab Compared 
With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma. The focus of this 
SAP is the planned primary analysis specified in this study protocol.  
Details of the pharmacokinetic/pharmacogenomics analyses are not described in this SAP.   
 
2 
STUDY OVERVIEW 
This is an international, phase 2, open-label, randomized, active-control study of BGB-3111 
(zanubrutinib) plus obinutuzumab versus obinutuzumab monotherapy in 210 patients with 
relapsed or refractory follicular lymphoma. The primary efficacy endpoint is overall response rate 
(ORR) determined by independent central review (ICR). Disease response will be assessed per the 
Lugano Classification for Non-Hodgkin Lymphoma (NHL) (Cheson et al, 2014) - hereafter 
referred to as Lugano Classification for NHL.  
Central randomization (2:1) will be used to assign patients to one of the following study drug 
treatments:  
Arm A: zanubrutinib plus obinutuzumab  
Arm B: obinutuzumab monotherapy  
Randomization will be stratified by the number of prior lines of therapy (2 to 3 vs ˃ 3), rituximab-
refractory status (yes vs no), and geographic region (China vs ex-China). Treatment with 
zanubrutinib plus obinutuzumab and treatment with obinutuzumab monotherapy will be open 
label. Study treatment must commence within 5 days after randomization. 
Each cycle consists of 28 days. Study drug treatments will be administered as follows, depending 
on cohort and treatment assignment: 
• Zanubrutinib will be administered as two 80 mg capsules by mouth twice a day (160 mg 
twice a day) with or without food. 
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• Obinutuzumab will be administered as follows: 1,000 mg intravenously on Days 1, 8, and 
15 of Cycle 1, then 1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 mg every 8 weeks (at 
the discretion of the investigator, obinutuzumab may be administered as 100 mg on Day 
1 and 900 mg on Day 2 of Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1). Responding 
patients may continue to receive maintenance obinutuzumab every 8 weeks for an 
additional 24 months (eg, maximum total duration of obinutuzumab of approximately 30 
months [maximum 20 doses]). 
• At the discretion of the investigator, patients in Arm B will be eligible to receive crossover 
treatment with zanubrutinib plus obinutuzumab if they experience progressive disease 
(PD) or their disease does not respond to therapy with a complete response (CR) or partial 
response (PR) after 12 months. This must be confirmed by ICR. For patients who initiate 
crossover treatment with zanubrutinib plus obinutuzumab, safety, laboratory, and 
response evaluation assessments will continue to be performed per the Schedule of 
Assessments (Appendix 9 in the protocol). 
Tumor assessments, including imaging studies, will be performed at screening, every 12 weeks 
from Cycle 1 Day 1 for 24 months, then every 24 weeks for 24 months, and then yearly until 
disease progression. All known sites of disease must be documented at screening and reassessed 
at each subsequent tumor evaluation. All patients must undergo PET-CT scan during screening. 
Patients whose disease is not [18F]fluorodeoxyglucose (FDG)-avid at screening will be followed 
by CT-based assessments alone. Patients whose disease is FDG-avid at screening, by either site 
assessment or the central imaging vendor, will be followed by an integration of PET-CT and CT-
based assessments as follows: 
• PET-CT scans are required at screening, end of Cycles 3, 6, and 12, and to confirm 
a result on CT scan (CR/PR or disease progression) 
• CT scans with contrast are required at all other tumor response assessments 
Patients receiving zanubrutinib should remain on study treatment until disease progression is 
confirmed by ICR. Patients receiving obinutuzumab should remain on study treatment until either 
disease progression is confirmed by ICR or approximately 30 months of treatment with 
obinutuzumab (maximum 20 doses), whichever occurs first. 
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Assessments of safety will include AEs, SAEs, clinical laboratory tests, physical examinations, 
and vital signs. AEs will be graded for severity per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. An independent data 
monitoring committee will periodically monitor safety data. 
 
