Clinical trial NCT02569476
Conditions: B-cell Lymphoid Malignancies
Keywords: BGB-3111 Zanubrutinib Obinutuzumab Lymphoma Leukemia Therapeutic uses B-cell
Sponsor: BeiGene
Start date: 2016-01-13; Completion date: 2020-09-02
Enrollment: 119 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluated the safety and preliminary efficacy of BGB-3111 (zanubrutinib) in combination with obinutuzumab in participants with B-cell lymphoid malignancies.

Detailed description:

Arms: arm 1: In the dose-escalation part, dose levels and regimens were evaluated. In the indication-specific expansion cohorts, participants were assigned to different cohorts based on histology type.
Interventions: intervention 1: Zanubrutinib intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
 
 
 
Page 1 of 122 
 
 
Clinical Study Protocol 
 
 
A Phase 1b Study to Assess Safety, Tolerability and Antitumor 
Activity of the Combination of BGB-3111 with Obinutuzumab in 
Subjects with B-Cell Lymphoid Malignancies 
 
 
 
 
Protocol Number: 
 
BGB-3111_GA101_Study_001 
IND Number: 
 
125326  
Product: 
 
Zanubrutinib (BGB-3111 [BTK inhibitor]) and 
obinutuzumab (glycoengineered, type 2 anti CD20 
monoclonal antibody) 
Indication: 
 
B-Cell Lymphoid Malignancies 
Clinical Phase: 
 
1b 
Principal Investigator: 
 
  
Disease Group Lead, Low Grade Lymphoma & CLL 
 
Sponsor: 
BeiGene AUS Pty Ltd.  
1C/528 Compton Road Stretton 
Queensland 4116, Australia 
Sponsor Medical 
Monitor: 
 
 
Version: 
 
6.0 
Date: 
03 January 2019 


 
CONFIDENTIAL 
 
 
 
Page 2 of 122 
 
 
Confidentiality Statement 
This document contains confidential information and is the proprietary property of BeiGene 
AUS Pty Ltd. This document is for use by authorized individuals and their designated 
representatives for their confidential review, consideration, and/or participation in 
investigational trial(s). This document may not be copied or distributed for review by any 
unauthorized individuals without the prior written authorization of BeiGene AUS Pty Ltd. Your 
acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without the prior written authorization from BeiGene AUS Pty Ltd. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 3 of 122 
PROTOCOL AMENDMENT, VERSION 6.0: RATIONALE 
Protocol BGB-3111_GA101_Study_001 has been updated: 
 To introduce the use of the International Nonproprietary Name (INN) of “zanubrutinib” 
for “BGB-3111.” 
 To add the Sponsor’s address to the Protocol Title Page. 
 To change the Sponsor’s Medical Monitor. 
 To update the Sponsor Medical Monitor’s address on the Protocol Title Page. 
 To remove the protocol amendment rationales for previous protocol amendments to 
align with the current BeiGene protocol format to show only the current protocol 
amendment rationale. 
 To update Section 1.2 (Overview of Clinical Pharmacology) with the results of a 
thorough QT study (BGB-3111-106) that was recently completed in healthy 
volunteers and has shown that both therapeutic and supratherapeutic doses of 
zanubrutinib had no clinically relevant effect on electrocardiogram (ECG) parameters, 
including QTc intervals and other ECG intervals. As a result, drug guidance and ECG 
monitoring for QT/QTc prolongation were removed from the protocol in Section 7.3 
(Medications to be used with Caution), Section 8.4 (Electrocardiogram), and 
Section 16.5 (Appendix 5). 
 To update Section 1.2 (Overview of Clinical Pharmacology) with the results of a 
drug-drug interaction study (BGB-3111-104) that was recently completed in healthy 
volunteers and showed that co-administration of zanubrutinib with a strong CYP3A 
inducer (rifampin) decreased AUC0-∞ of zanubrutinib by 13.5-fold and 
co-administration of zanubrutinib with a strong CYP3A inhibitor (itraconazole) 
increased AUC0-∞ of zanubrutinib by 3.8-fold. As a result, Section 7.2 
(Prohibited/Restricted Medications) and Section 7.3 (Medications to be used with 
Caution) were updated, and dose modification guidance for zanubrutinib when 
co-administered with strong/moderate CYP3A inhibitors and inducers was provided. 
 To update Section 1.2 (Overview of Clinical Pharmacology) with the results of a 
drug-drug interaction study using a cocktail approach (BGB-3111-108) that was 
recently completed in healthy volunteers and showed that zanubrutinib does not 
significantly affect drugs metabolized by CYP2C9 (warfarin) or transported by P-gp 
(digoxin) and BCRP (statins); however, zanubrutinib has a mild induction effect on 
CYP3A and CYP2C19 enzymes. Section 7.3 (Medications to be used with Caution) 
was updated accordingly. 
 To update Section 1.5 (Benefit and Risk Conclusions for Zanubrutinib) with the number 
of patients treated with zanubutinib and add a reference to the Investigator’s Brochure 
(IB) for more information. 
 To update the zanubrutinib treatment duration so that treatment can continue until 
disease progression, intolerance, death, subject withdraws from the study, or study 
closure, whichever occurs first. 
 To change tumor imaging frequency after Week 48 from investigator’s discretion to 
every 24 weeks to ensure consistent data are collected to assess response and 
progression in this study. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 4 of 122 
 To change the Week 52 assessment/visit to Week 48 in order to align the updated tumor 
imaging frequency with the assessment/visit schedule. To also reduce the frequency of 
visits after Week 48 of the study (from every 8 weeks [±7 days] to every 12 weeks 
[±10 days]).  
 To update Section 8.5 (Computed Tomography) to allow more flexibility around the 
timing of CT scans when a subject’s scan may fall outside the specified imaging 
procedure window (eg, due to out-of-town travel or other unforeseen circumstances).  
 To add a new Section 8.7 (Minimal Residual Disease for Subjects with CLL) that 
outlines samples to be taken for minimal residual disease testing in subjects with 
Chronic Lymphocytic Leukemia (CLL); all subsequent sections were renumbered. The 
Study Assessments and Procedures Schedule for Part 1 (Table 1) and Part 2 (Table 2) 
were updated for this testing as well. 
 To clarify procedures for an optional post-progression biomarker assessment sample 
for all patients at the Safety Follow-up Visit (added in Protocol Amendment, 
Version 5.0) and to update the associated exploratory endpoint. 
 To update the Study Assessments and Procedures Schedule for Part 1 (Table 1) and 
Part 2 (Table 2) to clarify when response assessments are performed and how response 
is assessed. 
 To update the Study Assessments and Procedures Schedule for Part 1 (Table 1) and 
Part 2 (Table 2), as well as Appendices 16.1 and 16.2, to remove coagulation testing 
after screening, and to remove selected hematology and clinical chemstry tests that were 
deemed unnecessary given the experience with zanubrutinib to date. In addition, the 
frequency of hematology, clinical chemistry, urine analysis, immunoglobulins, and 
serum EPG laboratory assessments were reduced after Week 25. 
 To update the Study Assessments and Procedures Schedule for Part 1 (Table 1) and 
Part 2 (Table 2), as well as Section 8.4 (Electrocardiograms), to remove ECGs after 
screening (post-screening ECGs will be performed at the investigator’s discretion if 
medically indicated).  
 To add clarifications in Section 6.2.1 (Dosage and Administration, Zanubrutinib) 
regarding zanubrutinib dosing and reference to the patient diary and Pharmacy Manual. 
 To add language in Section 7.1 (Permitted Medications) about the potential for 
opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP), in patients 
with 
hematologic 
malignancies, 
particularly 
those 
having 
received 
prior 
lymphodepleting chemotherapy or having prolonged corticosteroid exposure, and 
guidance to consider prophylaxis treatment per institutional standards. 
 To clarify in Section 7.2 (Prohibited/Restricted Medications) that limited duration doses 
≤20 mg of prednisone are allowed for malignant indications, not just doses <20 mg. 
 To change the collection of adverse events (AEs) and serious adverse events (SAEs) 
from 120 days after the last dose of obinutuzumab to 90 days after the last dose of 
obinutuzumab. 
 To revise text in Section 10.9 (Prompt Reporting of Serious Adverse Events) to update 
the serious adverse event reporting process. 
 To clarify and reduce redundancy in text regarding the analysis sets. 
 To delete text that is included in the Statistical Analysis Plan. 
 To clarify that the hematological improvement analysis is for CLL patients only. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 5 of 122 
 To clarify in Table 9 (Safety Laboratory Assessments) that bands are optional, and to 
remove selected  hematology and clinical chemstry tests that were deemed unnecessary 
given the experience with zanubrutinib to date. 
 To update and align language in Section 12 (Regulatory and Ethical Issues) and 
Section 13 (Study Management) with current BeiGene protocols. 
 To update Section 14 (References) with new references added to the protocol. 
 To update the format of Section 15 (Protocol Signatures). 
 To clarify the Categorical Waldenström’s Macroglobulinemia Response Definition for 
“very good partial response” in Appendix 16.3. In addition, to align with other BeiGene 
protocols, the repeat IgM level for determining progressive disease in the case of a drug 
hold was changed from 6 weeks to 10 weeks after restarting study administration, and 
“≥ 25% increase in serum IgM” was added for total increase from lowest nadir (to the 
already specified criterion of “at least 500mg/dL from lowest nadir”). 
 To incorporate the following updates to the protocol per administrative memos that 
have been issued since Protocol Amendment Version 5.0: 
o Correction of typo (ie, deletion of stray text) in Appendix 16.3, Response 
Criteria, Non-Hodgkin Lymphoma (including SLL; excluding WM) 
o Administrative change to Appendix 16.3 Guidelines for specific clinical or 
laboratory circumstances: Changed any reference of “central” laboratory to 
“local” laboratory because a central laboratory is not used in this study 
o Clarification change made to footnote 2 under Tables 1 and 2 Study assessments 
and Procedures Schedule to remove the restriction to perform biopsy at relapse 
for selected sites only, and this is now open to all sites and subjects who consent 
to have this procedure done 
o Addition of clarifying text regarding tumor assessments after Week 48 
 
 To note the following changes that were implemented in Protocol Amendment 
Version 5.0 but were omitted in error in the “Protocol Amendment, Version 5.0: 
Rationale” section of the previous protocol version: 
o To modify the adverse events and serious adverse events reporting period in 
Section 10.5.1. 
o To include specific instructions for recording adverse events and serious 
adverse events in Section 10.5.3. 
o To clarify the Assessment of Severity (previously Assessment of Intensity) in 
Section 10.7.1. 
o To add guidance for Assessment of Causality in Section 10.7.2. 
o To add Section 10.13 Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards and Ethics Committees. 
 
  To make other minor changes for consistency between protocol sections and clarity 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 6 of 122 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT, VERSION 6.0: RATIONALE ...................................... 3 
TABLE OF CONTENTS ................................................................................................ 6 
SYNOPSIS ................................................................................................................... 11 
LIST OF ABBREVIATIONS ....................................................................................... 19 
1 
INTRODUCTION ..................................................................................... 22 
1.1 
Background and Pharmacology ................................................................. 22 
1.2 
Overview of Clinical Pharmacology ......................................................... 23 
1.3 
Overview of Efficacy ................................................................................. 24 
1.4 
Overview of Safety of Zanubrutinib .......................................................... 24 
1.5 
Benefit and Risk Conclusions for Zanubrutinib ........................................ 25 
1.6 
Obinutuzumab ............................................................................................ 25 
1.7 
Rationale for the Combination of Zanubrutinib and Obinutuzumab ......... 26 
1.8 
Rationale to Change Zanubrutinib Dose from 320 mg QD to 160 mg BID 
(added per Amendment 4.0) ......................................................................................... 27 
1.9 
Rationale to Remove Food Restriction for Zanubrutinib (added per 
Amendment 4.0) ........................................................................................................... 28 
2 
STUDY OBJECTIVES ............................................................................. 29 
2.1 
Study Objectives in Part 1 ......................................................................... 29 
2.1.1 
Primary Objectives .................................................................................... 29 
2.1.2 
Secondary Objectives ................................................................................ 29 
2.1.3 
Exploratory Objectives .............................................................................. 29 
2.2 
Study Objectives in Part 2 ......................................................................... 29 
2.2.1 
Primary Objectives .................................................................................... 29 
2.2.2 
Secondary Objectives ................................................................................ 29 
2.2.3 
Exploratory Objectives .............................................................................. 29 
3 
STUDY ENDPOINTS ............................................................................... 30 
3.1 
Study Endpoints in Part 1 .......................................................................... 30 
3.1.1 
Primary Endpoints ..................................................................................... 30 
3.1.2 
Secondary Endpoints ................................................................................. 30 
3.1.3 
Exploratory Endpoints ............................................................................... 30 
3.2 
Study Endpoints in Part 2 .......................................................................... 31 
3.2.1 
Primary Endpoints ..................................................................................... 31 
3.2.2 
Secondary Endpoints ................................................................................. 31 
3.2.3 
Exploratory Endpoints ............................................................................... 31 
4 
INVESTIGATIONAL PLAN .................................................................... 32 
4.1 
Summary of Study Design ......................................................................... 32 
4.2 
Safety Evaluation ....................................................................................... 34 
4.2.1 
Safety Monitoring Committee ................................................................... 34 
4.2.2 
Dose Limiting Toxicity .............................................................................. 35 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 7 of 122 
4.2.3 
Dose Continuation and Dose Reduction .................................................... 35 
4.2.4 
Dose Interruption and Modification .......................................................... 36 
4.3 
Study Assessments and Procedures ........................................................... 37 
5 
STUDY POPULATION ............................................................................ 52 
5.1 
Inclusion Criteria ....................................................................................... 52 
5.2 
Exclusion Criteria ...................................................................................... 53 
5.3 
Other Eligibility Criteria Considerations ................................................... 55 
5.4 
Subject Completions and Withdrawals ...................................................... 55 
5.4.1 
Subject Completion ................................................................................... 55 
5.4.2 
Subject Withdrawal ................................................................................... 55 
6 
STUDY TREATMENT ............................................................................. 57 
6.1 
Description of Investigational Products ..................................................... 57 
6.1.1 
Zanubrutinib .............................................................................................. 57 
6.1.2 
Obinutuzumab ............................................................................................ 57 
6.2 
Dosage and Administration ....................................................................... 57 
6.2.1 
Zanubrutinib .............................................................................................. 57 
6.2.2 
Obinutuzumab ............................................................................................ 57 
6.3 
Packaging and Labelling ............................................................................ 58 
6.4 
Storage and Handling Procedures .............................................................. 59 
6.5 
Investigational Product Accountability ..................................................... 59 
6.6 
Treatment Assignment ............................................................................... 59 
6.7 
Warnings and Precautions ......................................................................... 60 
6.8 
Assessment of Compliance ........................................................................ 61 
6.9 
Treatment of Investigational Product Overdose ........................................ 61 
6.10 
Occupational Safety ................................................................................... 61 
6.11 
Infusion-Related Reactions with Obinutuzumab ....................................... 61 
6.12 
Severe Hypersensitivity Reactions and Flu-like Symptoms ...................... 62 
6.13 
Tumor Lysis Syndrome ............................................................................. 63 
7 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ... 65 
7.1 
Permitted Medications ............................................................................... 65 
7.2 
Prohibited/Restricted Medications ............................................................. 65 
7.3 
Medications to be used with Caution ......................................................... 65 
8 
STUDY ASSESSMENTS ......................................................................... 68 
8.1 
Demographic and Baseline Safety Assessments ....................................... 68 
8.2 
Laboratory Evaluations .............................................................................. 69 
8.3 
Physical Examination, Vital Signs, and B Symptoms ............................... 70 
8.4 
Electrocardiogram ...................................................................................... 70 
8.5 
Computed Tomography ............................................................................. 70 
8.6 
Bone Marrow Evaluation ........................................................................... 71 
8.7 
Minimal Residual Disease for Subjects with CLL .................................... 71 
8.8 
Adverse Events .......................................................................................... 71 
8.9 
Pregnancy .................................................................................................. 72 
8.9.1 
Pregnancy Testing ..................................................................................... 72 
8.9.2 
Action to be taken if a Pregnancy Occurs.................................................. 72 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 8 of 122 
8.10 
Follow-up Assessments ............................................................................. 73 
8.10.1 
Safety Follow-up ....................................................................................... 73 
8.10.2 
Progression and Survival Follow up .......................................................... 73 
8.11 
Efficacy ...................................................................................................... 73 
8.12 
Pharmacokinetic Assessments ................................................................... 73 
8.12.1 
Pharmacokinetic Blood Samples for Zanubrutinib and Obinutuzumab .... 74 
8.13 
Pharmacodynamic Assessments ................................................................ 74 
8.13.1 
PBMC Preparation ..................................................................................... 74 
8.13.2 
Sample Shipment and Analysis ................................................................. 74 
8.14 
Other Assessments ..................................................................................... 75 
8.14.1 
Subject Tissue Analysis ............................................................................. 75 
8.15 
Appropriateness of Measurements ............................................................ 75 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ........................ 76 
9.1 
Monitoring ................................................................................................. 76 
9.2 
Data Management/Coding ......................................................................... 77 
9.3 
Quality Assurance Audit ............................................................................ 78 
10 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................. 80 
10.1 
Definition of an Adverse Event ................................................................. 80 
10.2 
Definition of a Serious Adverse Event ...................................................... 80 
10.3 
Lack of Efficacy ........................................................................................ 81 
10.4 
Abnormal Assessments as AEs or SAEs ................................................... 81 
10.5 
Time Period, Frequency, and Method of Detecting AEs and SAEs .......... 82 
10.5.1 
Adverse Event Reporting Period ............................................................... 82 
10.5.2 
Eliciting Adverse Events ........................................................................... 82 
10.5.3 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events 
 ................................................................................................................... 82 
10.5.3.1 
Diagnosis versus Signs and Symptoms ..................................................... 82 
10.5.3.2 
Adverse Events Occurring Secondary to Other Events ............................. 83 
10.5.3.3 
Persistent or Recurring Adverse Events .................................................... 83 
10.5.3.4 
Disease Progression ................................................................................... 83 
10.5.3.5 
Death .......................................................................................................... 84 
10.6 
Recording of Adverse Events and Serious Adverse Events ...................... 84 
10.7 
Evaluating Adverse Events and Serious Adverse Events .......................... 84 
10.7.1 
Assessment of Severity .............................................................................. 84 
10.7.2 
Assessment of Causality ............................................................................ 85 
10.8 
Follow Up of Adverse Events and Serious Adverse Events ...................... 86 
10.9 
Prompt Reporting of Serious Adverse Events ........................................... 87 
10.9.1 
Timeframes for Submitting Serious Adverse Events ................................ 87 
10.9.2 
Completion and Transmission of the Serious Adverse Event Report ....... 87 
10.10 
Regulatory Reporting Requirements for Serious Adverse Events............. 87 
10.11 
Post Study Adverse Events and Serious Adverse Events .......................... 88 
10.12 
Serious Adverse Events Related to Study Participation ............................ 88 
10.13 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards and Ethics Committees ..................................................................................... 88 
11 
DATA ANALYSIS AND STATISTICAL  CONSIDERATIONS ........... 90 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 9 of 122 
11.1 
Sample Size Considerations ...................................................................... 90 
11.2 
General Considerations for Data Analysis ................................................ 90 
11.2.1 
Analysis Populations ................................................................................. 90 
11.2.2 
Interim Analysis ......................................................................................... 91 
11.2.3 
Withdrawal ................................................................................................ 91 
11.3 
Pharmacokinetic Analysis ......................................................................... 91 
11.4 
Pharmacodynamic Analyses ...................................................................... 93 
11.5 
Efficacy Analysis ....................................................................................... 93 
11.6 
Safety Data Analysis .................................................................................. 95 
11.6.1 
Dose Limiting Toxicity .............................................................................. 95 
11.6.2 
Adverse Event ............................................................................................ 95 
11.6.3 
Laboratory Assessments ............................................................................ 95 
11.6.4 
Electrocardiogram ...................................................................................... 96 
11.6.5 
Vital Signs ................................................................................................. 96 
11.6.6 
Extent of Exposure .................................................................................... 97 
11.6.7 
Physical Examination ................................................................................ 97 
11.6.8 
Other Safety Endpoints .............................................................................. 97 
11.7 
Other Explorative Endpoints ..................................................................... 97 
12 
REGULATORY AND ETHICAL ISSUES .............................................. 98 
12.1 
Regulatory Authority Approval ................................................................. 98 
12.2 
Good Clinical Practice ............................................................................... 98 
12.3 
Ethical Conduct of the Study and Ethics Approval ................................... 98 
12.4 
Informed Consent ...................................................................................... 99 
12.5 
Investigator Reporting Requirements ........................................................ 99 
12.6 
Confidentiality ........................................................................................... 99 
12.7 
Indemnity and Compensation .................................................................. 100 
12.8 
Electronic Case Report Forms ................................................................. 100 
12.9 
Drug Accountability ................................................................................ 101 
12.10 
Inspections ............................................................................................... 101 
12.11 
Protocol Adherence ................................................................................. 101 
12.12 
Protocol Modifications ............................................................................ 102 
12.13 
Access to Information for Monitoring ..................................................... 102 
12.14 
Access to Information for Auditing or Inspections ................................. 102 
13 
STUDY MANAGEMENT ...................................................................... 103 
13.1 
Study and Study Center Closure .............................................................. 103 
13.2 
Records Retention and Study Files .......................................................... 103 
13.3 
Provision of Study Results and Information to Investigators .................. 105 
13.4 
Information Disclosure and Inventions ................................................... 105 
13.4.1 
Publication Policy .................................................................................... 106 
14 
REFERENCES ........................................................................................ 107 
15 
PROTOCOL SIGNATURES .................................................................. 109 
16 
Appendix .................................................................................................. 111 
16.1 
Appendix 1:  Blood Volume Requirements for the Subjects in Part 1 .... 111 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 10 of 122 
16.2 
Appendix 2:  Blood Volume Requirements for the Subjects in Part 2 .... 114 
16.3 
Appendix 3:  Response Criteria ............................................................... 116 
16.4 
Appendix 4: Transfusion Dependence and Independence ....................... 122 
 