3 
 STUDY OBJECTIVES 
All primary and secondary objectives will compare zanubrutinib plus obinutuzumab versus 
obinutuzumab monotherapy. 
3.1 
PRIMARY OBJECTIVES:  
• To evaluate efficacy, as measured by ORR determined by ICR  
3.2 
SECONDARY OBJECTIVES:  
• To evaluate efficacy, as measured by the following: 
o ORR determined by investigator assessment  
o Duration of response (DOR) determined by ICR and by investigator assessment  
o Progression-free survival (PFS) determined by ICR and by investigator 
assessment  
o Overall survival (OS) 
o Rate of CR or complete metabolic response determined by ICR and by investigator 
assessment  
o Time to response determined by ICR and by investigator assessment  
o Patient-reported outcomes  
• Safety and tolerability  
• Pharmacokinetics (zanubrutinib plus obinutuzumab arm only)  
3.3 
EXPLORATORY OBJECTIVES:  
• ORR in obinutuzumab arm after crossover to receive zanubrutinib plus Obinutuzumab 
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4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• The primary endpoint is ORR determined by ICR using Lugano Classification for NHL. 
The ORR is defined as the proportion of patients who achieve either CR or PR as best 
overall response, defined as best response achieved during the entire follow-up period, until 
the data cutoff date, the start of a new anticancer therapy, or the crossover date for patients 
in Arm B who cross over to Arm A.  
4.2 
SECONDARY ENDPOINTS 
• ORR determined by investigator assessment, defined similarly as ORR determined by 
ICR.  
• DOR determined by ICR and by investigator assessment, defined as the time from the date 
that response criteria are first met to the date of first documentation of disease progression 
or death, whichever occurs first. For patients in Arm B who cross over to Arm A, the 
disease assessment after the crossover will not be included in the derivation. 
• PFS determined by ICR and by investigator assessment, defined as the time from 
randomization to the date of first documentation of disease progression or death, 
whichever occurs first. For patients in Arm B who cross over to Arm A, the disease 
assessment after the crossover will not be included in the derivation. 
• OS defined as the time from randomization to the date of death due to any reason.  
• Rate of CR or complete metabolic rate determined by ICR and by investigator assessment, 
defined as the proportion of patients who achieve CR or complete metabolic rate as best 
overall response from randomization until the data cutoff date, the start of a new anticancer 
therapy, or the crossover date for patients in Arm B who cross over to Arm A.  
• Time-to-response determined by ICR and by investigator assessment, defined as the time 
from randomization to the time the response criteria are first met. For patients in Arm B 
who cross over to Arm A, the disease assessment after the crossover will not be included 
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in the derivation. 
• Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L questionnaires.  
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams and vital 
signs.  
• Pharmacokinetic (PK) parameters such as apparent clearance of the drug from plasma 
(CL/F) and AUC0-12 
4.3 
EXPLORATORY ENDPOINT 
• ORR in Arm B after crossover to Arm A by investigator assessment, defined as the 
proportion of patients who achieve a CR or PR from the crossover date until the data cutoff 
date, or the start of a new anticancer therapy. 
 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the comparison of the primary endpoint of ORR in the ITT 
Analysis Set. Assuming ORRA = 0.55 and ORRB = 0.30, 210 patients will be enrolled in a 2:1 ratio 
(140 patients in Arm A and 70 patients in Arm B) to provide a power of approximately 91% in 
testing ORRA versus ORRB using a normal approximation to binomial distribution with a 2-sided 
significance level of 0.05 with continuity correction. The sample size calculation is based on 
methods in Hulley et al, 2013 and Fleiss et al, 1980. 
 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
Intent-to-Treat (ITT) Analysis Set 
The ITT Analysis Set includes all patients randomized to a treatment arm. Patients will be grouped 
by the assigned treatment at randomization. The ITT Analysis Set will be used for efficacy analyses 
unless otherwise specified. 
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Safety Analysis Set 
The Safety Analysis Set includes all patients in the ITT Analysis Set who received any dose of any 
study drug. Patients will be grouped by actual treatment received. The Safety Analysis Set will be 
used for all safety analyses unless otherwise specified. 
Per-Protocol Analysis Set 
The Per-Protocol Analysis Set includes all patients in the ITT Analysis Set who received any dose 
of any study drug and had no critical protocol deviations. The categories of critical protocol 
deviations are defined in Section 6.3.2.  
PK Analysis Set 
The PK Analysis Set includes zanubrutinib-treated patients in Arm A who have at least one post-
baseline PK concentration measurement. The PK Analysis Set will be used for PK analyses.  
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 
Definitions and Computations 
Study Treatment (study drug): Study drugs include zanubrutinib and/or obinutuzumab. 
Study Day: Study Day will be calculated in reference to the date of first dose of either study drug 
(Study Day 1).  For patients not dosed, randomization date will be used instead of the first dose 
date. For assessments conducted on or after Study Day 1, Study Day will be calculated as 
(assessment date – Study Day 1 + 1).  For assessments conducted before Study Day 1, Study Day 
will be calculated as (assessment date – Study Day 1).  There is no Study Day 0.  
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings. Study Day and any corresponding durations will be presented based on the imputations 
specified in the Appendix A. 
Treatment duration: Treatment duration will be calculated as (date of last dose of study treatment 
– Study Day 1 + 1). 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before Study Day 1 or before randomization for patients not dosed. Note that assessments 
that occur on the Study Day 1 but prior to the time of the first dose can qualify to be a baseline 
value. 
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Post-baseline: A post-baseline value or assessment is defined as a value or assessment after Study 
Day 1 or after randomization for patients not dosed.  
All calculations and analyses will be conducted using SAS version 9.3 or higher. 
6.2.2 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP.  Missing dates 
or partially missing dates will be imputed conservatively for adverse events (AEs) and 
prior/concomitant medications/procedures.  Specific rules for handling missing or partially 
missing dates for diagnosis, progression/relapse to prior therapy, AEs, and prior/concomitant 
medications/procedures are provided in the Appendix A  
When summarizing categorical variables, patients with missing data are generally included in the 
denominator to calculate percentages unless otherwise specified. When needed, the category of 
“Missing” is created and the number of patients with missing data is presented.  
When summarizing continuous variables, patients with missing data are not included in the 
calculations unless otherwise specified. 
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 
Adjustment for Covariates 
Stratified analysis will be performed to adjust for important baseline covariates for the primary and 
key secondary endpoints. Details of the stratified analyses are provided in Section 6.4. 
6.2.4 
Multiplicity Adjustment 
Not applicable. The only hypothesis test to be performed in this study is for the primary endpoint 
with the two-sided significance level of 0.05. All other p-values will be presented for descriptive 
purposes only.  
6.2.5 
Data Integrity 
Before pre-specified statistical analysis begins, the integrity of the data should 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 essential data should be complete 
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and reviewed up to a pre-specified cutoff date.  Critical consistency checks and appropriate source 
data verification should be completed according to the final data extraction plan. 
Though the study is open-label, access to study data is controlled for specific sponsor study team 
members overseeing the conduct of the study or analyzing study data. The sponsor will not have 
access to aggregated efficacy or safety data summaries by treatment arm according to the study’s 
data integrity protection plan (DIPP). 
6.3 
PATIENT CHARACTERISTICS 
6.3.1 
Patient Disposition 
The number (%) of patients screened, randomized, treated, discontinued from treatment with 
reasons, remained on treatment, completed treatment, discontinued from study with reasons, 
remained on study, completed study, and the duration of study follow-up will be summarized in 
the ITT Analysis Set. 
Study follow-up time is defined as the time from randomization to the date of death or the end of 
study (whichever occurs first) for the patients who discontinued from study, or the data cutoff date 
for patients still on study. Study follow-up time will be summarized descriptively.   
6.3.2 
Protocol Deviations 
Patients with important protocol deviations will be identified and documented.  Important protocol 
deviations will be summarized by category for all patients in the ITT Analysis Set. COVID-19-
related protocol deviations will be summarized. A listing of important protocol deviations will also 
be provided.   
Critical protocol deviations will also be identified and used to define the Per-Protocol Analysis 
Set. Critical protocol deviation criteria will be established before the database lock. The critical 
protocol deviations will include but are not limited to selected protocol deviations from the 
following categories: 
• Patient randomized without satisfying study eligibility criteria 
• Patient developed study drug withdrawal criteria but was not withdrawn 
• Patient received prohibited concomitant treatment 
• Patient received the wrong study treatment  
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6.3.3 
Randomization Stratification Factors 
The number of patients with each of the randomization stratification factors by IRT and EDC will 
be summarized by treatment arm.  The randomization stratification factors include number of prior 
lines of therapy (2 to 3 vs > 3), rituximab-refractory status (yes vs no), and geographic region 
(China vs ex-China).  In addition, stratification consistencies between IRC and EDC will be 
summarized.   
6.3.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics in the 
ITT Analysis Set, including the following variables:  
• Age (years) and age group (< 60 vs ≥ 60, < 65 vs ≥ 65 and < 75 vs  75) 
• Gender 
• Race and ethnicity 
• Geographic region 
• Weight and body mass index (BMI, kg/m2) 
• Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2) 
A listing of demographic and baseline characteristics will be also provided. 
6.3.5 
Disease History 
The number (%) of patients reporting a history of disease and characteristics, as recorded on the 
eCRF, will be summarized in the ITT Analysis Set. Disease characteristics include the following 
variables: 
• Time since initial diagnosis to first dose (months) 
• Follicular Lymphoma International Prognostic Index (FLIPI) score at initial diagnosis and 
screening (low [0-1], intermediate [2], high [≥3]) 
• Ann Arbor stage at initial diagnosis and screening (I-II, III-IV) 
• Age at initial diagnosis and screening (years) (< 60, ≥ 60) 
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• LDH at initial diagnosis and screening (≤ ULN, > ULN) 
• Hemoglobin level at initial diagnosis and screening (< 120 g/L, ≥ 120 g/L) 
• Number of nodal sites at initial diagnosis and screening (≤ 4, > 4) 
• Bone marrow involvement at initial diagnosis and screening (absent, present, missing) 
• Longest diameter of the largest involved node at initial diagnosis and screening (< 6 cm, ≥ 
6 cm, unknown) 
• Beta-2 microglobulin at initial diagnosis and screening (normal, raised, unknown, missing) 
• Baseline bulky disease (≥ 5 cm, ≥ 7 cm, ≥ 10 cm) 
• B symptoms (yes, no) 
o Unexplained fever of ≥ 101○F (yes, no) 
o Drenching night sweats (yes, no) 
o Unexplained > 10% weight loss in previous 6 months (yes, no) 
• Baseline platelet count (109/L) and category (≤ 100 x109/L, > 100 x109/L) 
• Baseline absolute neutrophil count (109/L) and category (≤ 1.5 x109/L, > 1.5 x109/L) 
6.3.6 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(version 24.0).  The number (%) of patients reporting a history of any medical condition, as 
recorded on the eCRF, will be summarized by system organ class (SOC) and preferred term (PT).   
6.3.7 
Prior Anticancer Therapies and Surgeries 
The following information related to prior therapy for lymphoma will be summarized by 
Anatomical Therapeutic Chemical (ATC) medication class Level 2 and World Health 
Organization Drug Dictionary (WHO DD) drug codes (version March 2021 or later) preferred 
name: 
• Number of regimens of prior anticancer therapies 
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• Time from the end of the last line of prior anticancer therapy to first dose of study drug 
(months) 
• Duration of last therapy (months) 
• Best response to the last line of prior anticancer therapy (CR, PR, stable disease, PD, 
unknown) 
• Rituximab-refractory status (yes, no, unknown) 
• Refractory to the most recent line of therapy (yes, no, unknown) 
• Progression-free and treatment-free for ≥ 12 months since last rituximab-containing 
regimen 
• Progression of disease within 24 months of completion of the first line of therapy 
• Progression of disease within 12 months of completion of the most recent line of therapy 
• Progression of disease within 12 months of completion of the most recent line of therapy 
or refractory disease 
• Prior anticancer radiotherapy  
• Prior anticancer surgeries 
• Prior stem cell transplantations 
Refractoriness to the most recent line of therapy is defined as less than a PR. Rituximab-refractory 
status will be summarized based on the enrollment page in eCRF. 
6.3.8 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO DD drug codes (version March 
2021 or later) and will be further classified to the appropriate Anatomical Therapeutic Chemical 
(ATC) code.  
Prior medications are defined as medications that started before the first dose date of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose of 
study treatment and were continuing at the time of the first dose of study treatment, or (2) started 
on or after the date of the first dose of study treatment up to 30 days after the last dose of 
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zanubrutinib or 90 days after the last dose of obinutuzumab or initiation of a new anticancer 
therapy. For the purpose of determining if a medication should be noted as a concomitant 
medication, the imputation rules stated in Error! Reference source not found. will be used.   
The number (%) of patients reporting prior medications and concomitant medications will be 
summarized by ATC medication class Level 2 and WHO DD preferred name.  
6.4 
EFFICACY ANALYSIS 
Statistical testing will be performed to compare the efficacy of zanubrutinib plus obinutuzumab 
(Arm A) and obinutuzumab (Arm B).  All efficacy analyses will be performed using the ITT 
Analysis Set. For patients in Arm B who crossed over to Arm A, data before the crossover date 
will be analyzed for primary and secondary efficacy endpoints unless otherwise specified.     
Stratified analyses will be based on the randomization stratification factors per IRT unless 
otherwise specified.   
6.4.1 
Primary Efficacy Endpoint 
The null and alternative hypotheses for comparing ORR by ICR are set as follows:  
           H0: ORRA = ORRB  
           Ha: ORRA > ORRB  
where ORRA is the ORR in Arm A (zanubrutinib plus obinutuzumab) and ORRB is the ORR in 
Arm B (obinutuzumab monotherapy). The null hypothesis will be tested using the Cochran-
Mantel-Haenszel method stratified by the randomization factors (number of prior lines of therapy 
[2 to 3 vs > 3], rituximab-refractory status [yes vs no], and geographic region [China vs ex-China]) 
per IRT, at the two-sided significance level of 0.05. If the null hypothesis can be rejected, it will 
be concluded that the superiority of Arm A over Arm B in ORR is demonstrated at the significance 
level. If the number of patients in a particular stratum is too small, this stratum may be combined 
with other strata for analysis. 