 
LIST OF TABLES 
Table 1 
Study Assessments and Procedures Schedule in Part 1 ................................... 38 
Table 2 
Study Assessments and Procedures Schedule in Part 2 ................................... 44 
Table 3 
Pharmacokinetic and Pharmacodynamic Sampling ........................................ 50 
Table 4 
Dose of Obinutuzumab to be Administered during the 6 Treatment Cycles ... 58 
Table 5 
Treatment Modification for Symptoms of Infusion-Related Reactions Caused 
by Obinutuzumab ............................................................................................................... 62 
Table 6 
CYP3A Inhibitors and Inducers ...................................................................... 66 
Table 7 
Dose 
Modification 
for 
Zanubrutinib 
when 
Co-Administered 
with 
Strong/Moderate CYP3A Inhibitors or Inducers ............................................................... 67 
Table 8 
Timeframes and Documentation for Reporting Serious Adverse Events to the 
Sponsor or Designee .......................................................................................................... 87 
Table 9 
Safety Laboratory Assessments ....................................................................... 96 
 
 
LIST OF FIGURES 
Figure 1 
BTK occupancy in LN tissue by dose/schedule .............................................. 28 
Figure 2 
Assessment and Initial management of Tumor Lysis Syndrome .................... 64 
 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 11 of 122 
SYNOPSIS 
 
Name of Sponsor/Company: 
BeiGene AUS Pty Ltd. 
Name of Finished 
Product(s): 
Zanubrutinib (BGB-3111) and obinutuzumab (GA101, Gazyva®) 
Name of Active 
Ingredient(s): 
Zanubrutinib (BGB-3111 [BTK inhibitor]) and obinutuzumab 
(glycoengineered, type 2 anti CD20 monoclonal antibody) 
Title of Study:  
A Phase 1b Study to Assess Safety, Tolerability and Antitumor Activity of the Combination of 
BGB-3111 with Obinutuzumab in Subjects with B-Cell Lymphoid Malignancies 
Study Duration: 
Screening (up to 28 days); treatment until disease progression, 
intolerance, death, subject withdraws from the study, or study 
closure, whichever occurs first; followed by a 28-day safety follow 
up.   
Clinical Phase: 
Phase 1b 
Objectives: 
Part 1 
Primary: 
• 
To evaluate the safety and tolerability of zanubrutinib (also known as BGB-3111) in 
combination with obinutuzumab. 
• 
To determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of 
zanubrutinib, in combination with obinutuzumab, when given continuously orally. 
Secondary: 
• 
To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
• 
To characterize the pharmacokinetics (PK) of zanubrutinib and obinutuzumab when 
administered in combination. 
Exploratory: 
• 
• 
• 
Part 2 
Primary: 
• 
To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
Secondary: 
• 
To further evaluate the safety and tolerability of zanubrutinib in combination with 
obinutuzumab. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 12 of 122 
• 
To further characterize the pharmacokinetics (PK) of zanubrutinib and obinutuzumab when 
administered in combination. 
Exploratory: 
• 
• 
Methodology: 
This is a two part, open label Phase 1b clinical trial designed to determine the safety, tolerability and 
preliminary antitumor activity of zanubrutinib in combination with obinutuzumab: Part 1 (safety 
evaluation) and Part 2 (indication specific expansion cohorts).  
Part 1: Safety Evaluation 
Part 1 is designed to evaluate the safety and tolerability of zanubrutinib in combination with 
obinutuzumab in subjects with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small 
lymphocytic lymphoma (SLL), R/R non-germinal center B-cell (non-GCB) diffuse large B-cell 
lymphoma (DLBCL), R/R follicular lymphoma (FL), R/R mantle cell lymphoma (MCL), R/R 
Waldenström’s macroglobulinemia (WM), and R/R marginal zone lymphoma (MZL).  
Two dose regimens of zanubrutinib, 320 mg once daily [QD] and 160 mg twice daily [BID] (added per 
Amendment Version 3.0), will be evaluated in combination with obinutuzumab, consistent with the 
U.S. label regimen as specified below, in a cohort of 6 subjects for each dose regimen. It is anticipated 
based on available data that both regimens will be well tolerated. However, if there appear 2 or more 
dose limiting toxicities (DLTs) in a 6-subject cohort in either regimen, the dose level is considered to 
have exceeded the MTD and a reduced dose level of zanubrutinib (160 mg QD or 80 mg BID) will be 
evaluated in combination with obinutuzumab in another cohort of 6 subjects in that regimen. Further 
reduction of the zanubrutinib dose level will be allowed until a safe dose combination is identified. The 
period for DLT assessment is 29 days from first administration of zanubrutinib. In the event that a 
MTD is not exceeded, the Sponsor will select both 320 mg QD and 160 mg BID for the Part 2 of the 
study.  
Zanubrutinib will be administered orally with or without food every day in each cycle (29 days for 
Cycle 1, and 28 days for Cycle 2 and each cycle thereafter) until disease progression, death, 
unacceptable toxicity, other reason for treatment discontinuation, or study closure, whichever occurs 
first.  
Obinutuzumab will be administered intravenously for up to 6 cycles consistent with the US label 
regimen: 
• 
Day 2 Cycle 1: 100 mg obinutuzumab,  
• 
Day 3 Cycle 1: 900 mg obinutuzumab,  
• 
Day 9 and Day 16 Cycle 1: 1000 mg obinutuzumab. 
• 
Day 1 Cycles 2 to 6: 1000 mg obinutuzumab. 
The continuous safety evaluation will be performed by a Safety Monitoring Committee (SMC) 
composed of the Sponsor, the Sponsor’s medical delegate, the coordinating investigator, up to 
2 additional investigators, and the contract research organization (CRO) medical monitor. The SMC 
composition and responsibilities will be further detailed in the SMC Charter. The SMC will be 
responsible for the determination of dose levels and regimens to be administered during the study. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 13 of 122 
The Sponsor, in consultation with investigators, may decide to explore alternative zanubrutinib and/or 
obinutuzumab dosing regimens. If this decision is made, the protocol will be appropriately amended. 
Part 2: Indication Specific Expansion 
In Part 2, the RP2D and the 2 regimens will be investigated in 5 expansion cohorts (revised per 
Amendment Version 4.0) with histology type of tumor defined as below. Based on the safety, 
tolerability, pharmacokinetic (PK), and antitumor activity data from the safety evaluation part (Part 1) 
of the study, additional cohorts may be enrolled: 
• 
Cohort 1: treatment-naïve CLL/SLL subjects (approximately 20 subjects divided by the 
2 regimens) 
• 
Cohort 2: R/R CLL/SLL subjects (approximately 20 subjects divided by the 2 regimens) 
• 
Cohort 3: R/R non-GCB DLBCL, defined by Hans algorithm (approximately 20 subjects 
divided by the 2 regimens) 
• 
Cohort 4: R/R FL, MCL, MZL, and WM (approximately of 20 subjects divided by the 
2 regimens) 
• 
Cohort 5: R/R FL (approximately of 40 subjects in 160 mg BID regimen. Among them, 10-15 
should meet double-refractory criterion, defined as refractoriness to both rituximab and an 
alkylating agent, whether administered together or in successive treatment regimens. 
Refractoriness was defined per protocol as less than a partial response or progression of 
disease within 6 months after completion of a prior therapy, added per Amendment Version 
4.0).   
In Part 2, once the SMC confirms that the 6 subjects in 160 mg BID regimen passed Part 1 DLT test, all 
new eligible subjects will be enrolled into 160 mg BID regimen in each of the 5 cohorts until the total 
number of that cohort reaches the pre-specified number (revised per Amendment Version 4.0).  
Subjects enrolled in zanubrutinib 320 mg QD dose regimen will have the option to switch to 160 mg 
BID once Amendment 4.0 is active.  
Zanubrutinib will be administered orally with or without food every day in each cycle (28 days for each 
cycle) until disease progression, death, unacceptable toxicity, other reason for treatment 
discontinuation, or study closure, whichever occurs first.  
Obinutuzumab will be administered intravenously for up to 6 cycles consistent with the US label 
regimen: 
• 
Day 1 Cycle 1: 100 mg obinutuzumab,  
• 
Day 2 Cycle 1: 900 mg obinutuzumab,  
• 
Day 8 and Day 15 Cycle 1: 1000 mg obinutuzumab. 
• 
Day 1 Cycles 2 to 6: 1000 mg obinutuzumab. 
The safety evaluation by the SMC will be performed on as needed basis (see the SMC Charter) but at a 
minimum of every 6 months to review all subjects enrolled, or when there is any significant safety 
finding. Any treatment-related death will also trigger review by the SMC. The SMC will determine 
whether it is safe to proceed with the study.   
If the frequency of Grade 3 or 4 toxicities or other unacceptable chronic toxicities in the indication 
expansion cohorts suggests that the MTD of zanubrutinib in combination with obinutuzumab has been 
exceeded at that dose level, any remaining accrual at that dose level will be halted. Consideration will 
then be given to enrolling an expansion cohort at a lower dose level or at a different schedule. The 
protocol will be appropriately amended. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 14 of 122 
Number of Subjects: 
Approximately 132 subjects (revised per Amendment Version 4.0) 
Study Population: 
Inclusion Criteria: 
1. Aged ≥18 years, able and willing to provide written informed consent and to comply with the 
study protocol. 
2. Part 1 (Safety evaluation): R/R CLL/SLL, FL, MCL, MZL, WM, and non-GCB DLBCL. 
3. Part 2 (Indication specific expansion): 
 
Cohort 1: treatment-naïve CLL/SLL. 
 
Cohort 2: R/R CLL/SLL. 
 
Cohort 3: R/R non-GCB DLBCL.  
 
Cohort 4: R/R FL, MCL, MZL, and WM. 
 
Cohort 5: R/R FL. About 10-15 out of 40 subjects should meet double-refractory 
criterion, defined as refractoriness to both rituximab and an alkylating agent, whether 
administered together or in successive treatment regimens. Refractoriness was defined per 
protocol as less than a partial response or progression of disease within 6 months after 
completion of a prior therapy (added per Amendment Version 4.0).   
o 
For R/R CLL, FL, MCL, MZL, and WM: Evidence of progression or lack of 
response following at least 1 prior treatment. 
o 
For R/R non-GCB DLBCL: Evidence of progression or refractory disease following 
at least a standard anthracycline/ rituximab based primary treatment regimen (eg, 
R-CHOP) and not currently appropriate for autologous stem cell transplantation. 
4. Laboratory parameters as specified below: 
o 
Hematologic: Platelet count >40x109/L (may be post-transfusion); absolute 
neutrophil count >1.0x109/L (growth factor use is allowed to bring pre-treatment 
neutrophils to >1.0x109 /L if marrow infiltration is involved). 
o 
Hepatic: Total bilirubin <3 x upper limit normal (ULN); and aspartate 
aminotransferase (AST) and alanine transaminase (ALT) ≤3xULN. 
o 
Renal: Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft Gault 
equation or as measured by nuclear medicine scan or 24-hour urine collection); 
subjects requiring hemodialysis will be excluded. 
5. Anticipated survival of at least 6 months. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
7. Female subjects of childbearing potential and non-sterile males must agree to practice at least 
one of the following methods of birth control with partner(s) throughout the study and for 
≥3 months after discontinuing zanubrutinib or ≥18 months following treatment with 
obinutuzumab, whichever is longer: total abstinence from sexual intercourse, double barrier 
contraception, intra uterine device (IUD) or hormonal contraceptive initiated at least 3 months 
prior to first administration of study drug. 
8. Male subjects must not donate sperm from first study drug administration, until ≥3 months 
after discontinuing zanubrutinib or ≥18 months following treatment with obinutuzumab, 
whichever is longer. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 15 of 122 
 
Key Exclusion Criteria:  
1. Known central nervous system lymphoma or leukemia. 
2. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome. 
3. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. 
4. History of significant cardiovascular disease, define as: 
o 
congestive heart failure greater than New York Heart Association (NYHA) class II 
according to the NYHA functional classification 
o 
unstable angina or myocardial infarction with 6 months of enrollment 
o 
serious cardiac arrhythmia or clinical significant electrocardiogram (ECG) 
abnormality: corrected QT wave (QTc) prolongation, defined as a QTc >450 msecs 
based on the Bazett’s formula (Subjects with QTc prolongation due to a cardiac 
pacemaker may be allowed with approval of the medical monitor), or other ECG 
abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV 
block, or bradycardia (ventricular rate less than 50 beats/min). 
5. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, 
chronic obstructive pulmonary disease [COPD]). 
6. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy. 
7. Prior BTK inhibitor treatment. 
8. Use of strong CYP3A inhibitors and strong CYP3A inducers (see Table 6). 
9. Vaccination with a live vaccine within 28 days of the initiation of treatment. 
10. Allogeneic stem cell transplantation within 6 months, or has active graft versus host disease 
(GvHD) requiring ongoing immunosuppression. 
11. Receipt of the following treatment prior to first administration of zanubrutinib, corticosteroids 
given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 3 weeks, 
monoclonal antibody within 4 weeks. 
12. Participate in any investigational drug study within 28 days of study entry, or not recovered 
from non-hematologic toxicity of any prior chemotherapy up to ≤ Grade 1 (except for 
alopecia). 
13. History of other active malignancies within 2 years of study entry, with exception of (1) 
adequately treated in situ carcinoma of cervix; (2) localized basal cell or squamous cell 
carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
14. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as 
malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory 
bowel disease, or partial or complete bowel obstruction (revised per Amendment Version 3.0). 
15. Major surgery in the past 4 weeks. 
16. Active symptomatic fungal, bacterial and/or viral infection including evidence of infection 
with human immunodeficiency virus (HIV), human T cell lymphotropic virus (HTLV 1) 
seropositive status. 
17. Subjects with positive serology for hepatitis B defined as positivity for hepatitis B surface 
antigen (HBsAg) or hepatitis B core antibody (anti-HBc); subjects who are positive for 
anti-HBc may be considered for inclusion in the study on a case-by-case basis if they are 
hepatitis B viral deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 16 of 122 
HBV DNA testing by real-time polymerase chain reaction (PCR); subjects with presence of 
hepatitis B surface antibody (anti-HBs) consistent with prior vaccination (ie, HBsAg negative, 
anti-HBc negative, anti-HBs positive) may participate; subjects suspected to have false 
positive serologic studies because of IV immunoglobulin administration are potentially 
eligible after negative PCR studies for viral DNA/ribonucleic acid (RNA) and discussion with 
the principal investigator. 
18. Evidence of active hepatitis C (HCV): subjects with positive hepatitis C serology and positive 
HCV RNA test 
19. Inability to comply with the study procedures. 
20. Pregnant or nursing women. 
21. Any illness or condition that in the opinion of the investigator may affect the safety of 
treatment or evaluation of any study’s endpoints. 
Test Product, Dose and Route of Administration: 
Zanubrutinib 80 mg oral capsules. 
Reference Therapy, Dose and Route of Administration: 
1000 mg/vial of obinutuzumab (preservative free liquid concentrate) by intravenous infusion. 
Duration of Treatment: 
Treatment until disease progression, intolerance, death, subject withdraws from the study, or study 
closure.  
Criteria for Evaluation: 
Part 1 
Primary Endpoints: 
• 
The safety and tolerability of zanubrutinib in combination with obinutuzumab will be 
evaluated by the incidence, nature, and severity of AEs, clinical laboratory abnormalities, 
deaths and cause of death, and DLTs. 
• 
The RP2D of zanubrutinib in combination with obinutuzumab will be determined based on the 
incidence of DLTs in Part 1 of the study according to the MTD/RP2D evaluation process 
described in Section 4. 
Secondary Endpoints: 
• 
Preliminary antitumor activity of zanubrutinib in combination with obinutuzumab will be 
assessed by the frequency, quality, and durability of objective responses for each of the 
specified disease cohorts (treatment-naïve CLL, R/R CLL/SLL, R/R non-GCB DLBCL, R/R 
FL, R/R MCL, R/R MZL and R/R WM)) as per the standard International Working Group 
(IWG) Criteria for each disease. 
• 
Clinical activity of zanubrutinib in combination with obinutuzumab will be further assessed 
by the frequency and rate of hematologic improvement for subjects with CLL with anemia 
and/or thrombocytopenia at baseline (hemoglobin <9 g/dL, platelets <100,000/uL). 
• 
The PK profile of zanubrutinib will be determined, following the Cycle 1 Day 1 and Cycle 2 
Day 1, by the area under the plasma concentration-time curve from zero to the last 
quantifiable concentration (AUClast), area under the plasma concentration-time curve from 
zero to infinity (AUC), maximum observed plasma concentration (Cmax), time to maximum 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 17 of 122 
observed plasma concentration (tmax), terminal half-life (t1/2), apparent clearance (CL/F), and 
apparent volume of distribution (Vzd/F). After steady state: AUClast,ss, Cmax,ss, and tmax,ss. 
• 
The PK profile of obinutuzumab will be determined by plasma concentration prior to start of 
the infusion, and at 4 hours (end of infusion) on Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 9, 
Cycle 1 Day 16, as well as Day 1 Cycles 2, 4, and 6. 
Exploratory Endpoints: 
• 
• 
• 
Part 2 
Primary Endpoints: 
• 
Preliminary antitumor activity of zanubrutinib in combination with obinutuzumab will be 
assessed by the frequency and durability of objective responses for each of the specified 
disease cohorts as per the standard International Working Group (IWG) Criteria for each 
disease. 
Secondary Endpoints: 
• 
The safety and tolerability of zanubrutinib in combination with obinutuzumab will be further 
evaluated as described for Part 1. 
• 
Activity of zanubrutinib in combination with obinutuzumab will be assessed by the frequency 
and rate of hematologic improvement for subjects with CLL with anemia and/or 
thrombocytopenia at baseline (hemoglobin <9 g/dL, platelets <100,000/uL). 
• 
The PK profiles of zanubrutinib and obinutuzumab will be further characterized as described 
for Part 1.  
Exploratory Endpoints: 
• 
• 
• 
Statistical Methods 
The number of dose levels in the safety evaluation part and the emerging zanubrutinib in combination 
with obinutuzumab toxicities will determine the sample size. It is anticipated that approximately 132 
(revised per Amendment Version 4.0) subjects (12 subjects in the safety evaluation part and 
120 subjects in the indication specific expansion part) will be required to complete the Phase 1b trial of 
zanubrutinib in combination with obinutuzumab. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 18 of 122 
Data will be listed and summarized according to the Sponsor agreed reporting standards, where 
applicable. 
All subjects who are exposed to (or started receiving) zanubrutinib in combination with obinutuzumab 
will be included in the safety analysis set. All subjects for whom valid zanubrutinib PK sample can be 
estimated and no major protocol deviations affecting PK will be included in the PK analysis set on an 
as treated basis. Similarly, subjects for whom valid obinutuzumab PK sample can be estimated and no 
major protocol deviations affecting PK will be included in the PK analysis set on an as treated basis. 
For other parameters, all evaluable data will be included in the summaries. 
No formal statistical hypothesis testing will be performed for safety and tolerability. All safety and 
tolerability data recorded during the study will be listed and summarized as appropriate. Continuous 
variables will be summarized using descriptive statistics by treatment and by time points where 
applicable. Categorical variables will be summarized in frequency tables by treatment. 
 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 19 of 122 
LIST OF ABBREVIATIONS  
Abbreviations 
Definition 
ABC 
activated B-cell-like 
ACD 
acid citrate dextrose 
ADCC 
antibody dependent cell-mediated cytotoxicity 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve from zero to 
infinity  
AUClast 
area under the plasma concentration-time curve from zero to the 
last quantifiable concentration 
AUClast.ss 
area under the plasma concentration-time curve from zero to the 
last quantifiable concentration at steady state 
AV 
Atrioventricular 
BCR 
B-cell receptor 
BID 
twice daily 
BMI 
body mass index 
BQL 
below quantifiable limit 
BTK 
Bruton’s tyrosine kinase 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
Cmax.ss 
maximum observed plasma concentration at steady state 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRR 
complete response rate 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV% 
coefficient of variation  
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetra acetic acid 
EGFR 
epithelial growth factor receptor 
EPG 
serum electrophoresis 
FDA 
Food and Drug Administration 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 20 of 122 
Abbreviations 
Definition 
FL 
follicular lymphoma 
FRK 
Fyn-related kinase (tyrosine protein kinase 5) 
FGR 
Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog 
GA101 
Gazyva® (obinutuzumab) 
GCB 
germinal center B-cell-like 
GCP 
Good Clinical Practice 
GvHD 
graft-versus-host disease 
HBc 
hepatitis B core antibody  
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCL 
hairy cell leukemia 
HCV 
hepatitis C virus  
HER2 
human epidermal growth factor receptor 2 (erb-b2 receptor 
kinase 2) 
HER4 
human epidermal growth factor receptor 4 (erb-b4) 
HIV 
human immunodeficiency virus 
Hgb 
Hemoglobin 
HTLV-1 
human T-cell lymphotropic virus 
IB 
investigator’s brochure 
IC50 
50% maximal inhibiting concentration 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible T-cell kinase 
IUD 
intra-uterine device 
IWG 
International Working Group 
JAK3 
janus kinase 3  
λz 
terminal rate constant 
LCK 
lymphocyte-specific protein tyrosine kinase 
MCH 
mean corpuscular hemoglobin 
MCL 
mantle cell lymphoma  
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging  
MTD 
maximal tolerated dose 
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer cells 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 21 of 122 
Abbreviations 
Definition 
PD 
Pharmacodynamics 
PET 
positron emission tomography 
PFS 
progression free survival 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
Pharmacokinetic 
PLCγ2 
phospholipase gamma 2 (phosphatidylinositol-specific) 
PR 
partial response 
PRR 
partial response rate 
PT 
preferred term 
QD 
once daily 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SOP 
standard operating procedure 
t1/2 
terminal half-life 
TEAE 
treatment–emergent adverse events 
TEC 
tyrosine kinase expressed in hepatocellular carcinoma 
TESAE 
treatment-emergent serious adverse event 
tmax 
time to maximum observed plasma concentration 
tmax,ss 
time to maximum observed plasma concentration at steady state 
ULN 
upper limit of normal 
Vd,ss 
volume of distribution at steady state 
Vzd/F 
volume of distribution 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
WM 
Waldenström’s macroglobulinemia 
zanubrutinib 
BGB-3111 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 22 of 122 
1 INTRODUCTION   
1.1 Background and Pharmacology 
Bruton’s tyrosine kinase (BTK), a member of the tyrosine kinase expressed in 
hepatocellular carcinoma (TEC) family kinases, is a critical component of the B-cell 
receptor (BCR) signalling cascade. Inhibition of BTK has emerged as a promising 
strategy for targeting B-cell malignancies. Ibrutinib has demonstrated promising 
anti-tumor activity in several B-cell malignancies, including mantle cell lymphoma 
(MCL), chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), 
follicular lymphoma (FL), multiple myeloma (MM), and activated B-cell like (ABC) 
subtype of diffuse large B-cell lymphoma (DLBCL).1,2,3,4 It was recently approved by the 
Food and Drug Administration (FDA) for treatment of subjects with MCL and CLL who 
had received at least one prior therapy, and subjects with WM and CLL with 17p deletion 
at any line.  
While ibrutinib treatment frequently generates objective responses in these diseases, few 
of them are complete responses, thus management requires continuous treatment.5,6 In 
addition, though ibrutinib is well-tolerated in comparison to traditional chemotherapies, it 
is associated with adverse reactions that in some cases can be life-threatening or 
treatment-limiting. These adverse reactions, including but not limited to skin rash, nausea, 
vomiting, thrombocytopenia, bleeding and atrial fibrillation, are believed to be related to 
ibrutinib’s off-target activities against epithelial growth factor receptor (EGFR)/janus 
kinase 3 (JAK3)/TEC. 
Thus there is a clear medical need for a more potent, more specific, and better-tolerated 
secondary generation BTK inhibitor. 
Zanubrutinib (also known as BGB-3111) is a potent, specific and irreversible BTK 
inhibitor with a favorable pharmacology/toxicology profile. Preclinical data suggests that 
zanubrutinib is differentiated from ibrutinib in the following aspects: 
1. 
Zanubrutinib is more selective than ibrutinib in the inhibition of BTK versus 
epithelial growth factor receptor (EGFR), Gardner-Rasheed feline sarcoma viral 
(v-fgr) oncogene homolog (FGR), Fyn-related kinase (tyrosine protein kinase 5) 
(FRK), human epidermal growth factor receptor (HER)2, HER4, interleukin-2-
inducible T cell kinase (ITK), JAK3, lymphocyte-specific protein tyrosine kinase 
(LCK), and TEC. The predicted efficacious dose of zanubrutinib in subjects is 
much lower than ibrutinib. Accordingly, off-target kinase inhibition potentially 
associated with common, and occasionally severe, adverse effects seen with 
ibrutinib therapy, such as thrombocytopenia, bleeding, atrial fibrillation, rash, and 
gastrointestinal toxicities may be reduced relative to ibrutinib.   


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 23 of 122 
2. 
Zanubrutinib has better oral bioavailability than ibrutinib.   
3. 
Due to its weaker ITK inhibitory activity, zanubrutinib displayed significantly less 
inhibitory effect on rituximab-induced antibody dependent cell-mediated 
cytotoxicity (ADCC) than ibrutinib7,8 in preclinical studies and is therefore 
unlikely to adversely impact the anti-tumor effects of agents such as 
obinutuzumab. 
In vivo studies demonstrated that zanubrutinib had dose dependent anti-tumor activity 
against Rec-1 MCL xenografts engrafted either subcutaneously or systemically in mice. 
Zanubrutinib was significantly more effective than ibrutinib in both models. In 
pharmacokinetic (PK)/pharmacodynamic (PD) studies, oral administration of 
zanubrutinib resulted in time dependent occupancy of BTK in both blood and spleen of 
mice. 
Refer to the Investigator’s Brochure (IB) for more detailed information on the 
background of zanubrutinib.9 
1.2 Overview of Clinical Pharmacology 
In the Phase 1, first-in-human trial of zanubrutinib as monotherapy (A Phase 1, 
open-label, multiple-dose, dose escalation and expansion study to investigate the safety 
and pharmacokinetics of the BTK inhibitor zanubrutinib in subjects with B-cell lymphoid 
malignancies; protocol number BGB-3111-AU-003)10, interim PK data in a limited 
number of subjects showed that zanubrutinib is rapidly absorbed and eliminated after oral 
administration. The maximum plasma concentration and the drug exposure (area under 
the concentration-time curve [AUC]) increased in a nearly dose-proportional manner 
from 40 mg to 320 mg both after the single dose and at steady state. The terminal half-life 
(t1/2) ranged from 1.8 hours to 3.7 hours. At 320 mg once daily (QD) and 160 mg twice 
daily (BID), the means for maximum observed plasma concentration (Cmax) and the area 
under the concentration-time curve from 0 to 24 hours (AUC0-24h) are around 646 ng/mL 
and 2,704 ng/mL*h, and 282 ng/mL and 3,006 ng/mL*h, respectively, at the steady state.  
In the same Phase 1 trial, the pharmacodynamic activity of zanubrutinib as measured by 
BTK occupancy in peripheral blood mononuclear cells (PBMCs) was determined in a 
limited number of subjects. The data indicates that even at the starting dose (40 mg), 
zanubrutinib achieved rapid, durable, and near complete inhibition of BTK, which is 
comparable to the reported effect of ibrutinib at 560 mg in clinic4. These data suggest that 
zanubrutinib is a very potent BTK inhibitor. 
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 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 24 of 122 
QTc intervals and other ECG intervals. Because of the short half-life and no accumulation 
seen upon multiple-dosing, these results are also applicable for steady-state conditions. 
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicate that 
co-administration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg 
every day 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 every day 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. 
Based on the in vitro study, a clinical drug-drug interaction study (BGB-3111-108) was 
conducted to assess the effect of zanubrutinib on the PK of substrates of CYP3A 
(midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), P-gp (digoxin), BCRP 
(rosuvastatin) using a cocktail approach.  The results show that zanubrutinib does not 
significantly affect drugs metabolized by CYP2C9 (warfarin) or transported by P-gp 
(digoxin) and BCRP (statins).   Zanubrutinib has a mild induction effect on CYP3A and 
CYP2C19 enzymes.  AUC0-t and Cmax values were approximately 47% and 30% lower, 
respectively, when midazolam was coadministered with zanubrutinib.  AUC0-t and Cmax 
values were approximately 36% and 20% lower, respectively, when omeprazole was 
coadministered with zanubrutinib. 
1.3 Overview of Efficacy 
As of 30 July 2015, the preliminary results from the Phase 1 trial of zanubrutinib 
demonstrates promising anti-tumor activity in subjects with B-cell malignancies, 
including CLL, WM, MCL, hairy cell leukemia (HCL), DLBCL, MZL, and FL. Among 
the twenty-five (25) subjects enrolled in the dose-escalation phase of the study, the best 
responses are: one (1) subject with MCL achieved complete response/remission (CR); 
fifteen (15) subjects achieved partial responses/remission (PR), including six (6) subjects 
with CLL, five (5) subjects with WM, three (3) subjects with MCL, and one (1) subject 
with HCL; six (6) subjects achieved stable disease (SD), including two (2) subjects with 
CLL, one (1) subject with MCL, one (1) subject with MZL, one (1) subject with DLBCL, 
and one (1) subject with FL. Three (3) subjects, including one (1) subject with WM, one 
(1) subject with MCL, and one (1) subject with DLBCL, presented with progressive 
disease. 
1.4 Overview of Safety of Zanubrutinib 
Zanubrutinib has also demonstrated a favorable toxicology and safety pharmacology 
profile in non-clinical experiments compared to ibrutinib in terms of the overall tolerance 
and severe toxicities in single and repeat dose toxicity studies.  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 25 of 122 
The preliminary results from the ongoing first-in-human Phase 1 trial demonstrates that 
zanubrutinib is well tolerated in subjects with advanced B-cell malignancies. As of 30 
July 2015, except for 4 subjects who had disease progression, all the other 21 subjects 
enrolled in the dose-escalation part of the zanubrutinib study have received zanubrutinib 
treatment for more than 100 days. No dose limiting toxicities (DLT) were encountered, 
and the maximum tolerated dose (MTD) was not reached. There were no drug-related 
SAEs, AEs leading to drug discontinuation, or AE-related deaths. Of 21 >grade 3 AEs, 3 
were assessed by investigators as potentially drug-related - all were self-limiting 
neutropenia in CLL subjects, two of whom had neutropenia at baseline. No G3/4 bleeding 
events were recorded. Four subjects had a baseline history of atrial fibrillation/flutter 
(AF); no exacerbation or new event of AF was reported. All subjects have received 
regular electrocardiogram (ECG) monitoring and none has demonstrated any clinically 
significant cardio-electric changes such as QTc prolongation. 
1.5 Benefit and Risk Conclusions for Zanubrutinib 
Zanubrutinib has demonstrated a very favorable toxicology and safety pharmacology 
profile in the ongoing Phase 1 study. The dose escalation portion of the study has been 
completed. Preliminary data from the current Phase 1 study showed that zanubrutinib has 
been well tolerated and has demonstrated promising anti-tumor activity in advanced 
B-cell malignancies, including CLL, MCL, WM, HCL, DLBCL, FL, and MZL. The study 
is currently ongoing to further evaluate the safety, PK, PD, and efficacy of zanubrutinib.  
Zanubrutinib is an investigational drug with safety data in more than 600 patients as of 
15 September 2017. Refer to the IB for more detailed information. Subjects enrolled in 
clinical studies with zanubrutinib must be closely monitored by means of AEs, vital signs, 
electrocardiograms, and clinical laboratory safety tests of blood and urine. 
1.6 Obinutuzumab 
Obinutuzumab (Gazyva®)11,12 is a recombinant monoclonal humanized and 
glycoengineered Type II anti-CD20 antibody of the IgG1 isotype. It specifically targets 
the extracellular loop of the CD20 transmembrane antigen on the surface of 
non-malignant and malignant pre-B and mature B-lymphocytes, but not on hematopoietic 
stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering of 
the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune 
effector cells such as natural killer (NK) cells, macrophages and monocytes as compared 
to non-glycoengineered antibodies. Obinutuzumab in combination with chlorambucil has 
been approved by the US Food and Drug Administration and the Australia Therapeutic 
Goods Administration (TGA) to treat patients with previously untreated CLL. 
Obinutuzumab in combination with bendamustine followed by GAZYVA monotherapy, 
is indicated for the treatment of patients with follicular lymphoma (FL) who relapsed 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 26 of 122 
after, or are refractory to, a rituximab-containing regimen. Refer to Section 6 for more 
details. 
1.7 Rationale 
for 
the 
Combination 
of 
Zanubrutinib 
and 
Obinutuzumab  
As noted above, signaling via the aberrantly activated B-cell receptor (BCR) has a critical 
role in the pathogenesis of B-cell tumors by promoting survival and clonal expansion of 
malignant B-cells. Ibrutinib, a FDA-approved BTK inhibitor, has demonstrated objective 
responses among different B-cell malignancies in clinical trials, including CLL/SLL, 
MCL, DLBCL, FL and WM. Zanubrutinib, differentiated from ibrutinib, is a more potent, 
more specific second-generation BTK inhibitor. An ongoing Phase 1 trial 
(BGB-3111-AU-003) has shown zanubrutinib to be very well tolerated, safe and active in 
B-cell malignancies of various histologies.  
Anti-CD20 antibodies are widely used in treating B-cell malignancies and their 
anti-tumor activities are largely dependent on ADCC effect. Ibrutinib was tested in 
combination with rituximab, an anti-CD20 antibody, in a Phase 2 trial of CLL.8,13 After a 
follow-up of 6 months, the overall response rate (ORR) was 83% with a large and rapid 
reduction in lymph-node and spleen sizes. 13 However, most of the responses were partial 
responses (PRs). A recent pre-clinical study also showed that ibrutinib could antagonize 
rituximab induced ADCC by inhibiting ITK.14 Since zanubrutinib is more selective than 
ibrutinib against off-target kinases including ITK, zanubrutinib did not show any 
interference with the ADCC effect induced by anti-CD20 antibodies in the pre-clinical 
studies. In addition, zanubrutinib has demonstrated good combination activity with 
rituximab or obinutuzumab in preclinical xenograft models. 
Obinutuzumab is a humanized anti-CD20 monoclonal antibody which demonstrated 
clinical superiority compared with rituximab in a recent Phase 3 study. This is a type II 
glycoengineered monoclonal antibody, with an enhanced ADCC and direct-cell killing 
activity, but without complement-dependent cytotoxicity. Obinutuzumab alone or in 
combination with other chemo-therapy drugs, as well as with other BTK inhibitors, ie, 
ibrutinib and ACP-196, are being evaluated in different B-cell malignancies. 
Based upon these background data and the promising results from the combination of 
ibrutinib and rituximab, this combination study offers a path to evaluation of the promise 
of an improved therapy for these subjects. 
This trial is designed to evaluate the safety, tolerability, and PK profile as well as 
preliminary evidence of the anti-tumor activity of zanubrutinib in combination with 
obinutuzumab in subjects with B-cell malignancies. The starting doses and regimens of 
zanubrutinib, 160 mg BID and 320 mg QD, are the recommended Phase 2 dose (RP2Ds) 
for monotherapy that have been determined based on the PK, safety and tolerability, PD 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 27 of 122 
and preliminary efficacy in the ongoing zanubrutinib trial (BGB-3111-AU-003). The dose 
and regimen of obinutuzumab was selected based on the US label to treat patients with 
untreated CLL. The Phase 1/2 experiences with ibrutinib in combination with other anti-
CD20 antibodies, such as rituximab and ofatumumab, has shown that the combinations 
are active, lack overlapping toxicity, and can be combined at full monotherapy doses of 
the respective agents. 
The study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP) guidelines, the Declaration of Helsinki and any applicable regulatory 
requirements. 
1.8 
Rationale to Change Zanubrutinib Dose from 320 mg QD to 
160 mg BID (added per Amendment 4.0)  
Before Amendment 3.0, zanubrutinib was administrated 320 mg QD. Starting from 
Amendment 3.0, zanubrutinib will be administrated 160 mg BID for new subjects enrolled. 
The change is based on lymph node (LN) BTK occupancy findings in study 
BGB-3111-AU-003. Thirty subjects from the study were evaluated for BTK occupancy in 
LN tissue using a fluorescent probe assay on paired lymph node biopsies. Median 
occupancy was 100% in subjects receiving zanubrutinib 160 mg BID (n=18) vs 94% in 
subjects receiving zanubrutinib 320 mg QD (n=12) (p=0.002, Wilcoxon). The proportion 
of subjects with > 90% BTK occupancy was 94% (160 mg BID) vs 58% (320 mg QD) 
(p=0.027, Fisher’s exact). Occupancy did not appear to differ amongst histologic subtype. 
BTK occupancy in LN tissue by dose/schedule is shown in the following Figure 1. 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 28 of 122 
Figure 1 BTK occupancy in LN tissue by dose/schedule 
 