The 95% confidence interval (CI) for the Mantel-Haenszel common risk difference (Mantel-
Haenszel, 1959) will be constructed using a normal approximation and Sato’s standard error (Sato 
1989) stratified by the randomization factors (number of prior lines of therapy [2 to 3 vs > 3], 
rituximab-refractory status [yes vs no]), and geographic region [China vs ex-China]) per IRT. 
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A Clopper-Pearson 95% CI of ORR will be constructed for each arm.  
Disease control rate by ICR, defined as the proportion of patients who achieved CR, PR, or stable 
disease, will be also analyzed using the same methods as in the analysis of ORR. 
The data cutoff for the primary efficacy analysis will be 3 months after randomization of the last 
patient.  
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 ORR by Investigator Assessment 
ORR per investigator assessment will be summarized and analyzed using the same methods used 
for ORR per ICR. 
6.4.2.2 Progression-Free Survival  
Progression-free survival (PFS) by ICR is defined as the time (in months) from the randomization 
date to the first documented disease progression or death due to any cause, whichever occurs first. 
The disease assessments after crossover for patients in Arm B who cross over to Arm A will not 
be included in the PFS analysis. 
PFS will be right-censored for patients who met one of the following conditions: 1) alive without 
baseline or post-baseline tumor assessment; 2) start a new anticancer treatment before documented 
PD or death; 3) PD or death after missing ≥ 2 consecutive planned disease assessments; 4) alive 
without documented PD; 5) lost to follow-up without documented PD or death; 6) crossover from 
Arm B to Arm A. For such patients, the primary analysis of PFS will be right-censored according 
to the convention described in Table 1. The censoring rule is based on the FDA Guidance for 
Industry, ‘Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics’ (2015, Table C1, https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-trial-endpoints-approval-non-small-cell-lung-cancer-drugs-and-biologics). 
Table 1: Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression Event 
Outcome 
Death or PD between 2 planned disease 
assessments 
Date of death or PD, whichever occurs first 
Event 
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Death before the first disease assessment 
Date of death 
Event 
Alive without baseline or post-baseline 
disease assessment 
Date of randomization  
Censored 
Start new anticancer treatment before 
documented PD or death 
Date of last disease assessment prior to the date 
of new anticancer treatment 
Censored 
PD or death after missing ≥ 2 consecutive 
planned disease assessments 
Date of last disease assessment before death or 
PD; Use date of randomization if no 
assessment was performed before death or PD. 
Censored 
Alive without documented PD 
Date of last disease assessment 
Censored 
Lost to follow-up* without documented PD 
or death 
Date of last disease assessment 
Censored 
Crossover from Arm B to Arm A 
Date of last disease assessment prior to the 
first zanubrutinib treatment after crossover 
Censored 
 *This includes the consent withdrawal. 
The hazard ratio (Arm A/Arm B) for PFS and its 95% CI will be estimated from a stratified Cox 
regression model stratified by the randomization factors (number of prior lines of therapy [2 to 3 
vs > 3], rituximab-refractory status [yes vs no], and geographic region [China vs ex-China]).  
The distribution of PFS, including median and other quartiles and PFS rate at selected timepoints 
such as 12, 18 and 24 months, will be estimated using the Kaplan-Meier method.  The 95% CI for 
median and other quartiles of PFS will be generated by using the Brookmeyer method 
(Brookmeyer and Crowley 1982), whereas the 95% CI for PFS event-free rate at landmark times 
will be generated by using the Greenwood formula (Greenwood 1926).  Duration of follow-up for 
PFS will be estimated by the reverse Kaplan-Meier method (Schemper and Smith 1996).  
Kaplan-Meier curves for PFS will be presented for each arm. A listing of the PFS-related 
information (eg, the date of progression or censoring and the corresponding reasons) will also be 
provided. 
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A sensitivity analysis of PFS by ICR will also be provided using the Per-Protocol Analysis Set. To 
account for the impact of COVID-19, a sensitivity analysis of PFS by ICR will be performed by 
censoring deaths due to COVID-19. 
PFS per investigator assessment will be performed using the same methods used for PFS per ICR. 
6.4.2.3 Duration of Response  
DOR by ICR is defined as the time from the date of the earliest PR or CR to the date of PD or 
death for any cause, whichever occurs earlier. DOR will be analyzed using the same methods as 
in the analysis of PFS with the exception that treatment arm comparisons will not be performed.  
A sensitivity analysis of DOR by ICR will also be analyzed in the Per-Protocol Analysis Set. To 
account for the impact of COVID-19, a sensitivity analysis of DOR by ICR will be performed by 
censoring deaths due to COVID-19. 
DOR per investigator assessment will be performed using the same methods used for DOR per 
ICR. 
6.4.2.4 Overall Survival 
OS is defined as the time from randomization to the date of death due to any cause. All patients, 
including those who crossed over from Arm B to Arm A and remained alive before data cutoff or 
discontinued the study (discontinued the study due to reasons other than death), will be censored 
at the last known date the patient is alive on or prior to data cutoff. OS will be analyzed using the 
same methods as in the analysis of PFS.    
A sensitivity analysis will be performed where crossover from Arm B to Arm A will be treated as 
a censoring event. To account for the impact of COVID-19, a sensitivity analysis of OS will be 
performed by censoring deaths due to COVID-19. 
6.4.2.5 Complete Response Rate 
CR rate by ICR is defined as the proportion of patients who achieve CR or complete metabolic 
response  as best overall response from randomization until the data cutoff date, the start of a new 
anticancer therapy, or the crossover date for patients in Arm B who cross over to Arm A. The CR 
rate will be compared between treatment groups using Fisher’s exact test. A Clopper-Pearson 95% 
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CI of CR rate will be presented for each arm. 
CR rate per investigator assessment will be performed using the same methods used for CR rate 
per ICR. 
6.4.2.6 Time to Response 
Time to response by ICR for responders is defined as the time from the randomization date to the 
date of the earliest qualifying response until the data cutoff date, the start of a new anticancer 
therapy, or the crossover date for patients in Arm B who cross over to Arm A. Time to response 
will be summarized by descriptive statistics for each arm.  
Time to response per investigator assessment will be performed using the same methods used for 
time to response per ICR.  
6.4.2.7 Patient-Reported Outcomes 
The scoring of the EORTC QLQ-C30 and EQ-5D-5L will follow their corresponding manuals 
(Fayers et al. 2001; EuroQol Group 1990; Herdman et al 2011).   
Compliance rates will be provided for both EORTC QLQ-C30 and EQ-5D-5L, which is defined 
as ratio of the number of patients that completed questionnaires to the number of patients that 
expected to complete the questionnaires per each visit and arm from the ITT Analysis Set.  
EORTC QLQ-C30 
Descriptive Analysis: 
The scores of the EORTC QLQ-C30 questionnaire will be summarized at each assessment 
timepoint for each treatment arm. Summaries will include: scores and changes from baseline in 
the 1 global health status scale, 5 functional scales (physical, role, emotional, cognitive, and social), 
3 symptom scales (fatigue, pain, and nausea/vomiting), and 6 single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties).   
The key PRO end points are global health status/QoL (GHS/QoL), physical function, role function, 
fatigue, pain, nausea/vomiting and diarrhea. The key clinical cycles are cycle 3 (Week 12) and 
cycle 6 (Week 24). The two cycles are clinically justifiable as there will be enough patients in both 
cycles to assess the short-term and long-term effects of treatments for comparison purposes.  
 