 
Subjects enrolled in zanubrutinib 320 mg QD dose regimen will have the option to switch 
to 160 mg BID once Amendment 4.0 is active.  
 
1.9 Rationale to Remove Food Restriction for Zanubrutinib 
(added per Amendment 4.0) 
Before Amendment 4.0, food was restricted 2 hours before and 1 hour after zanubrutinib 
administration. Starting from Amendment 4.0, this food restriction will be removed for all 
subjects. This is based on the preliminary result from a dedicated food-effect study, 
BGB-3111-103, which indicated that zanubrutinib plasma exposure was not affected by a 
high-fat breakfast and was increased by 37% and 56% for AUC and Cmax, respectively, by 
a standard breakfast, as compared to fasting. Since the increase fall within the variability 
of zanubrutinib clearance (approximately 50% coefficient of variation) and that a wide 
therapeutic index was observed on zanubrutinib, it is recommended that all food restriction 
on zanubrutinib administration be removed from this trial, and subjects may take 
zanubrutinib with or without food. 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 29 of 122 
2 STUDY OBJECTIVES 
2.1 Study Objectives in Part 1 
2.1.1 Primary Objectives 
• 
To evaluate the safety and tolerability of zanubrutinib in combination with 
obinutuzumab. 
• 
To determine the MTD and/or the RP2D of zanubrutinib, in combination of with 
obinutuzumab, when given continuously orally. 
2.1.2 Secondary Objectives 
• 
To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
• 
To characterize the PK of zanubrutinib and obinutuzumab when administered in 
combination. 
2.1.3 Exploratory Objectives 
• 
• 
• 
2.2 Study Objectives in Part 2 
2.2.1 Primary Objectives 
• 
To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
2.2.2 Secondary Objectives 
• 
To further evaluate the safety and tolerability of zanubrutinib in combination with 
obinutuzumab. 
• 
To further characterize the PK of zanubrutinib and obinutuzumab when 
administered in combination. 
2.2.3 Exploratory Objectives 
• 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 30 of 122 
• 
3 STUDY ENDPOINTS 
3.1 Study Endpoints in Part 1 
3.1.1 Primary Endpoints 
• 
The safety and tolerability of zanubrutinib in combination with obinutuzumab will 
be evaluated by the incidence, nature, and severity of AEs, clinical laboratory 
abnormalities, deaths and cause of death, and DLTs. 
• 
The RP2D dose regimens of zanubrutinib in combination with obinutuzumab will 
be determined based on the incidence of DLTs in the Part 1 of the study according 
to the MTD/RP2D evaluation process described below. 
3.1.2 Secondary Endpoints 
• 
Preliminary antitumor activity of zanubrutinib in combination with obinutuzumab 
will be assessed by the frequency, quality, and durability of objective responses 
for each of the specified disease cohorts (treatment-naïve CLL, R/R CLL/SLL, 
R/R non-GCB DLBCL, R/R FL, R/R MCL, R/R MZL and R/R WM) as per the 
standard International Working Group (IWG) Criteria for each disease.15,16,17  
• 
Clinical activity of zanubrutinib in combination with obinutuzumab will be further 
assessed by the frequency and rate of hematologic improvement for subjects with 
CLL with anemia and/or thrombocytopenia at baseline (hemoglobin <9 g/dL, 
platelets <100,000/uL). 
• 
The PK profile of zanubrutinib will be determined, following the Cycle 1 Day 1 
and Cycle 2 Day 1, by the area under the plasma concentration-time curve from 
zero to the last quantifiable concentration (AUClast), area under the plasma 
concentration-time curve from zero to infinity (AUC), maximum observed plasma 
concentration (Cmax), time to maximum observed plasma concentration (tmax), 
terminal half-life (t1/2), apparent clearance (CL/F), and apparent volume of 
distribution (Vzd/F).  After steady state: AUClast,ss, Cmax,ss, and tmax,ss. 
• 
The PK profile of obinutuzumab will be determined by plasma concentration prior 
to start of the infusion, and at 4 hours (end of infusion) on Cycle 1 Day 2, Cycle 1 
Day 3, Cycle 1 Day 9, Cycle 1 Day 16, as well as Day 1 Cycles 2, 4, and 6. 
3.1.3 Exploratory Endpoints 
• 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 31 of 122 
• 
• 
3.2 Study Endpoints in Part 2 
3.2.1 Primary Endpoints 
• 
Preliminary antitumor activity of zanubrutinib in combination with obinutuzumab 
will be assessed by the frequency and durability of objective responses for each of 
the specified disease cohorts as per the standard International Working Group 
(IWG) Criteria for each disease. 
3.2.2 Secondary Endpoints 
• 
The safety and tolerability of zanubrutinib in combination with obinutuzumab will 
be further evaluated as described for the Part 1. 
• 
Activity of zanubrutinib in combination with obinutuzumab will be assessed by 
the frequency and rate of hematologic improvement for subjects with CLL with 
anemia and/or thrombocytopenia at baseline (hemoglobin <9 g/dL, platelets 
<100,000/uL). 
• 
The PK profiles of zanubrutinib and obinutuzumab will be further characterized 
as described for the Part 1.  
3.2.3 Exploratory Endpoints 
• 
• 
• 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 32 of 122 
4 INVESTIGATIONAL PLAN 
4.1 Summary of Study Design 
This is a two-part, open-label Phase 1b clinical trial designed to determine the safety, 
tolerability, and clinical activity of zanubrutinib in combination with obinutuzumab: Part 
1 (safety evaluation) and Part 2 (indication specific expansion cohorts).  
Part 1: Safety Evaluation  
Part 1 is designed to evaluate the safety and tolerability of zanubrutinib in combination 
with obinutuzumab in subjects with R/R CLL/SLL, R/R non-GCB DLBCL, R/R FL, R/R 
MCL, R/R WM, and R/R MZL.  
Two dose regimens of zanubrutinib (320 mg QD and 160 mg BID [added per 
Amendment Version 3.0]) will be evaluated in combination with obinutuzumab 
consistent with the US label regimen (as specified below), in a cohort of 6 subjects for 
each dose regimen. If there appear 2 or more DLTs in a 6-subject cohort in either 
regimen, the dose level is considered to have exceeded the MTD; and a reduced dose 
level of zanubrutinib (160 mg QD or 80 mg BID) will be evaluated in combination with 
obinutuzumab in another cohort of 6 subjects in that regimen. Further reduction of 
zanubrutinib dose level will be allowed until a safe dose combination is identified. The 
period for DLT assessment is 29 days from first administration of zanubrutinib. In the 
event that a MTD is not exceeded, the Sponsor will select both 320 mg QD and 160 mg 
BID for the Part 2 of the study. 
Zanubrutinib will be administered orally with or without food every day in each cycle 
(29 days for Cycle 1, and 28 days for Cycle 2 and each cycle thereafter) until disease 
progression, death, unacceptable toxicity, other reason for treatment discontinuation, or 
study closure, whichever occurs first. 
Obinutuzumab will be administered intravenously for up to 6 cycles consistent with the 
U.S. label regimen: 
• 
Day 2 Cycle 1: 100 mg obinutuzumab 
• 
Day 3 Cycle 1: 900 mg obinutuzumab 
• 
Day 9 and Day 16 Cycle 1: 1000 mg obinutuzumab 
• 
Day 1 Cycles 2 to 6: 1000 mg obinutuzumab 
The continuous safety evaluation will be performed by a Safety Monitoring Committee 
(SMC) composed of the Sponsor, the Sponsor’s medical delegate, the coordinating 
investigator, and up to two (2) additional investigators, and the contract research 
organization (CRO) medical monitor. The SMC composition and responsibilities will be 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 33 of 122 
further detailed in the SMC Charter. The SMC will be responsible for the determination 
of dose levels and regimens to be administered during the study. 
The Sponsor, in consultation with investigators, may decide to explore alternative 
zanubrutinib and/or obinutuzumab dosing regimens.  If this decision is made, the protocol 
will be appropriately amended. 
Part 2: Indication Specific Expansion Cohorts 
In Part 2, the RP2D and the 2 regimens will be investigated in 5 expansion cohorts 
(revised per Amendment Version 4.0) with histology type of tumor defined as below. 
Based on the safety, tolerability, PK, and antitumor activity data from the safety 
evaluation part (Part 1) of the study, additional cohorts may be enrolled: 
• 
Cohort 1: treatment-naïve CLL/SLL subjects (approximately 20 subjects divided 
by the 2 regimens) 
• 
Cohort 2: R/R CLL/SLL subjects (approximately 20 subjects divided by the 
2 regimens) 
• 
Cohort 3: R/R non-GCB DLBCL, defined by Hans algorithm (approximately 
20 subjects divided by the 2 regimens)  
• 
Cohort 4: R/R FL, MCL, MZL, and WM (approximately of 20 subjects divided by 
the 2 regimens) 
• 
Cohort 5: R/R FL (approximately of 40 subjects in 160 mg BID. About 10-15 of 
them should meet double-refractory criterion, defined as refractoriness to both 
rituximab and an alkylating agent, whether administered together or in successive 
treatment regimens. Refractoriness was defined per protocol as less than a partial 
response or progression of disease within 6 months after completion of a prior 
therapy, added per Amendment Version 4.0).   
In Part 2, once the SMC confirms that the 6 subjects in 160 mg BID regimen passed 
Part 1 DLT test, all new eligible subjects will be enrolled into 160 mg BID regimen in 
each of the 5 cohorts until the total number of that cohort reaches the pre-specified 
number (revised per Amendment Version 4.0).  
Subjects enrolled in zanubrutinib 320 mg QD dose regimen will have the option to switch 
to 160 mg BID once Amendment 4.0 is active.  
Zanubrutinib will be administered orally with or without food every day in each cycle 
(28 days for each cycle) until disease progression, death, unacceptable toxicity, other 
reason for treatment discontinuation, or study closure, whichever occurs first. 
Obinutuzumab will be administered intravenously for up to 6 cycles consistent with the 
U.S. label regimen: 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 34 of 122 
• 
Day 1 Cycle 1: 100 mg obinutuzumab 
• 
Day 2 Cycle 1: 900 mg obinutuzumab  
• 
Day 8 and Day 15 Cycle 1: 1000 mg obinutuzumab 
• 
Day 1 Cycles 2 to 6: 1000 mg obinutuzumab 
The safety evaluation by the SMC will be performed on as needed basis (see the SMC 
Charter) but at a minimum of every 6 months to review all subjects enrolled, or when 
there is any significant safety finding. Any treatment-related death will also trigger 
review by the SMC. The SMC will determine whether it is safe to proceed with the study.  
If the frequency of Grade 3 or 4 toxicities or other unacceptable chronic toxicities in the 
indication expansion cohorts suggests that the MTD of zanubrutinib in combination with 
obinutuzumab has been exceeded at that dose level, any remaining accrual at that dose 
level will be halted. Consideration will then be given to enrolling an expansion cohort at a 
lower dose level or at a different schedule. The protocol will be appropriately amended. 
4.2 Safety Evaluation 
Two dose regimens of zanubrutinib will be evaluated, 320 mg QD and 160 mg BID. The 
plan is to dose 6 subjects in each of the 2 dose regimens with the plan modified as 
necessary by DLT experience.  The DLT assessment period is defined as 29 days from 
the first administration of zanubrutinib. If 2 or more of the subjects in either of the 
6-subject cohorts develop a DLT during the DLT assessment period, the MTD is 
considered to have been exceeded and no further subjects will be treated in that dose 
regimen. 
In the event that a MTD is not exceeded, the Sponsor will select both 320 mg QD and 
160 mg BID for the Part 2 of the study. 
If the starting regimen (320 mg QD or 160 mg BID of zanubrutinib in combination with 
obinutuzumab) is not tolerated, 160 mg QD or 80 mg BID of zanubrutinib in combination 
with obinutuzumab may be tested (as determined by the SMC and the Sponsor) to define 
a potential RP2D. The period for DLT assessment is 29 days from the first administration 
of zanubrutinib. 
Depending on the decision of the SMC and on review of available data, an additional 
intermediate dose level may be explored prior to a final decision on a RP2D. 
4.2.1 Safety Monitoring Committee 
The continuous safety evaluation will be performed by a SMC composed of the Sponsor, 
the Sponsor’s medical delegate, the coordinating investigator, up to two (2) additional 
investigators, and the CRO medical monitor. The SMC composition and responsibilities 
will be further detailed in the SMC Charter. Ad hoc members will be consulted as needed 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 35 of 122 
and may include, but are not restricted to a biostatistician and a pharmacokineticist. The 
SMC will be responsible for the determination of dose levels and regimens to be 
administered during the study. 
4.2.2 
Dose Limiting Toxicity 
For Part 1 subjects only. The period for DLT assessment is 29 days from first 
administration of zanubrutinib. 
All toxicities or AEs will be graded according to the NCI CTCAE Version 4.03.18 Subjects 
who initiate treatment with an ANC <1000/μl will not be considered evaluable for 
neutrophil toxicity as outlined in the 2008 IWCLL guidelines.15 
Dose limiting toxicities are defined as a toxicity or AE occurring during the DLT 
assessment period (first 29 days of treatment), which is not clearly attributable to a cause 
other than zanubrutinib and/or obinutuzumab (such as disease progression, underlying 
illness, concurrent illness or concomitant medication) and meets one of the following 
criteria:  
• 
Grade 3 or 4 drug-related non-hematologic toxicity (excluding Grade 3 nausea, 
vomiting, hypertension, and asymptomatic laboratory abnormalities).  
• 
Grade 4 drug-related hematologic toxicity persisting for >14 days. 
• 
 Any grade toxicity which in the judgment of the investigator or Sponsor requires 
removal of the subject from the study. 
Resumption of zanubrutinib and obinutuzumab administration for subjects experiencing 
DLTs is permitted, if clinically appropriate and after discussion with the Sponsor medical 
monitor, contingent on the return of the DLT to ≤ Grade 1 severity within 14 days and 
interruption or delay of treatment for no more than 21 days. Resumption of treatment 
after resolution of a DLT will be at the 50% decreased dose level of zanubrutinib. The 
administration of obinutuzumab will be resumed at the same dose according to the 
original schedule. 
If a subject could only receive 75% of the expected dose of either component of the 
combination for reasons other than treatment related toxicity, then an additional subject 
will be enrolled in the cohort.  
4.2.3 
Dose Continuation and Dose Reduction  
The continuous safety evaluation will be performed by the Sponsor, the CRO medical 
monitor, the investigators and the SMC (see Section 4.2.1 above). At the conclusion of 
the dose regimen safety evaluation part (Part 1), the SMC will determine the RP2D to be 
further investigated. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 36 of 122 
In the absence of unacceptable toxicity, disease progression, or subject withdrawal, 
subjects may continue with daily administrations of zanubrutinib at the discretion of the 
investigator. Subjects with disease progression may continue study drug treatment if they 
are benefitting from the treatment in the judgment of the investigators and approved by 
Sponsor medical monitor. 
In the event of a DLT, treatment with both investigational drugs will be stopped and 
supportive therapy administered as required. If the toxicity resolves or subsides to 
Grade 0 or Grade 1 (or baseline) within 14 days of the onset of the DLT and the subject is 
showing clinical benefit in the investigator’s opinion, treatment of zanubrutinib may be 
restarted at the 50% decreased dose level (at the investigator’s discretion after discussions 
with the Sponsor’s medical monitor). The administration of obinutuzumab will be 
resumed at the same dose according to the original schedule. 
If the toxicity does not resolve to Grade 0 or Grade 1 (or baseline) within 14 days of 
onset, the subject must be withdrawn from further investigational drug treatment. Any 
exception to this must be agreed upon by the investigator and the Sponsor’s medical 
monitor. 
4.2.4 Dose Interruption and Modification  
The continuous safety evaluation will be performed by the Sponsor, the CRO medical 
monitor, the coordinating investigator, and investigators.  When at least 6 or more 
subjects have been treated with zanubrutinib in an expansion cohort and ≥ 33% of the 
treated subjects experience a DLT during the first cycle, study accrual will be held 
pending data review by the SMC. 
Dosing of zanubrutinib will be held for individual subjects under any of the following 
conditions: 
 Grade 4 neutropenia related to zanubrutinib lasting > 7 days or Grade ≥ 3 febrile 
neutropenia  
 Grade 4 thrombocytopenia related to zanubrutinib lasting > 7 days or Grade ≥ 3 
thrombocytopenia associated with Grade ≥ 2 bleeding  
 Any Grade ≥ 3 non-hematologic toxicity related to zanubrutinib except for 
asymptomatic laboratory abnormalities 
After the subject’s toxicity improved to Grade ≤ 1 or to baseline values within 14 days, 
the investigator may elect to have the subject restart the treatment. If the subject’s toxicity 
improves to Grade 1 or baseline within 15 to 28 days of study drug discontinuation and if, 
in the investigator’s opinion, it is in the subject’s best interest to restart treatment after 
more than 14 days, then a written approval must be obtained from the Sponsor Medical 
Monitor. 
The causality of the toxicity should be assessed by the investigator. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
Page 37 of 122 
If, in the investigator’s opinion, the toxicity is unrelated to zanubrutinib, the subject may 
be restarted at the preceding dose, zanubrutinib 320 mg QD or 160 mg BID. However, if 
the toxicity recurs, the dose must be reduced to 160 mg QD or 80 mg BID (revised per 
Amendment Version 3.0). If in the investigator’s opinion, the toxicity is related to 
zanubrutinib, the subject may restart therapy at a reduced dose of 160 mg QD or 80 mg 
BID (revised per Amendment Version 3.0). A second dose reduction to 80 mg QD for both 
regimens (revised per Amendment Version 3.0), based on the criteria outlined above, may 
be considered upon consultation with the Sponsor Medical Monitor. Any subjects, who do 
not tolerate 80 mg QD (revised per Amendment Version 3.0), must be removed from the 
study. 
If, in the investigator’s opinion, the toxicity is related to obinutuzmab,  obinutuzmab may 
be interrupted or discontinued. There will be no dose modification for obinutuzmab. 
If a non-disease related surgery is required during the study, zanubrutinib should be 
interrupted 3 days before and 7 days after the surgery. Obinutuzmab should also be 
interrupted, if applicable. 
4.3 Study Assessments and Procedures 
The schedule of assessments is presented in Table 1, Table 2, and Table 3.  
 
 
 


 
                                                                          CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 38 of 122 
Table 1 
Study Assessments and Procedures Schedule in Part 1 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(29 days, DLT period) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
3 
9 
±1 day 
16 
±1 day 
23 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
General medical 
history & baseline 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical 
examination7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (& height 
at screening) 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
B symptoms6 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Target physical 
examination7 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG status 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Zanubrutinib 
administration9,12 
 
Orally  
 
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 39 of 122 
Table 1 
Study Assessments and Procedures Schedule in Part 1 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(29 days, DLT period) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
3 
9 
±1 day 
16 
±1 day 
23 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Obinutuzumab 
administration 
 
 
100 
mg 
900 
mg 
1000 
mg 
1000 
mg 
 
1000 
mg 
 
 
 
 
 
Review of 
concomitant 
medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs (including 
serious) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Response 
Assessment25 
 
Every 12 weeks (end of week 12, 24, 36 and 48) 
X 
X10 
X3 
Tumor assessment 
by CT or MRI10 
X 
Every 12 weeks (end of week 12, 24, 36 and 48) 
X10 
X10 
X3 
Bone Marrow 
evaluation11 
X 
End of Week 12  
 
 
 
Local Laboratory 
 
Hematology13 
X 
X 
 
 
X 
X 
X 
X 
X 
X26 
X 
X 
X 
Clinical 
chemistry14 
X 
X 
 
 
X 
X 
X 
X 
X 
X26 
X 
X 
X 
Coagulation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IgA, IgG, IgM 
level and serum 
EPG 15 
X 
 
 
 
 
 
 
X 
 
X26 
X26 
X 
X 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 40 of 122 
Table 1 
Study Assessments and Procedures Schedule in Part 1 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(29 days, DLT period) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
3 
9 
±1 day 
16 
±1 day 
23 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Pregnancy test16 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
Viral serologies17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis18 
X 
X 
 
 
X 
X 
X 
X 
X 
X26 
X 
X 
 
CLL prognostic 
factors19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory 
 
Tumor tissue 
and/or bone 
marrow sampling 
X20 
 
 
 
 
 
 
 
 
 
 
X23 
 
Blood sampling 
for biomarker 
analysis 
 
 
 
 
 
 
 
 
 
 
 
X24 
 
Pharmacokinetic 
blood sampling21 
 
X 
X 
X 
X 
X 
 
X22 
 
 
 
 
 
Pharmacodynamic 
blood sampling21 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
MRD sampling 
(CLL subjects 
only) 
 
 
 
 
 
 
 
 
 
 
X27 
 
 
Abbreviations: AE:  adverse event, ALT:  alanine aminotransferase, AST:  aspartate aminotransferase, CLL:  chronic lymphoid leukemia, CR:  complete response, CT:  
computed tomography, DLT:  dose limiting toxicity, ECG:  electrocardiogram, ECOG:  Eastern Cooperative Oncology Group, EPG:  serum electrophoresis, DLBCL:  diffuse 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 41 of 122 
large B-cell lymphoma, GCB:  germinal center B-cell-like, HBsAg:  hepatitis B surface antigen, HBV:  hepatitis B virus, HCV:  hepatitis C virus, Ig:  immunoglobulin, 
MCV:  mean corpuscular volume, MRD:  minimal residual disease, MRI:  magnetic resonance imaging, PCR:  polymerase chain reaction. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified.  
1. 
Perform within 28 days prior to Day 1. Assessments performed as standard of care may be used for screening.  
2. 
Perform 28 days after the last dose of zanubrutinib (± 7 days). Subjects who have disease relapse at any time will be asked to undergo biopsies of representative 
tumour sites and/or blood collection to obtain samples for studying mechanisms of resistance (see Section 8.14.1).  
3. 
Subjects who discontinue study drug due to reasons other than disease progression will remain on study and be followed every 3 months until subject exhibits first 
progression, withdraws consent, starts new anti-cancer therapy, death or study closure, whichever occurs first. Once subjects progress or start use of alternative anti-
cancer therapy, subjects will not return to the study center but will be contacted every 3 months by telephone, to assess survival until death, withdrawal of consent or 
study closure, whichever occurs first (see Section 8.10.2). 
4. 
Windows: days allowed for reschedule of an entire visit due to logistic reasons (eg, public holidays). In all cases elements relating to medical assessments may be 
performed 48 hours prior to the scheduled day. These are: B symptoms, physical examination, ECOG, concomitant medications, AE, hematology, clinical chemistry, 
coagulation, pregnancy test and urinalysis.  
5. 
Written informed consent form(s) must be signed by the subject before any study specific procedures are performed.  
6. 
Unexplained weight loss >10% over previous 6 months, fever (>38°C), and/or drenching night sweats.  
7. 
Complete physical examination includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical 
relevance (ie, cardiovascular, respiratory, lymph nodes, liver, and spleen), and those systems associated with clinical signs/symptoms.  
8. 
Perform a single 12-lead ECG. Subjects should be in the semi-recumbent or supine position. Additional ECGs will be performed at the discretion of the investigator 
if medically indicated.  
9. 
Administer one dose of zanubrutinib in the study center, review and dispense diary.   
10. 
Tumor assessments must be performed within 7 days of the end of Weeks 12, 24, 36 and 48, every 24 weeks after Week 48, and at disease progression. Computed 
tomography scans must encompass neck, chest, abdomen and pelvis and use intravenous contrast or follow investigators’ decision. A CT scan of diagnostic quality 
performed as part of positron emission tomography (PET)/CT is acceptable, provided bidimensional nodal and liver/spleen measurements can be made. MRI may be 
used in place of CT, at investigator discretion. If the subject has no assessable disease by CT/MRI at study entry (eg, Waldenström’s macroglobulinemia without 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 42 of 122 
nodal enlargement), repeat scans are not required during the study. For the early termination visit, CT/MRI and response assessment are required if the previous scan 
was performed more than 3 months ago. 
11. 
A bone marrow examination must be performed at screening for all participants and within 7 days of the end of week 12 for subjects with baseline marrow disease. 
In those subjects who had evidence of bone marrow disease at the time of enrollment, upon achieving a possible CR (eg, physical examination or CT/MRI scan 
indicating a possible CR), a bone marrow aspirate and biopsy will be obtained to confirm the CR. Peripheral blood and/or bone marrow aspirate/biopsy with flow 
cytometry assessment(s) for minimal residual disease should be done at least 3 months after the last dose if there is evidence of CR in all of the response parameters 
(ie, hematology, CT/MRI scan). 
12. 
Zanubrutinib will be taken at least 30 minutes before obinutuzumab infusion on the day obinutuzumab is administrated.  
13. 
Hematology, including hemoglobin, MCV, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes, blasts), bands (optional), and platelet 
count. In the event of neutropenia (absolute neutrophil count <1000/mm3) or thrombocytopenia (platelets of less than 50,000/mm3), these assessments will be 
conducted as frequently as the physician feels needed until toxicity resolves to ≤ Grade 2.  
14. 
Clinical chemistry includes sodium, potassium, glucose, urea, creatinine, calcium, magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, lactose 
dehydrogenase, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequently as the 
physician feels needed until toxicity resolves to ≤ Grade 2.  
15. 
Serum EPG on first test for WM subjects only, and if a paraprotein is present, repeated on all subsequent immunoglobulin assessments. IgA, IgG and IgM tests 
should be performed for all subjects at screening and only for those with significant abnormal findings at subsequent visits.  
16. 
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Urine pregnancy tests will be 
performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
17. 
Viral serology include hepatitis B (HBsAg and total hepatitis B core antibody [anti HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), HCV 
antibody (as well as HCV RNA by PCR if the subject is HCV antibody positive), and HIV1/2 antibodies.  
18. 
Collect urine dipstick, as well as urine microscopy if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24 hour urine for total protein and a random urine for 
total protein and creatinine will be obtained and evaluated (see Section 8.2). 
19. 
Subjects with CLL should have a blood sample sent at screening for interphase FISH for chromosomal abnormalities including 17p, 11q, 13q, and +12. Other 
analysis, including IgVH and P53 mutational status, is optional.  
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 43 of 122 
20. 
Subjects with non-GCB DLBCL must have archival tumor tissues or agree to a tumor biopsy for confirmation of the DLBCL subtype and for exploratory biomarker 
analysis. 
21. 
Serial pharmacokinetic and pharmacodyamic blood samples will be collected at the time points specified in Table 3. 
22. 
PK blood samples will be collected only on Day 1 of Cycle 2, Cycle 4, and Cycle 6. 
23. 
Subjects (except CLL) who have disease relapse at any time will be asked to undergo biopsies of representative tumor sites (bone marrow will be collected for WM 
patients). These procedures are optional. 
24. 
Subjects who have disease relapse at any time will be asked to undergo blood collection to obtain samples for studying mechanisms of resistance. This procedure is 
optional. 
25. 
Response should be assessed against baseline per disease relevant instructions in Appendix 16.3. Physical exam should be used at any time points where 
imaging is not required, but physical exam revealing disease progression or potential progression may require confirmation via imaging. Visits that contain 
components sufficient to determine a change in overall response in the patient (ie, unscheduled CT scans and labs, IgM-based change response between 
scheduled efficacy assessments for WM patients) should complete an overall efficacy response assessment as needed. 
26. 
For Weeks 25 through 48, hematology, clinical chemistry, urine analysis, immunoglobulins, and serum EPG assessments will be conducted every 12 weeks. After 
Week 48, hematology and clinical chemistry assessments and urine analysis, will continue every 12 weeks; however, immunoglobulins and serum EPG assessments 
will be conducted every 24 weeks until disease progression. 
27. 
Samples will be taken from subjects with CLL to assess MRD at the following time points:  
• Peripheral blood sample at Cycle 18, or at the earliest opportunity after Cycle 18, in all CLL subjects on study; a bone marrow sample is requested if the peripheral 
blood sample is MRD negative 
• Peripheral blood sample at the time of newly attained CR, and at each CR assessed timepoint thereafter, for continuing CLL subjects; a bone marrow sample is 
requested if the peripheral blood sample is MRD negative 
 
 
 
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 44 of 122 
Table 2 
Study Assessments and Procedures Schedule in Part 2 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(28 days) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
8 
±1 day 
15 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
General medical 
history & baseline 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete 
physical 
examination7 
X 
 
 
 
 
 
 
 
 
 
 
Weight (& height 
at screening) 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
B symptoms6 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Target physical 
examination7 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG status 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG8 
X 
 
 
 
 
 
 
 
 
 
 
Zanubrutinib 
administration9 
 
Orally  
 
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 45 of 122 
Table 2 
Study Assessments and Procedures Schedule in Part 2 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(28 days) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
8 
±1 day 
15 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Obinutuzumab 
administration 
 
100 mg 
900 mg 
1000 mg 
1000 mg 
1000 
mg 
 
 
 
 
 
Review of 
concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
AEs (including 
serious) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Response 
Assessment24 
 
Every 12 weeks (end of week 12, 24, 36 and 48) 
X 
X10 
X3 
Tumor assessment 
by CT or MRI10 
X 
Every 12 weeks (end of week 12, 24, 36 and 48) 
X10 
X10 
X3 
Bone Marrow 
evaluation11 
X 
End of Week 12  
 
 
 
Local Laboratory 
 
Hematology13 
X 
X 
 
X 
X 
X 
X 
X25 
X 
X 
X 
Clinical 
chemistry14 
X 
X 
 
X 
X 
X 
X 
X25 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
IgA, IgG, IgM 
level and serum 
EPG 15 
X 
 
 
 
 
X 
 
X25 
X25 
X 
X 
Pregnancy test16 
X 
X 
 
 
 
X 
 
X 
X 
 
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 46 of 122 
Table 2 
Study Assessments and Procedures Schedule in Part 2 
 
 
Treatment Period 
Safety 
Follow-up2 
Follow-up 
Visit3 
 
Screening1 
-28 to -1 
Cycle 1 
(28 days) 
Cycle 2 to 6 
(28 days) 
Weeks 25 
 to 48 
Weeks 48+ 
Days 
Window (days)4 
1 
2 
8 
±1 day 
15 
±1 day 
1 
±2 days 
15 
±2 days 
Every 
4 weeks 
±4 days 
Every 
12 weeks 
±10 days 
28 days after 
last dose 
± 7 days 
Every 
3 months 
±7 days 
Viral serologies17 
X 
 
 
 
 
 
 
 
 
 
 
Urine analysis18 
X 
X 
 
X 
X 
X 
X 
X25 
X 
X 
 
CLL prognostic 
factors19 
X 
 
 
 
 
 
 
 
 
 
 
Central Laboratory 
 
Tumor tissue 
and/or bone 
marrow sampling 
X20 
 
 
 
 
 
 
 
 
X22 
 
Blood sampling 
for biomarker 
analysis 
 
 
 
 
 
 
 
 
 
X23 
 
Pharmacokinetic 
blood sampling21 
 
 
 
 
 
X 
 
 
 
 
 
MRD sampling 
(CLL subjects 
only) 
 
 
 
 
 
 
 
 
X26 
 
 
Abbreviations: AE:  adverse event, ALT:  alanine aminotransferase, AST:  aspartate aminotransferase, CLL:  chronic lymphoid leukemia, CR:  complete response, CT:  
computed tomography, DLT:  dose limiting toxicity, ECG:  electrocardiogram, ECOG:  Eastern Cooperative Oncology Group, EPG:  serum electrophoresis, DLBCL:  diffuse 
large B-cell lymphoma, GCB:  germinal center B-cell-like, HBsAg:  hepatitis B surface antigen, HBV:  hepatitis B virus, HCV:  hepatitis C virus, Ig:  immunoglobulin, 
MCV:  mean corpuscular volume, MRD:  minimal residual disease, MRI:  magnetic resonance imaging, PCR:  polymerase chain reaction. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified.  