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Mixed Model Analysis: 
In addition, the key PRO end points (GHS/QoL, physical function, role function, fatigue, pain, 
nausea/vomiting and diarrhea) will be used to assess the clinically meaningful differences between 
treatment arms using a restricted maximum likelihood-based linear mixed model for repeated 
measures (MMRM) to account for missing data under Missing at Random (MAR) assumption 
(Mallinckrodt et al, 2008). The model will include the repeated measurement of the key PRO end 
points scale score at baseline, Week 12 and Week 24 as the dependent variable, and treatment, 
time (as categorical variable), treatment by time interaction, and randomization stratification 
factors (number of prior lines of therapy [2 to 3 vs > 3] and rituximab-refractory status [yes vs no] 
only, no geographic region) as covariates. The random patient effects will include patient random 
intercept on QLQ-C30 GHS/QoL score which is assumed to follow a normal distribution. A point 
estimate of the treatment difference between treatment arms, 95% CI, and the corresponding p-
value will be provided. 
EQ-5D-5L 
The EQ-5D-5L comprises a descriptive domain and a Visual Analogue Scale (VAS) with the 
following 
5 
dimensions: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems.  The EQ VAS records the respondent’s self-
rated health on a 0 to 100 scale, with 100 labelled ‘the best health you can imagine’ and 0 ‘the 
worst health you can imagine’.   
EQ-5D-5L scores of the descriptive domain will be summarized descriptively by treatment arm at 
each assessment timepoint, including the number and percentage of patients reporting each level 
of problem on each dimension of the EQ-5D-5L. Change from baseline in scores of VAS will be 
summarized descriptively. 
6.4.3 
Sensitivity Analysis 
For the primary endpoint of ORR, the following sensitivity analyses may be performed: 
• ORR using the Per-Protocol Analysis Set 
• ORR excluding patients who died due to COVID-19 to account for the impact of COVID-
19 
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• ORR using logistic regression adjusting stratification factors by IRT, progression of 
disease within 12 months of completion of the most recent line of therapy (yes vs no), age 
at baseline, and FLIPI risk category [0-1 vs 2 vs > 3] at baseline 
The sensitivity analyses for the secondary endpoints are addressed in Section 6.4.2.  
 