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 47 of 122 
1. 
Perform within 28 days prior to Day 1. Assessments performed as standard of care may be used for screening.  
2. 
Perform within 28 days after the last dose of zanubrutinib (± 7 days). Subjects who have disease relapse at any time will be asked to undergo biopsies of 
representative tumour sites and/or blood collection to obtain samples for studying mechanisms of resistance (see Section 8.14.1).  
3. 
Subjects who discontinue study drug due to reasons other than disease progression will remain on study and be followed every 3 months until subject exhibits first 
progression, withdraws consent, starts new anti-cancer therapy, death or study closure, whichever occurs first. Once subjects progress or start use of alternative anti-
cancer therapy, subjects will not return to the study center but will be contacted every 3 months by telephone, to assess survival until death, withdrawal of consent or 
study closure, whichever occurs first (see Section 8.10.2). 
4. 
Windows: days allowed for reschedule of an entire visit due to logistic reasons (eg, public holidays). In all cases elements relating to medical assessments may be 
performed 48 hours prior to the scheduled day. These are: B symptoms, physical examination, ECOG, concomitant medications, AE, hematology, clinical chemistry, 
coagulation, pregnancy test and urinalysis.  
5. 
Written informed consent form(s) must be signed by the subject before any study specific procedures are performed.  
6. 
Unexplained weight loss >10% over previous 6 months, fever (>38°C), and/or drenching night sweats.  
7. 
Complete physical examination includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical 
relevance (ie, cardiovascular, respiratory, lymph nodes, liver, and spleen), and those systems associated with clinical signs/symptoms.  
8. 
Perform a single 12-lead ECG at screening. Subjects should be in the semi-recumbent or supine position. Additional ECGs will be performed at the discretion of the 
investigator if medically indicated.  
9. 
Administer one dose of zanubrutinib in the study center, review and dispense diary.   
10. 
Tumor assessments must be performed within 7 days of the end of Weeks 12, 24, 36 and 48, every 24 weeks after Week 48, and at disease progression. Computed 
tomography scans must encompass neck, chest, abdomen and pelvis and use intravenous contrast or follow investigators’ decision. A CT scan of diagnostic quality 
performed as part of positron emission tomography (PET)/CT is acceptable, provided bidimensional nodal and liver/spleen measurements can be made. MRI may be 
used in place of CT, at investigator discretion. If the subject has no assessable disease by CT/MRI at study entry (eg, Waldenström’s macroglobulinemia without 
nodal enlargement), repeat scans are not required during the study. For the early termination visit, CT/MRI and response assessment are required if the previous scan 
was performed more than 3 months ago. 
11. 
A bone marrow examination must be performed at screening for all participants and within 7 days of the end of week 12 for subjects with baseline marrow disease. 
In those subjects who had evidence of bone marrow disease at the time of enrollment, upon achieving a possible CR (eg, physical examination or CT/MRI scan 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 48 of 122 
indicating a possible CR), a bone marrow aspirate and biopsy will be obtained to confirm the CR. Peripheral blood and/or bone marrow aspirate/biopsy with flow 
cytometry assessment(s) for minimal residual disease should be done at least 3 months after the last dose if there is evidence of CR in all of the response parameters 
(ie, hematology, CT/MRI scan). 
12. 
The study drug will be taken at least 30 minutes before obinutuzumab infusion on the day obinutuzumab is administrated.  
13. 
Hematology, including hemoglobin, MCV, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes, blasts), bands (optional), and platelet 
count. In the event of neutropenia (absolute neutrophil count <1000/mm3) or thrombocytopenia (platelets of less than 50,000/mm3), these assessments will be 
conducted as frequently as the physician feels needed until toxicity resolves to ≤ Grade 2.  
14. 
Clinical chemistry includes sodium, potassium, glucose, urea, creatinine, calcium, magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, lactose 
dehydrogenase, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequently as the 
physician feels needed until toxicity resolves to ≤ Grade 2.  
15. 
Serum EPG on first test for WM subjects only, and if a paraprotein is present, repeated on all subsequent immunoglobulin assessments. IgA, IgG and IgM tests 
should be performed for all subjects at screening and only for those with significant abnormal findings at subsequent visits.  
16. 
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Urine pregnancy tests will be 
performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
17. 
Viral serology include hepatitis B (HBsAg and total hepatitis B core antibody [anti HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), HCV 
antibody (as well as HCV RNA by PCR if the subject is HCV antibody positive), and HIV1/2 antibodies.  
18. 
Collect urine dipstick, as well as urine microscopy if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24 hour urine for total protein and a random urine for 
total protein and creatinine will be obtained and evaluated (see Section 8.2). 
19. 
Subjects with CLL should have a blood sample sent at screening for interphase FISH for chromosomal abnormalities including 17p, 11q, 13q, and +12. Other 
analysis, including: Ig VH and P53 mutational status, is optional.   
20. 
Subjects with non-GCB DLBCL must have archival tumor tissues or agree to a tumor biopsy for confirmation of the DLBCL subtype and for exploratory biomarker 
analysis. 
21. 
Serial pharmacokinetic blood samples will be collected at the time points specified in Table 3 on Day 1 of Cycle 2, Cycle 4, and Cycle 6. 
22. 
Subjects (except CLL) who have disease relapse at any time will be asked to undergo biopsies of representative tumor sites (bone marrow will be collected for WM 
patients). These procedures are optional. 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 49 of 122 
23. 
Subjects who have disease relapse at any time will be asked to undergo blood collection to obtain samples for studying mechanisms of resistance. This procedure is 
optional. 
24. 
Response should be assessed against baseline per disease relevant instructions in Appendix 16.3. Physical exam should be used at any time points where 
imaging is not required, but physical exam revealing disease progression or potential progression may require confirmation via imaging. Visits that contain 
components sufficient to determine a change in overall response in the patient (ie, unscheduled CT scans and labs, IgM-based change response between 
scheduled efficacy assessments for WM patients) should complete an overall efficacy response assessment as needed. 
25. 
For Weeks 25 through 48, hematology, clinical chemistry, urine analysis, immunoglobulins, and serum EPG assessments will be conducted every 12 weeks. After 
Week 48, hematology and clinical chemistry assessments and urine analysis will continue every 12 weeks; however, immunoglobulins and serum EPG assessments 
will be conducted every 24 weeks until disease progression. 
26. 
Samples will be taken from subjects with CLL to assess MRD at the following time points:  
 
• Peripheral blood sample at Cycle 18, or at the earliest opportunity after Cycle 18, in all CLL subjects on study; a bone marrow sample is requested if the peripheral 
blood sample is MRD negative 
• Peripheral blood sample at the time of newly attained CR, and at each CR assessed timepoint thereafter, for continuing CLL subjects; a bone marrow sample is 
requested if the peripheral blood sample is MRD negative 
 
 
 


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 50 of 122 
Table 3 
Pharmacokinetic and Pharmacodynamic Sampling 
Procedure 
Cycle 1 Day 1 
Cycle 1 
Day 2 
Cycle 1 
Day 3 
Cycle 1 
Day 9 
Cycle 1 
Day 16 
Cycle 2 Day 1 
Cycle 4 
Day 1 
Cycle 6 Day 
1 
Hours 
Pre-
dose 
1 
2 
4 
7 
Pre-
dose 
4 
Pre-
dose 
4 
Pre-
dose 
4 
Pre-
dose 
4 
Pre-
dose 
1 
2 
4 
7 
Pre-
dose 
4 
Pre-
dose 
4 
PK blood 
sampling for 
zanubrutinib for 
Part 1 
X4 
X1 
X2 
X2 
X5 
X3 
 
 
 
 
 
 
 
X3 
X1 
X2 
X2 
X5 
 
 
 
 
PK blood 
sampling for 
obinutuzuma for 
Part 1* 
 
 
 
 
 
X3 
X2 
X3 
X2 
X3 
X2 
X3 
X2 
X3 
 
 
X2 
 
X3 
X2 
X3 
X2 
PD blood 
sampling for  
Part 1 
X4 
 
 
X2 
 
X3 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
PK blood 
sampling for 
zanubrutinib for 
Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
X1 
X2 
X2 
X5 
 
 
 
 
PK blood 
sampling for 
obinutuzumab 
for Part 2* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
X2 
X3 
X2 
Vital signs and 
12-lead ECGs 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
* Four hours post obinutuzumab is in reference to the start of the infusion. As obinutuzumab may generally be infused within 4 hours, 4 hours post obinutuzumab marks the end of 
obinutuzumab infusion. Should the infusion be interrupted or delayed beyond 4 hours, the 4 hours post obinutuzumab PK samples should be taken at the end of the infusion. 
Abbreviations: PD:  pharmacodynamics; PK:  pharmacokinetics 
General note:  


 
                                                                 CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
                       IND Number:125326 
 
 
Page 51 of 122 
If cycle 1 and 2 vital signs and ECGs listed in tables 1 and 2 are performed before GA101 and/or zanubrutinib are administered, the pre-dose vital signs/ECGs may be omitted.  
 
It is important that PK and PD sampling occurs as close as possible to the scheduled time. In order to achieve this, some of the other assessments scheduled at the same time 
need to be initiated prior to or after the time point to allow for completion of these measurements in enough time for the PK/PD sampling to be taken at the designated time 
point. Thus, the sequence at a particular time point is: 1) scheduled ECG and vital signs measurements; 2) PK/PD blood samples (to be performed at the precise protocol 
scheduled time); and 3) any other scheduled or unscheduled measurements at that time point. 
1. 
A window period of ±10 minutes exists. 
2. 
A window period within 30 minutes from the end of infusion.   
3. 
Within 2 hours prior to dosing. 
4. 
Within 3 hours prior to dosing. 
5. 
A window period of ±1 hour exists.  
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 52 of 122 
5 
STUDY POPULATION 
Approximately 132 subjects (12 subjects in the safety evaluation part and 120 subjects in 
the indication expansion part) will be required to complete the Phase 1b trial of 
zanubrutinib in combination with obinutuzumab. Subjects with B-cell lymphoid 
malignancies will be entered into this study provided that they satisfy the inclusion and 
exclusion criteria. 
5.1 Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria 
1. 
Aged ≥18 years, able and willing to provide written informed consent and to 
comply with the study protocol. 
2. 
Part 1 (Safety evaluation): R/R CLL/SLL, R/R FL, R/R MCL, R/R MZL, R/R 
WM, and R/R non-GCB DLBCL. 
3. 
Part 2 (Indication specific expansion):   
 
Cohort 1: treatment-naïve CLL/SLL. 
 
Cohort 2: relapsed/refractory CLL/SLL. 
 
Cohort 3: relapsed/refractory non-GCB DLBCL.  
 
Cohort 4: relapsed/refractory FL, R/R MCL, R/R MZL, and R/R WM.  
 
Cohort 5: relapsed/refractory FL. About 10-15 out of 40 should meet 
double-refractory criterion, defined as refractoriness to both rituximab and 
an alkylating agent, whether administered together or in successive 
treatment regimens. Refractoriness was defined per protocol as less than a 
partial response or progression of disease within 6 months after completion 
of a prior therapy (added per Amendment Version 4.0).     
o For R/R CLL, R/R FL, R/R MCL, R/R MZL, and R/R WM: Evidence of 
progression or lack of response following at least 1 prior treatment. 
o For R/R non-GCB DLBCL: Evidence of progression or refractory disease 
following at least a standard anthracycline/ rituximab-based primary 
treatment regimen (eg, R-CHOP), and not currently appropriate for 
autologous stem cell transplantation. 
4. 
Laboratory parameters as specified below: 
o Hematologic: Platelet count >40x109/L (may be post-transfusion); absolute 
neutrophil count >1.0x109/L (growth factor use is allowed to bring the 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 53 of 122 
pre-treatment neutrophils to >1.0x109  /L if marrow infiltration is 
involved). 
o Hepatic: Total bilirubin <3 x upper limit normal (ULN); and aspartate 
aminotransferase (AST) and alanine transaminase (ALT) ≤3xULN. 
o Renal: Creatinine clearance ≥ 30 ml/min (as estimated by the Cockcroft 
Gault equation or as measured by nuclear medicine scan or 24 hour urine 
collection); Subjects requiring hemodialysis will be excluded. 
5. 
Anticipated survival of at least 6 months. 
6. 
ECOG performance status of 0 to 2. 
7. 
Female subjects of childbearing potential and non-sterile males must agree to 
practice at least one of the following methods of birth control with partner(s) 
throughout the study and for ≥3 months after discontinuing zanubrutinib or 
≥ 18 months following treatment with obinutuzumab, whichever is longer: total 
abstinence from sexual intercourse, double barrier contraception, intrauterine 
device (IUD) or hormonal contraceptive initiated at least 3 months prior to first 
dose of study drug. 
8. 
Male subjects must not donate sperm from initial study drug administration, until 
≥3 months after discontinuing zanubrutinib or ≥18 months following treatment 
with obinutuzumab, whichever is longer. 
5.2 Exclusion Criteria 
1. Known central nervous system lymphoma or leukemia. 
2. Known prolymphocytic leukemia or history of, or currently suspected, Richter's 
syndrome. 
3. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.  
4. History of significant cardiovascular disease, define as: 
o congestive heart failure greater than New York Heart Association (NYHA) class 
II according to the NYHA functional classification 
o unstable angina or myocardial infarction with 6 months of enrollment 
o serious cardiac arrhythmia or clinical significant electrocardiogram (ECG) 
abnormality: corrected QT wave (QTc) prolongation, defined as a QTc 
>450 msecs based on the Bazett’s formula (Subjects with QTc prolongation due to 
a cardiac pacemaker may be allowed with approval of the medical monitor), or 
other ECG abnormalities including 2nd degree atrioventricular (AV) block type II, 
3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). 
5. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of 
breath, chronic obstructive pulmonary disease [COPD]). 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 54 of 122 
6. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy. 
7. Prior BTK inhibitor treatment. 
8. Use of strong CYP3A inhibitors and strong CYP3A inducers (see Table 6). 
9. Vaccination with a live vaccine within 28 days of the initiation of treatment. 
10. Allogeneic stem cell transplantation within 6 months, or has active graft versus host 
disease (GvHD) requiring ongoing immunosuppression. 
11. Receipt of the following treatment prior to first administration of zanubrutinib, 
corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or 
radiotherapy within 3 weeks, monoclonal antibody within 4 weeks. 
12. Participate in any investigational drug study within 28 days of study entry, or not 
recovered from non-hematologic toxicity of any prior chemotherapy up to ≤ Grade 1 
(except for alopecia). 
13. History of other active malignancies within 2 years of study entry, with exception of 
(1) adequately treated in situ carcinoma of cervix; (2) localized basal cell or squamous 
cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery 
or other modality) with curative intent. 
14. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 
(revised per Amendment Version 3.0). 
15. Major surgery in the past 4 weeks. 
16. Active symptomatic fungal, bacterial and/or viral infection including evidence of 
infection with human immunodeficiency virus (HIV), human T cell lymphotropic 
virus (HTLV 1) seropositive status. 
17. Subjects with positive serology for hepatitis B defined as positivity for hepatitis B 
surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc); subjects who are 
positive for anti-HBc may be considered for inclusion in the study on a case-by-case 
basis if they are hepatitis B viral deoxyribonucleic acid (DNA) negative and are 
willing to undergo ongoing HBV DNA testing by real-time polymerase chain reaction 
(PCR); subjects with presence of hepatitis B surface antibody (anti-HBs) consistent 
with prior vaccination (ie, HBsAg negative, anti-HBc negative, anti-HBs positive)  
may participate; subjects suspected to have false positive serologic studies because of 
IV immunoglobulin administration are potentially eligible after negative PCR studies 
for viral DNA/ribonucleic acid (RNA) and discussion with the principal investigator. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 55 of 122 
18. Evidence of active hepatitis C (HCV): subjects with positive hepatitis C serology and 
positive HCV RNA test. 
19. Inability to comply with study procedures. 
20. Pregnant or nursing women. 
21. Any illness or condition that in the opinion of the investigator may affect safety of 
treatment or evaluation of any study’s endpoints. 
5.3 Other Eligibility Criteria Considerations 
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the IB for detailed information regarding warnings, precautions, 
contraindications, AEs, and other significant data pertaining to the study drug being used 
in this study. 
5.4 Subject Completions and Withdrawals 
5.4.1 
Subject Completion 
A subject will be considered complete if he/she has completed at least one full cycle of 
zanubrutinib plus obinutuzumab treatment and has not withdrawn from the study prior to 
completing the first cycle (29 days for subjects in Part 1 and 28 days for subjects in 
Part 2). 
5.4.2 
Subject Withdrawal 
A subject may voluntarily discontinue participation in this study at any time. The 
investigator may also, at his/her discretion, discontinue the subject from participating in 
this study at any time. If a subject is prematurely discontinued from participation in the 
study for any reason, the investigator must make every effort to perform the following 
evaluations 28 days from the last administration of zanubrutinib: physical examination, 
vital signs, computed tomography (CT) scan (if it has been more than 3 months since the 
previous CT scan), B symptoms, ECG, laboratory tests (hematology, clinical chemistry, 
coagulation, urinalysis, and serum protein), and AE assessment. These data will be 
recorded as they comprise an essential evaluation that needs to be done prior to 
discharging any subject from the study. 
In the event that a subject is prematurely discontinued from the study at any time due to 
an AE (as defined in Section 10.1), the procedures stated in Section 10 must be followed. 
In addition to the post study assessments, if a DLT occurs, the investigator will obtain, 
when possible, a 4 mL blood sample for analysis of plasma zanubrutinib concentration. 
Subjects who drop out or are withdrawn for any reason which does not fall under a DLT 
will be considered for replacement after due consideration from the Sponsor and safety 
committee. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 56 of 122 
Subject Withdrawal from the Investigational Product  
Premature discontinuation of zanubrutinib would be any time a subject is discontinued for 
reasons other than unacceptable toxicity. The reason for discontinuation of zanubrutinib 
will be recorded in the electronic case report form (eCRF). These reasons include:  
• 
Withdrawal of consent by the subject 
• 
Discontinuation of zanubrutinib by the Sponsor 
• 
Pregnancy 
• 
Any significant AE that compromises the subject’s ability to participate in the 
study (including infusion reactions) 
• 
The investigator or Sponsor determines it is in the best interest of the subject. 
• 
Intercurrent illness 
• 
Progression of disease at any time during the study 
• 
Need for prohibited medication 
• 
Lack of compliance with the study and/or study procedures (eg, study drug 
administration instructions, study visits) 
• 
Significant deviation from the protocol by the investigator without the consent of 
the Sponsor 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 57 of 122 
6 STUDY TREATMENT 
6.1 Description of Investigational Products 
6.1.1 Zanubrutinib 
Zanubrutinib is available as 20 mg blue opaque capsules (size 3), or 80 mg white opaque 
capsules (size 0), depending on the dose level. Zanubrutinib is intended for oral use. 
6.1.2 Obinutuzumab 
Obinutuzumab is provided as a sterile, clear, colorless to slightly brown, preservative free 
liquid concentrate for intravenous administration in 1000 mg/40 mL (25 mg/mL) single 
use vials.  
Obinutuzumab is for intravenous use and should be administered as an intravenous 
infusion through a dedicated line after dilution. The U.S. label indicates a duration of 
treatment of 6 cycles, each 28 days duration. 
6.2 Dosage and Administration 
6.2.1 Zanubrutinib 
Zanubrutinib (either 320 mg or 160 mg based on QD or BID) will be administered orally, 
at least 30 minutes before obinutuzumab infusion on the day obinutuzumab is 
administered, in each cycle (Cycle 1: 29 days for subjects in the Part 1 and 28 days for 
subjects in the Part 2; Cycle 2 and each cycle thereafter: 28 days). Treatment with 
zanubrutinib will continue until disease progression, death, unacceptable toxicity, 
withdrawal from the study, other reason for treatment discontinuation, or study closure, 
whichever occurs first. 
Zanubrutinib will be dispensed by the study center personnel to subjects 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 
subject to take the study drug exactly as prescribed and at approximately the same time 
each day of dosing. Subjects will be asked to complete a patient diary that records dates 
and times of dosing between clinic visits. 
If a dose of the study drug is not taken at the scheduled time, the subject 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 subject vomits after taking the zanubrutinib capsules, that dose should not be 
repeated. 
6.2.2 Obinutuzumab 
Obinutuzumab will be administered at a final concentration of 0.4 mg/mL to 4 mg/mL as 
an intravenous infusion only for up to 6 cycles, see Table 4. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 58 of 122 
Table 4 Dose of Obinutuzumab to be Administered during the 6 Treatment Cycles  
Cycle 
Day of Treatment 
Dose of Obinutuzumab 
Cycle 1 
Day 2 (Part 1) 
Or  
Day 1 (Part 2) 
100 mg 
Administer at 25 mg/hr over 4 hours.  
Do not increase the infusion rate 
Day 3 (Part 1) 
Or  
Day 2 (Part 2) 
 