6.4.4 
Subgroup Analyses 
The primary and selected secondary endpoints will be summarized, as appropriate, in the following 
subgroups (if collected in both IRT and in the EDC, data in the EDC will be used to define the 
subgroups): 
• Age group (< 65 vs ≥ 65 years; < 75 vs ≥ 75 years) 
• Sex (male vs female) 
• Geographic region (China vs ex-China)  
• Prior lines of therapy (2-3 vs > 3) 
• Baseline ECOG performance status (0 vs ≥ 1) 
• Bulky disease (yes: any target lesion longest diameter ≥ 5 cm vs no) 
• Bulky disease (yes: any target lesion longest diameter ≥ 7 cm vs no) 
• Bulky disease (yes: any target lesion longest diameter ≥ 10 cm vs no) 
• FLIPI risk category (low [0-1], intermediate [2], high [≥3]) 
• Rituximab-refractory status (refractory, not refractory, or unknown) 
• Refractory status to the most recent line of therapy (refractory, not refractory, or unknown) 
• Progression of disease within 24 months of starting the first line of therapy (yes, no, or 
unknown) 
The subgroup variables and the cutoff values are subject to change if warranted to better represent 
the data. Some subgroup analyses may not be done if majority patients are in one category. 
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6.4.5 
Exploratory Efficacy Endpoints 
For patients in Arm B cross over to Arm A, ORR by investigator assessment after crossover will 
be summarized. The ORR is defined as the proportion of patients who achieve either CR or PR 
from the crossover date until the data cutoff date or the start of a new anticancer therapy.  
6.5 
SAFETY ANALYSES 
All safety analyses will be performed by treatment arms based on the Safety Analysis Set. Safety 
and tolerability will be assessed, where applicable, by incidence, severity, and change from 
baseline values for all relevant parameters including AEs, laboratory values, vital signs, and 
physical examination. For patients in Arm B who cross over to Arm A, data before the crossover 
date will be included for the safety analyses unless otherwise specified.     
6.5.1 
Extent of Exposure 
The following measures of the extent of study drug exposure will be summarized: 
• Duration of study treatment exposure (in months)  
• Number (%) of treatment cycles for zanubrutinib and obinutuzumab respectively 
• Total dose (mg) received for zanubrutinib and obinutuzumab, respectively 
• Actual dose intensity (ADI, mg/day) and relative dose intensity (RDI, %) of zanubrutinib  
• Number of infusions and relative infusion frequency (%) of obinutuzumab  
• Number (%) of patients with dose reduced, interrupted, missed along with the 
corresponding reasons for zanubrutinib 
• Number (%) of patients with dose interrupted along with the corresponding reasons for 
obinutuzumab  
Duration of exposure in months is defined as (the last zanubrutinib/ obinutuzumab/ combination 
administration date [data cutoff date for treatment ongoing patients] – the first zanubrutinib/ 
obinutuzumab/ combination administration date + 1)/30.4375. 
Number of treatment cycles is defined as duration of treatment (days) divided by 28.  
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The ADI of zanubrutinib is defined as the cumulative dose (mg) of zanubrutinib divided by the 
duration of zanubrutinib (day), which is defined as the last zanubrutinib administration date – the 
first zanubrutinib administration date + 1.  
The RDI of zanubrutinib is defined as the ratio of ADI (mg/day) of zanubrutinib and the planned 
dose intensity (PDI, mg/day) of zanubrutinib, which is 320 mg/day. 
The relative infusion frequency of obinutuzumab is defined as the ratio of the actual number of 
infusions administered and the planned number of infusions (1,000 mg on Day 1, 8, and 15 of 
Cycle 1, then 1,000 mg on Day 1 of Cycles 2 to 6, then 1,000 every 8 weeks). Infusions on Day 1 
and 2 of Cycle 1 are counted as one infusion. 
6.5.2 
Adverse Events  
AEs will be graded by the investigators using CTCAE v4.03. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA).  AEs will be coded to the MedDRA 
(version 24.0) lower level term closest to the verbatim term.  The linked MedDRA PT and primary 
SOC are also captured in the database.   
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or increase 
in severity level on or after the first dose of study drug through 30 days after the last dose of 
zanubrutinib or 90 days after the last dose of obinutuzumab (permanent discontinuation of study 
drug) or prior to the initiation of new anticancer therapy, whichever is sooner. Worsening of an 
AE to Grade 5 after 30/90 days from the last dose of zanubrutinib/obinutuzumab (prior to the 
initiation of new anticancer therapy) will also be considered as TEAE.  Summary tables will be 
based on TEAEs.  
An AE overview table, including the number of patients with TEAEs, treatment-emergent serious 
AEs (SAEs), TEAEs with Grade 3 or above, TEAEs that led to death, TEAEs that led to treatment 
discontinuation, TEAEs that led to dose modification (reduction, interruption, delay), treatment-
related TEAEs, TEAEs of special interest, Grade 3 or above TE AESIs, and serious TE AESIs will 
be provided.  
Treatment-related AEs include those events considered by the investigator to be related, possibly 
or probably related to study drug or with a missing assessment of the causal relationship. 
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The incidence of TEAEs will be reported as the number (%) 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.  
Summaries of TEAEs by SOC and PT will be presented for the following categories: 
• Any TEAE 
• Any Grade 3 or higher TEAE  
• Any treatment-related TEAE 
• Any treatment-related Grade 3 or higher TEAE 
• Any serious TEAE 
• Any treatment-related serious TEAE 
• Any TEAE leading to dose reduction  
• Any TEAE leading to dose interruption  
• Any TEAE leading to dose delay (obinutuzumab only)   
• Any TEAE leading to dose discontinuation 
• Any TEAE leading to death 
• Any treatment-related TEAE leading to death 
Moreover, all the summaries above will also be provided by PT only and by SOC, PT and 
maximum severity. 
Incidence of TEAEs of special interest by category and PT will be presented for the following 
categories: 
• Any TEAE of special interest 
•  Any Grade 3 or higher TEAE of special interest 
• Any treatment-related TEAE of special interest 
• Any treatment-related Grade 3 or higher TEAE of special interest 
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• Any serious TEAE of special interest 
• Any treatment-related serious TEAE of special interest  
• Any TEAE of special interest leading to dose reduction 
• Any TEAE of special interest leading to dose interruption 
• Any TEAE of special interest leading to dose discontinuation  
The categories and detailed search criteria for TEAEs of special interest are described in 
Appendix B.  
Time to the first TEAE of special interest along with the cumulative event rate and monthly hazard 
rate will be provided.  
Given the imbalance in treatment duration between the two arms, an exposure-adjusted incidence 
rate (EAIR) for the TEAE of special interest will be provided. EAIR is calculated as the number 
of patients experiencing the TEAE of special interest divided by the total time from Study Day 1 
to the first event date or the last dose date if the first event occurred after the last dose date or if 
there is no event. 
An overall summary of death and cause of death will be presented for the following categories: 
• Total deaths  
• Deaths within 30/90 days of last dose of study drug 
• Deaths more than 30/90 days of last dose of study drug 
Listings of all AEs, SAEs, AEs leading to dose reduction, AEs leading to dose interruption, AEs 
leading to dose delay, AEs leading to dose discontinuation, and all deaths will be provided. 
6.5.3 
Laboratory Values 
All hematology, serum chemistry, and coagulation results for each patient will be presented in data 
listings.  The baseline value, post-baseline value and change from baseline for all hematology and 
serum chemistry parameters will be summarized at each scheduled visit. 
The laboratory parameters of interest for these summaries are: 
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Hematology 
Serum Chemistry 
Coagulation 
Hemoglobin (decrease) 
Alanine 
transaminase 
(ALT) (increase) 
Albumin (decrease) 
Activated partial thromboplastin 
time (aPTT) (increase) 
Platelets (decrease) 
Aspartate transaminase 
(AST) (increase) 
Uric Acid (increase) 
International Normalized Ratio 
(INR) (increase) 
WBC 
(increase, 
decrease) 
Alkaline 
Phosphatase 
(increase) 
Sodium 
(increase, 
decrease) 
 