900 mg 
Administer at 50 mg/hr. The rate of the infusion can be 
escalated in increments of 50 mg/hr every 30 minutes  
to a maximum rate of 400 mg/hr 
Day 9 (Part 1) 
Or  
Day 8 (Part 2) 
1000 mg 
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 
Day 16 (Part 1) 
Or 
Day15 (Part 2) 
1000 mg 
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 
Cycles 2 to 6 
Day 1 
1000 mg 
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 
 
If a planned treatment is missed, the missed treatment should be administered as soon as 
possible and the treatment schedule adjusted accordingly. If appropriate, subjects who do 
not complete the Day 2 Cycle 1 treatment may proceed to the Day 3 Cycle 1 treatment. 
Preparation of obinutuzumab 
The obinutuzumab solution for intravenous solution should be prepared aseptically and 
diluted into a 0.9% sodium chloride PVC or non PVC polyolefin infusion bag. The 
prepared solution should be mixed by gentle inversion. It should not be frozen, but be 
administered immediately after preparation. If not used immediately, the solution may be 
stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The solution 
should be inspected visually for any particulate matter and discoloration prior to 
administration. 
6.3 Packaging and Labelling 
The zanubrutinib capsules will be provided in a child resistant closure and be open 
labelled with space to enter the subject number and name of investigator. The label will 
also include content and quantity of zanubrutinib, protocol number, batch number, 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 59 of 122 
administration instructions, storage conditions, and cautions. The contents of the study 
treatment labels will be in accordance with all applicable regulatory requirements. 
A release document signed by a legally authorized Qualified Person (QP) at the CRO will 
be placed in the appropriate section of the Trial Master File to document labeling and 
dispensing of the study drugs to the subject.  
6.4 Storage and Handling Procedures 
The study drug will be dispatched to a study center only after receipt of the required 
documents in accordance with applicable regulatory requirements and the Sponsor’s 
procedures. 
The study drug must be dispensed or administered according to procedures described 
herein. Only subjects enrolled in the study may receive study drug, in accordance with all 
applicable regulatory requirements. Only authorized study center personnel may supply 
or administer study drug. 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 drug must 
be stored at the condition as specified on the labels, or according to the latest version of 
the IB. 
6.5 Investigational Product Accountability 
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(s) will document the amount of study 
drug received from the Sponsor, the amount supplied and/or administered to and returned 
by subjects, if applicable.  
After completion of the study, all unused study drug will be inventoried and packaged for 
return shipment by the hospital unit pharmacist. The inventoried supplies will be returned 
to the Sponsor or destroyed on site, after receiving written Sponsor approval. 
6.6 Treatment Assignment 
Subjects will be identified by a subject number. Each subject enrolled in this study will 
receive a unique subject number which will be assigned when the subject is screened or 
enrolled in the study. Each subject receiving zanubrutinib in combination with 
obinutuzumab will also receive a treatment allocation number. Subject and treatment 
numbers will be assigned in chronological order starting with the lowest number. Once a 
subject number and treatment number have been assigned to a subject, it cannot be 
reassigned to any other subject. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 60 of 122 
If a subject is replaced, the replacement subject will be assigned the next available subject 
number. 
6.7 Warnings and Precautions 
Warnings and precautions to obinutuzumab include the following adverse reactions: HBV 
reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis 
syndrome, infections, neutropenia, and thrombocytopenia. 
• 
Infusion reactions: Obinutuzumab can cause severe and life-threatening infusion 
reactions. For subjects with Grade 4 infusion reactions, including but not limited 
to anaphylaxis, acute life-threatening respiratory symptoms, or other life-
threatening infusion reaction, stop and permanently discontinue obinutuzumab 
therapy. Management of Gazyva-related infusion reactions should be conducted 
per the Gazyva package insert. It is recommended to closely monitor subjects 
during the entire infusion. Infusion reactions within 24 hours of receiving 
obinutuzumab have occurred. For Grade 1, 2, or 3 infusion reactions, interrupt or 
discontinue the infusion (see Section 6.11 initial management of infusion 
reaction). 
• 
Tumor Lysis Syndrome (TLS): TLS can occur within 12 to 24 hours after the first 
infusion. Subjects with high tumor burden and/or high circulating lymphocyte 
count (> 25x109/L) are at greater risk for TLS and should receive appropriate 
tumor lysis prophylaxis per the Gazyva package insert. In addition, BTK inhibitor 
can also induce TLS in subjects with high tumor burden. Even though no 
incidence of TLS has been observed in the ongoing Phase 1 monotherapy trial 
(BGB-3111-AU-003), there is a potentially enhanced risk of TLS when 
obinutuzumab is administered in combination with zanubrutinib (see Section 6.13 
for initial management of TLS).   
• 
Infection: Serious bacterial, fungal, and new or reactivated viral infections can 
occur during and following obinutuzumab therapy. Do not administer 
obinutuzumab to subjects with an active infection as fatal infections have been 
reported. 
• 
Neutropenia: Severe neutropenia can occur. Monitor subjects with Grade 3 to 4 
neutropenia frequently with regular laboratory tests until resolution. Neutropenia 
can also be of late onset and/or prolonged. 
• 
Thrombocytopenia: Fatal hemorrhagic events have been reported. Monitor 
subjects for thrombocytopenia and hemorrhagic events. In subjects with Grade 3 
or 4 thrombocytopenia, monitor platelet counts frequently until resolution and 
consider dose delays of obinutuzumab.  11 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 61 of 122 
Detailed information regarding warnings, precautions, contraindications, AEs, and other 
significant data pertaining to the study drugs being used in this study are provided in the 
Obinutuzumab Prescribing Information, Genentech Gazyva® Safety Information, and the 
Zanubrutinib IB.9,11, 12  Facilities and staff for resuscitation and the treatment of other 
medical emergencies will be provided. 
6.8 Assessment of Compliance 
On all visits to the study center, subjects will be questioned in regard to compliance with 
study instructions. 
6.9 Treatment of Investigational Product Overdose 
Since an actual efficacious dose for the zanubrutinib -obinutuzumab combination is 
unknown, an overdose cannot be defined. Subjects with a suspected overdose should be 
managed with appropriate supportive therapy as determined by the investigator in 
consultation with the Sponsor medical monitor. Any adverse effects occurring as a result 
of an overdose should be reported to the Sponsor medical monitor. 
6.10  Occupational Safety 
The investigational product is not expected to pose significant occupational safety risk to 
the study center personnel under normal conditions of use and administration. A material 
safety data sheet describing occupational hazards and recommended handling precautions 
will be provided to the investigator, where this is required by local laws, or is available 
upon request from the Sponsor. 
6.11  Infusion-Related Reactions with Obinutuzumab 
Symptoms of infusion-related reactions with obinutuzumab include fever, chills, rigors, 
diaphoresis, and headache (Table 5). 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 62 of 122 
Table 5 Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Obinutuzumab 
NCI-CTCAE Grade 
Treatment Modification for Obinutuzumab 
Grade 1 – mild 
Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated. 
 
Decrease the obinutuzumab infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for 24 hr. 
 
Stop obinutuzumab infusion. 
Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least Grade 1 
in severity, and monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
 
 
Stop the obinutuzumab infusion immediately and disconnect 
infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
obinutuzumab treatment and must not receive any further 
obinutuzumab treatment. 
Abbreviations: IV:  intravenous, NCI-CTCAE:  National Cancer Institute-Common Terminology Criteria 
for Adverse Event, NSAIDs:  non-steroidal anti-inflammatory drugs. 
 
6.12  Severe Hypersensitivity Reactions and Flu-like Symptoms 
If a hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice. A complete guideline for the emergency treatment of 
anaphylactic reactions according to the Working Group of the Resuscitation Council 
(United Kingdom) can be found at https://www.resus.org.uk/pages/reaction.pdf. Subjects 
should be instructed to report any delayed reactions to the Investigator immediately. 
Symptoms: 
• 
Impaired airway 
• 
Decreased oxygen saturation (<92%) 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 63 of 122 
• 
Confusion 
• 
Lethargy 
• 
Hypotension 
• 
Pale/clammy skin 
• 
Cyanosis 
Management: 
1. 
Epinephrine injection and intravenous dexamethasone 
2. 
Subject should be placed on cardiac, blood pressure, heart rate, and oxygen 
saturation monitor immediately 
3. 
Alert intensive care unit for possible transfer if required 
For prophylaxis of flu-like symptoms, follow the premedication instructions in 
Section 6.7. 
6.13  Tumor Lysis Syndrome 
Since obinutuzumab can induce ADCC, there is a potential risk of TLS.  In addition, 
zanubrutinib can also induce TLS in subjects with high tumor burden although no 
incidence of TLS has been observed in the ongoing Phase 1 monotherapy trial 
(BGB-3111-AU-003). There is a potentially enhanced risk of TLS when obinutuzumab is 
administered in combination with zanubrutinib.  Should this occur, subjects should be 
treated per the local guidelines and the management algorithm stipulated in Figure 2.19 




 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 65 of 122 
7 CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
7.1 Permitted Medications 
All concomitant medications taken during the study will be recorded in the eCRF with 
indication, dose information, and dates of administration. 
As vomiting and nausea are the known side effects of obinutuzumab, prophylaxis of 
emesis would be allowed as per institutional standard at the physician’s discretion (added 
per Amendment Version 3.0). 
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 Prohibited/Restricted Medications 
Subjects should not receive other anticancer therapy (cytotoxic, biologic, or hormone 
other than for replacement) 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.  
• 
Bisphosphonate use is permitted if the subject has already been on it for 3 or more 
months and on a stable dose.  
• 
Corticosteroid courses of limited duration (2 weeks or less) and dose (≤20 mg 
prednisone per day, or equivalent) are permitted, if used to treat a concomitant 
(non-cancer) medical condition, with the exception of glucocorticoids used for 
management of Gazyva-related infusion reaction (see Section 6.7).  
7.3 Medications to be used with Caution  
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A  
inducers (refer to Table 6 for a list of these medications) and grapefruit juice and Seville 
oranges should be used with caution as they may affect the metabolism of zanubrutinib 
(Section 1.2). 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 in Table 7. The Medical Monitor should be 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 66 of 122 
consulted in these situations.  Please refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list. 
Table 6 
CYP3A Inhibitors and Inducers 
Strong CYP3A Inhibitors 
Antibiotics:  clarithromycin, telithromycin, troleandomycin 
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals:  boceprevir, telaprevir 
Other:  cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease inhibitors:  indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Moderate CYP3A Inhibitors 
Antibiotics:  ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir 
Calcium channel blockers:  diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer):  imatinib, crizotinib 
Food products:  grapefruit juice (citrus paradisi juice) 
Herbal medications:  Schisandra sphenanthera 
Others:  amiodarone, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam  
 
Strong/Moderate CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s 
wort (hypericum perforatum), enzalutamide, mitotane, bosentan, efavirenz, etravirine, modafinil 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, 
Drug Development and Drug Interactions and Inducers. Note: The list of drugs in this table is not 
exhaustive. Please refer to the prescribing information of concomitant medication to check for CYP3A 
inhibition or induction risks or contact the medical monitor of the protocol. 
For a more complete list, please refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/  or  
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine.  http://medicine.iupui.edu/flockhart/table.htm 
Abbreviation: CYP: cytochrome P450. 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 67 of 122 
Table 7 
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. 
 