Absolute 
Neutrophil 
Count (ANC, decrease) 
Total 
Bilirubin 
(increase) 
Phosphorus 
(decrease) 
 
Absolute 
Lymphocyte 
Count 
(increase, 
decrease) 
Creatinine (increase) 
Potassium (increase, 
decrease) 
 
 
Calcium 
(increase, 
decrease) 
Magnesium (increase, 
decrease) 
 
 
Glucose 
(increase, 
decrease) 
 
 
For hypocalcemia and hypercalcemia, serum calcium will be corrected using the formula: 
Corrected calcium = Serum calcium + 0.8 * (4 – serum albumin) where serum calcium is 
recorded in mg/dL and serum albumin is recorded in g/dL. 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables) for laboratory parameters and their changes 
from baseline will be summarized by visit. 
Shift tables assessing the toxicity grade at baseline versus worst toxicity recorded post-baseline 
will be presented.  A summary of the number (%) of patients with Grade 3 or higher toxicity will 
be provided for each laboratory parameter of interest.  A listing of all Grade 3 or higher laboratory 
values will be provided.  Box-whisker plots may be generated for parameters of interest. 
Incidence of patients who met one or more of the Hy’s law criteria will be summarized. A listing 
of patients that met one or more of the Hy’s law criteria will be generated.   
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6.5.4 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
temperature, and weight) and changes from baseline will be presented by visit and treatment group 
for all visits.  A listing by patient and assessment timepoint will be generated.   
6.5.5 
Electrocardiograms (ECG) 
The QTc-Fridericia (QTcF) interval values will be listed. 
6.5.6 
ECOG 
ECOG performance status will be summarized at each visit.  Shift tables assessing the ECOG 
performance status at baseline versus worst performance status post-baseline will be presented.   
6.6 
PK ANALYSES 
No PK analyses are planned for the primary analysis. 
 
7 
INTERIM ANALYSIS 
No formal interim analyses are planned for this study.     
 
8 
CHANGES IN THE PLANNED ANALYSIS 
This SAP provides more detail on the statistical methods than is provided in the protocol.  
For the primary efficacy endpoint analysis, the null hypothesis was tested at the 2-sided 
significance level of 0.05, which gives the equivalent test result with 1-sided significance level of 
0.025 as in the protocol. 
 
9 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
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Cheson, B.D., et al. Recommendations for Initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical 
Oncology, 2014; 32(27): 3059–3068. 
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. 
Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of Life Group. The 
EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for 
Research and Treatment of Cancer, Brussels. 2001. 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical patients. 
1926;33:1-26. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727-36. 
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, and Mancuso, JP. Recommendations for the 
primary analysis of continuous endpoints in longitudinal clinical trials. Drug Information Journal, 
2008;42:303-319.  
Mantel N, Haenszel W. Statistical Aspects of Analysis of Data from Retrospective Studies of 
Disease. Journal of the National Cancer Institute. 1959;22:719–748. 
Sato T. On the Variance Estimator of the Mantel-Haenszel Risk Difference. Biometrics. 1989; 
45:1323–1324. 
 
 
 
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APPENDIX A. 
IMPUTATION OF MISSING OR PARTIALLY MISSING DATES 
In general, missing or partial dates will not be imputed.  The following rules will apply for the 
specific analysis and summary purposes mentioned below only.   
A.1 Prior/Concomitant Medications/Procedures               
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant.  The following rules will be applied to 
impute partial dates for medications: 
If start date of a medication is 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 is 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 start date or end date of a medication is completely missing, do not impute. 
A.2 Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an AE is partially missing, the date will be imputed to determine 
whether the AE is treatment-emergent. When in doubt, the AE will be considered treatment-
emergent by default. The following rules will be applied to impute partial dates for AEs: 
If the start date of an AE is partially missing, impute as follows: 
• If both month and day are missing, then the imputed day and month will be January 01 or 
the first dosing date if they have the same year, whichever is later. 
• If only day is missing, then the imputed day will be the first day of the month or the first 
dosing date if they have the same month and year, whichever is later 
• If the start date is completely missing, the imputed day will be the first dosing date as long 
as AE end date is not before the first dosing date. 
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If the end date of an AE 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 end date is completely missing, do not impute. 
• If the imputed AE end date > last known alive date or end of study date, then set to the last 
known alive date or end of study date, whichever occurs first. 
A.3 Deaths 
In case complete death dates are not recorded, impute as follows: 
• If both month and day are missing, then the imputed month and day will be 01Jan or 
the last date of a patient known to be alive + 1, whichever is later. 
• If only day is missing, the death will be assumed to be on the first day of the month or 
the last date of a patient known to be alive +1, whichever is later. 
A.4 New Anticancer Therapy 
If the start day of a new anticancer treatment, radiotherapy, or surgery is incomplete or missing, 
impute as follows: 
• If only day is missing, then the imputed day will be the first day of the month. 
• No imputation will be performed for all other types of missing dates. 
A.5 Date of Diagnosis or Date of Progression to Any Prior Therapy 
If an initial diagnosis date or disease progression date to any prior therapy is 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 a diagnosis date or progression date is completely missing, do not impute. 
A.6 Prior Therapies, Radiotherapies, or Surgeries 
If a prior therapy, radiotherapy, or surgery date is missing, impute as follows:  
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BGB-3111-212                                                                                   
Statistical Analysis Plan Version 1.0                                                            
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• If only day is missing, then set to the 15th of the month or the first study drug dose date -
1, whichever is earlier.  
• No imputation will be performed for all other types of missing dates. 
A.7 Date of Last Study Drug Administration  
When the end date of a study drug administration is partially missing, the date will be imputed to 
calculate the extent of exposure and to define the duration of the TEAE. The following rules will 
be applied to impute the partial dates for the end date of a study drug administration: 
• If both month and day are missing, then set to the start date of the corresponding cycle. 
• If only day is missing, then the imputed day will be the first day of the month or the start 
date of the corresponding cycle if they have the same month and year, whichever is later. 
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BGB-3111-212                                                                                   
Statistical Analysis Plan Version 1.0                                                            
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APPENDIX B. 
ADVERSE EVENTS OF SPECIAL INTEREST CATEGORIES AND 
SEARCH CRITERIA 
AESI Category 
Search Criteria 
Hemorrhage 
Haemorrhage terms (excluding laboratory terms) (SMQ) Narrow  
Major hemorrhage - Defined as serious or 
≥ Grade 3 bleeding at any site, or central 
nervous system bleeding of any grade 
Major haemorrhage: 
Subdural haematoma PT, Subdural haemorrhage PT 
All haemorrhage PTs if AE SOC is “Nervous system disorders” or 
Serious or ≥ Grade 3 haemorrhage PT if AE SOC is not “Nervous system 
disorders” 
Atrial fibrillation and/or flutter 
Atrial fibrillation PT, Atrial flutter PT 
Hypertension 
Hypertension (SMQ) Narrow 
Second primary malignancies 
Skin cancers 
Malignant tumours (SMQ) Narrow 
Subcategory - Skin malignant tumours (SMQ) narrow 
Tumor lysis syndrome 
Tumour lysis syndrome (SMQ) Narrow 
Infection 
Opportunistic Infections 
Infections: Infections and Infestations SOC 
Subcategory - Opportunistic infections: Opportunistic infections (SMQ) 
Narrow 
Neutropenia 
Neutropenia PT, Neutrophil count decreased PT, Febrile neutropenia PT, 
Agranulocytosis PT, Neutropenic infection PT, Neutropenic sepsis PT 
Thrombocytopenia 
Thrombocytopenia PT, Platelet count decreased PT 
Anemia 
Anaemia PT, Haemoglobin decreased PT 
 
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