Clinical drug-drug interaction study indicated that zanubrutinib is a mild inducer of 
CYP3A4 and CYP2C19 (Section 1.2). 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. For subjects using hormonal contraceptives such as birth 
control pills or devices, a second barrier method of contraception (eg, condoms) must be 
used. 
In the interests of subject safety and acceptable standards of medical care the investigator 
will be permitted to prescribe treatment(s) at his/her discretion. All treatments must be 
recorded in the subjects’ eCRF (medication, dose, treatment duration and indication).  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 68 of 122 
8 STUDY ASSESSMENTS 
A signed, written informed consent must be obtained prior to screening assessments and 
before any study specific assessments are initiated. The study specific assessments and 
procedures are shown in the study assessments and procedures schedule in Table 1 and 
Table 2. The PK and PD sampling time points are presented in Table 3. 
8.1 Demographic and Baseline Safety Assessments 
Demographic data will include date of birth, race, height (in cm), body weight (in kg), 
and body mass index (BMI; in kg/m2). For height and weight measurements, the subject 
will be allowed to wear indoor daytime clothing with no shoes. This data will be captured 
in the eCRF and database. 
Having given consent, subjects will be required to undergo a medical screen to determine 
whether they are eligible to participate in the study according to the criteria listed in 
Section 5. Screening assessments will be completed within 28 days prior to the first 
treatment. Screening assessments completed within 72 hours of administration can be 
used as Day 1 assessments as indicated in Table 1 and Table 2. 
The screening assessments will include: 
• 
Demographic data 
• 
General medical history & baseline conditions 
• 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse 
rate, temperature, and respiratory rate) 
• 
B symptoms (unexplained weight loss >10% over previous 6 months, fever 
[>38°C], and/or drenching night sweats) 
• 
Complete physical examination 
• 
ECOG performance status 
• 
Echocardiogram 
• 
12 lead ECG 
• 
Review of concurrent medication 
• 
Recording of AEs and serious adverse events (SAEs) 
• 
Tumor assessment by CT/ MRI scan (neck, chest, abdomen and pelvis) 
• 
Bone marrow evaluation (aspirate or biopsy) 
• 
Hematology 
• 
Clinical chemistry 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 69 of 122 
• 
Coagulation 
• 
Immunoglobulin (Ig) A, IgG, IgM level and serum electrophoresis 
• 
Pregnancy test for women of childbearing potential 
• 
Viral serology (HBV, HCV, HIV) 
• 
Urinalysis 
The aforementioned data will be captured in the source documents. Any results falling 
outside the normal range will be repeated at the discretion of the investigator. 
Safety assessments should be performed at all visits to the study center and throughout 
the study. The list of events and the time when they will be performed are presented in 
Table 1 and Table 2.  
Measurements used to evaluate safety will include vital signs, B symptoms, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, urinalysis, and 
immunoglobulin assessment and serum EPG), 12 lead ECG, and physical examinations. 
Throughout the study, the study center personnel will be monitoring AEs. Adverse events 
and toxicities will be graded according to NCI CTCAE, Version 4.03.18 Subjects who 
initiate treatment with an ANC <1000/μl will not be considered evaluable for neutrophil 
toxicity as outlined in the 2008 IWCLL guidelines.15  
8.2 Laboratory Evaluations 
Laboratory assessments should be performed at a local certified laboratory on Day 1 
before the study drug administration. Laboratory assessments need not be repeated on 
Day 1 if these assessments were completed for screening within 72 hours of the first 
administration. Other laboratory assessments will be sent to central laboratory for the 
required procedures. Required assessments are listed in Table 9. 
Clinical chemistry, hematology, coagulation, urinalysis, and immunoglobulin assessment 
and serum EPG will be performed at the time points specified in Table 1 and Table 2. 
All subjects, who have any Grade 3 or Grade 4 laboratory abnormalities at withdrawal 
from the study, must be followed up until they have returned to Grade 1 or Grade 2, 
unless these are not likely to improve due to the underlying disease. 
On routine urinalysis, if urine protein is ≥2+ by dipstick, a 24 hour urine sample for total 
protein and a random urine sample for total protein and creatinine will be obtained. If 
urine protein is >2 g/24 hours, the study drug administration will be interrupted until it 
returns to ≤2 g/24 hours. If urine protein is ≤2 g/24 hours, further clinical evaluation 
and/or more frequent testing may be performed as clinically indicated. A random urine 
protein to creatinine ratio can serve as a reliable surrogate for the 24 hour urine protein 
when following subjects with urine protein of ≤2 g, documented by a 24 hour urine 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 70 of 122 
collection. In such cases, the 24 hour urine for total protein should be repeated only if a 
clinically significant increase is observed in the random urine protein to creatinine ratio.  
Serum electrophoresis should be tested during screening for all subjects, and if a 
paraprotein is present, it should be repeated on all subsequent immunoglobulin 
assessments. 
8.3 Physical Examination, Vital Signs, and B Symptoms 
A complete or targeted physical examination, vital signs (SBP, DBP, pulse rate, 
temperature, and respiratory rate), weight, and B symptoms assessment will be performed 
at the time points specified in Table 1 and Table 2. 
Complete physical examination includes assessment of cardiovascular, respiratory, 
abdominal and neurological systems as well as lymph nodes, spleen, skin, oropharynx 
and extremities. Targeted physical exams should be limited to systems of clinical 
relevance (ie, cardiovascular, respiratory, lymph nodes, liver, and spleen) and those 
systems associated with clinical signs/symptoms. B symptoms include unexplained 
weight loss >10% over previous 6 months, fever (>38°C), and/or drenching night sweats. 
8.4 Electrocardiogram 
Perform a single 12 lead ECG at screening and as medically indicated. Subjects should be 
in the semi recumbent or supine position. Electrocardiograms will be obtained at the time 
points specified in Table 1 and Table 2. 
8.5 Computed Tomography 
Tumor assessments must be performed within 7 days of the end of Weeks 12, 24, 36 and 
48, every 24 weeks after Week 48, and at disease progression. In rare instances the timing 
of a subject’s scan may fall outside this specified imaging procedure window – for 
example, due to out-of-town travel or other unforeseen circumstances. Rare occurrences 
of missing scans or scans outside the procedure window will not necessarily be 
considered as a protocol deviation; the Sponsor will make the final determination.  
Subjects continue treatment and undergo additional tumor assessments until disease 
progression or intolerance, death, subject withdraws from the study, or at the discretion of 
the investigators, or study closure, whichever occurs first.  Computed tomography scans 
must encompass neck, chest, abdomen and pelvis and use intravenous contrast or 
investigators’ decision. A CT scan of diagnostic quality performed as part of positron 
emission tomography (PET)/CT is acceptable, provided bidimensional nodal and 
liver/spleen measurements can be made. For lesions not amenable to measurement by CT, 
MRI may be utilized after consultation with the Sponsor Medical Monitor. If the subject 
has no assessable disease by CT at study entry (eg, WM without nodal enlargement), 
repeat scans are not required during the study. The CT scan will be used for disease 
assessment by the investigator at each study center. For subjects who discontinue early, a 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 71 of 122 
CT scan will be performed at the discontinuation visit if the previous scan was more than 
3 months ago. 
8.6 Bone Marrow Evaluation 
A bone marrow examination must be performed at screening for all participants and 
within 7 days of the end of Week 12 for subjects with baseline marrow disease. In those 
subjects who had evidence of bone marrow disease at the time of enrollment, upon 
achieving a possible complete response (CR) (eg, physical exam or CT scan indicating a 
possible CR), based on the response criteria of NHL, repeated bone marrow aspirations 
and biopsies are required to confirm CR. 
Peripheral blood and/or bone marrow aspirate/biopsy with flow cytometry assessment(s) 
for minimal residual disease should be done at least 3 months after the last dose if there is 
evidence of CR in all of the response parameters (ie, hematology, CT scan). 
8.7 Minimal Residual Disease for Subjects with CLL 
Chemo-immunotherapy combinations are standard treatments for many patients with 
CLL. Novel targeted agents are being used in front-line and relapsed settings. Minimal 
residual disease (MRD) status has been shown to be a predictor of both progression-free 
survival (PFS) and overall survival (OS) following chemo-immunotherapy.20,21 In this 
study, samples will be requested from subjects with CLL to assess MRD at the following 
timepoints: 
 Peripheral blood sample at Cycle 18, or at the earliest opportunity after Cycle 18, 
in all CLL subjects on study; a bone marrow sample is requested if the peripheral 
blood sample is MRD negative 
 Peripheral blood sample at the time of newly attained CR, and at each CR assessed 
timepoint thereafter, for continuing CLL subjects; a bone marrow sample is 
requested if the peripheral blood sample is MRD negative 
 
CLL subjects who do not achieve CR will not have the second set of peripheral blood and 
bone marrow samples taken. 
Samples will be analyzed at a central laboratory. 
8.8 Adverse Events 
After informed consent has been signed, but prior to the administration of the study drug, 
only SAEs should be reported. After initiation of study drug, all AEs and SAEs, 
regardless of the relationship to the study drug, will be collected until 30 days after the 
last zanubrutinib treatment or 90 days after the last dose of obinutuzumab, and until 
resolution of all treatment related AEs. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 72 of 122 
8.9 Pregnancy 
8.9.1 Pregnancy Testing 
A serum pregnancy test will be performed at screening and a urine pregnancy test at the 
time points specified in Table 1 and Table 2 in women of childbearing potential. Any 
female subject who is pregnant will not be eligible for the study. A subject who has a 
positive pregnancy test result at any time after the study drug administration will be 
immediately withdrawn from participation in the study. The results of pregnancy tests 
will not be recorded in the database. 
8.9.2 Action to be taken if a Pregnancy Occurs 
A subject who has a positive pregnancy test result at any time after the study drug 
administration will be immediately withdrawn from participation in the study. All post 
study assessments will be collected at the time of discontinuation as described in 
Section 5.4.1. 
The investigator, or his/her designee, will collect pregnancy information on any female 
subject of childbearing potential or a female partner of a male subject who becomes 
pregnant while participating in this study. The investigator, or his/her designee, will 
record pregnancy information on the appropriate form and submit it to the Sponsor within 
2 weeks of learning of a subject’s pregnancy. The subject will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, follow up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any premature termination of the 
pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or 
SAE, as described in Section 10.6 and will be followed as described in Section 10.8. 
A spontaneous abortion is always considered to be an SAE and will be reported as 
described in Section 10. Furthermore, any SAE occurring as a result of a post study 
pregnancy and is considered reasonably related to the study drug (zanubrutinib in 
combination with obinutuzumab) by the investigator, will be reported to the Sponsor as 
described in Section 10.11. While the investigator is not obligated to actively seek this 
information in former subjects, he/she may learn of an SAE through spontaneous 
reporting. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 73 of 122 
8.10 Follow-up Assessments 
8.10.1 
Safety Follow-up 
Approximately 28 days after the last administration of the study drug, all subjects should 
return for a final evaluation. Assessments to be performed are presented in Table 1 and 
Table 2. 
Any abnormal finding of clinical consequence and not related to the disease progression 
will be monitored until resolution or baseline status. 
8.10.2 
Progression and Survival Follow up  
Subjects who discontinue study drug due to reasons other than disease progression will 
remain in the study and be followed every 3 months until the subject exhibits first 
progression, withdraws consent, starts new anti-cancer therapy, death or study closure, 
whichever occurs first. Once a subject progresses or starts use of alternative anti-cancer 
therapy, he/she will not return to the study center, but will be contacted every 3 months 
by telephone, to assess survival until death, withdrawal of consent or study closure, 
whichever occurs first. 
8.11  Efficacy 
The following efficacy endpoints will be assessed:  
• 
The number and proportion of subjects who achieve objective tumor response 
(CR, PR, PR-L, and CR+PR) or SD. 
• 
Minimal residual disease (MRD) clearance rate. 
• 
Hematological improvement. 
• 
Progression free survival (PFS). It is the responsibility of the investigator to 
determine the date of disease progression. 
• 
Overall survival. 
• 
Duration of response for responders (CR or PR). Duration: time from date of first 
occurrence of CR or PR to date of progression. 
Efficacy assessments will use the applicable response criteria (IWCLL for CLL15,22 , NCI 
WG for NHL16, and IWWM for WM17, as shown in Section 16.3) with CT (or PET if 
applicable) scans after Weeks 12, 24, 36 and 48, every 24 weeks after Week 48, and bone 
marrow aspirate and trephine after 12 weeks (and repeated subsequently if the subject 
attains criteria for complete remission in every other respect beyond 12 weeks).      
8.12  Pharmacokinetic Assessments 
Blood will be collected to describe the PK profiles of zanubrutinib and obinutuzumab and 
may be used for a preliminary analysis of major metabolites. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 74 of 122 
The maximum total amount of blood taken for the PK analysis will be approximately 
150 mL. These samples will be collected at the time points presented in Table 3. Frozen 
plasma samples should be shipped as soon as possible after collection since exposure will 
be monitored while the study is ongoing. 
8.12.1 Pharmacokinetic Blood Samples for Zanubrutinib and 
Obinutuzumab 
Cannulation for blood sampling for PK will be performed. Blood will be collected via the 
intravenous cannula predose and at the time points specified in Table 3. A 1 mL blood 
sample will be taken (for flush of the cannula) and discarded prior to each blood sample. 
The actual time each sample was collected will be captured to the nearest minute in the 
eCRF and recorded in the database. 
Blood samples (4 mL and 5 mL) for zanubrutinib and obinutuzumab PK analysis, 
respectively, will be collected according to the Lab Manual. Plasma (for zanubrutinib) 
and serum (for obinutuzumab) will be separated and immediately frozen. Samples must 
remain frozen in a freezer set at or below -70°C and in a box with dry ice during shipping. 
Prior to collection, the collection tube and serum or plasma storage tube must be labelled 
with the corresponding labels provided by the Sponsor. The labels must be placed along 
the length of the tube so they can be read easily. Tape must not be used to secure the 
labels as the tube will not fit into the autoanalyzer test tube rack. The labels are of high 
quality and will not peel off of the tube even under extreme conditions. 
Samples will be shipped to the central laboratory where all samples will be analyzed for 
plasma zanubrutinib and obinutuzumab concentrations using a validated method. 
8.13  Pharmacodynamic Assessments 
Pharmacodynamics is not a primary objective of this study. BTK occupancy in PBMCs 
will be determined and used as direct PD biomarker for BTK inhibition. This is for the 
subjects enrolled in Part 1 only. 
8.13.1 
PBMC Preparation 
Blood samples (8 mL) for PD analysis will be collected into plastic potassium EDTA 
collection tubes immediately following PK blood sampling at the time points specified in 
Table 3. PBMCs will be prepared using the peripheral blood mononuclear cell 
preparation kit provided by the Sponsor. PBMC samples will be immediately frozen in a 
freezer at or below -70°C. 
8.13.2 
Sample Shipment and Analysis 
Samples must remain frozen in a box with dry ice during shipping. Samples will be 
shipped to the central laboratory where all samples will be analysed for BTK occupancy 
using a validated method. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 75 of 122 
8.14  Other Assessments 
8.14.1 
Subject Tissue Analysis 
Subjects who have DLBCL must have archival tumor tissues or agree to a tumor biopsy 
for confirmation of the DLBCL subtype and further genetic analysis, either prior to 
enrollment or during/after the study treatment. Either a formalin fixed, paraffin embedded 
block with tumor tissue (preferred) or 10 to 15 unstained slides must be sent to the central 
laboratory to confirm the DLBCL subtype and conduct exploratory biomarker analysis. 
Subjects who have disease relapse at any time will be asked for a blood sample and asked 
to undergo biopsies of representative tumor sites (or BM) to obtain samples for studying 
mechanisms of resistance. These studies may include phosphoprotein analysis of relevant 
pathways, whole exome or genome sequencing, and assessments of RNA expression. To 
achieve these goals, at disease progression, subjects who have CLL will be asked to 
provide a peripheral blood sample, subjects who have WM will be asked to provide a 
bone marrow aspirate, and subjects from other indications will be asked to undergo tissue 
biopsies of representative tumor sites. If feasible, samples collected for disease 
progression confirmation may be used for biomarker testing in lieu of requesting 
additional marrow and biopsy samples from patients. For non-CLL subjects, while bone 
marrow collection or tumor tissue re-biopsy is preferred, peripheral blood samples are 
acceptable if bone marrow or biopsies are not accessible. 
8.15  Appropriateness of Measurements 
All safety and PK assessments used in this study are standard, ie, widely used and 
generally recognized as reliable, accurate, and relevant. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 76 of 122 
9 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the GCP guidelines, the Sponsor is responsible for implementing and 
maintaining quality assurance and quality control systems with written Standard 
Operating Procedures (SOPs). 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Investigator meeting(s) 
• 
Certified local laboratories for laboratory measurements and ECGs 
• 
Study center initiation visit 
• 
Early study center visits after enrollment 
• 
Routine study center monitoring 
• 
Ongoing study center communication and training 
• 
Data management quality control checks 
• 
Continuous data acquisition and cleaning 
• 
Internal review of data 
• 
Quality control check of the final clinical study report 
In addition, the Sponsor and/or the CRO clinical quality assurance department may 
conduct periodic audits of the study processes, including, but not limited to the study 
center, study center visits, central laboratories, vendors, clinical database, and the final 
clinical study report. When audits are conducted, access must be authorized for all study 
related documents including medical history and concomitant medication documentation 
to authorized Sponsor’s representatives and regulatory authorities. 
9.1 Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, the Sponsor 
and/or CRO monitors will contact the study center prior to the subject enrollment to 
review the protocol and data collection procedures with the study center personnel. In 
addition, the monitor will periodically contact the study center, including conducting on 
site visits. The extent, nature and frequency of onsite visits will be based on such 
considerations as the study objective and/or endpoints, the purpose of the study, study 
design complexity, and enrollment rate. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 77 of 122 
During these contacts, the monitor will: 
• 
Check the progress of the study 
• 
Review study data collected 
• 
Conduct source document verification 
• 
Identify any issues and address their resolution 
This will be done in order to verify that the: 
• 
Data are authentic, accurate, and complete 
• 
Safety and rights of subjects are being protected 
• 
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her personnel to the monitor to discuss findings 
and any relevant issues. 
At study closure, monitors will also conduct all activities described in Section 13.1. 
9.2 Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs 
of the data management and biostatistics departments of the CRO. 
An electronic data capture (EDC) system will be used for this study, meaning that all 
eCRF data will be entered in electronic forms at the study center. Data collection will be 
completed by authorized study center personnel designated by the investigator.  
Appropriate training and security measures will be completed with the investigator and all 
authorized study center personnel prior to the study being initiated and any data being 
entered into the system for any subjects. 
The eCRFs should always reflect the latest observations of the subjects participating in 
the study. Therefore, the eCRFs are to be completed as soon as possible during or after 
the subject’s visit. To avoid inter observer variability, every effort should be made to 
ensure that the same individual who made the initial baseline determinations completes 
all safety evaluations. The investigator must verify that all data entries in the eCRFs are 
accurate and correct. If some assessments are not done, or if certain information is not 
available or not applicable or unknown, the investigator should indicate this in the eCRF. 
The investigator will be required to electronically sign off on the clinical data once 
complete. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. 
The eCRF will be compared with the source documents to ensure that there are no 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 78 of 122 
discrepancies between critical data. All entries, corrections, and alterations are to be made 
by the responsible investigator or his/her designee. The monitor cannot enter data in the 
eCRFs. Once clinical data has been entered into the eCRF, any corrections or alterations 
to the data fields will be traceable via an audit trail, meaning that the reason for change, 
the name of the person who performed the change, together with time and date will be 
logged. Roles and rights of the study center personnel responsible for entering the clinical 
data into the eCRF will be determined in advance. If additional corrections are needed, 
the responsible monitor or data manager will raise a query in the EDC application. The 
appropriate study center personnel will respond to any queries raised. 
The eCRF is essentially considered a data entry form and should not constitute the 
original (or source) medical records unless otherwise specified. Source documents are all 
documents used by the investigator or hospital that relate to the subject’s medical history, 
that verify the existence of the subject, the inclusion and exclusion criteria and all records 
covering the subject’s participation in the study. They include laboratory notes, ECG 
results, memoranda, pharmacy dispensing records, subject files, etc. 
The investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. The investigator 
must submit a completed eCRF for each subject who receives the study drug, regardless 
of the duration. All supportive documentation submitted with the eCRF, such as 
laboratory or hospital records, should be clearly identified with the study and subject 
number. Any personal information, including subject name, should be removed or 
rendered illegible to preserve individual confidentiality. 
Electronic CRF records will be automatically appended with the identification of the 
creator, by means of their unique User ID. Specified records will be electronically signed 
by the investigator to document his/her review of the data and acknowledgement that the 
data are accurate. This will be facilitated by means of the investigators unique User ID 
and password; date and time stamps will be added automatically at the time of the 
electronic signature. If an entry on an eCRF requires change, the correction should be 
made in accordance with the relevant software procedures. All changes will be fully 
recorded in a protected audit trail, and a reason for the change will be required. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 17.0 or higher. Concomitant medications will be coded using the 
World Health Organization Drug Dictionary (WHO DD). Concomitant diseases/medical 
history will be coded using MedDRA Version 17.0 or higher. 
9.3 Quality Assurance Audit 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor 
may conduct a quality assurance audit. Regulatory agencies may also conduct a 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 79 of 122 
regulatory inspection of this study. Such audits/inspections can occur at any time during 
or after completion of the study. If an audit or inspection occurs, the investigator and 
institution agree to allow the auditor/inspector direct access to the facilities used for this 
trial and all relevant documents and to allocate his/her time and the time of his/her 
personnel to the auditor/inspector to discuss findings and any relevant issues. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 80 of 122 
10 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
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. During the study, 
when there is a safety evaluation, the investigator or study center personnel will be 
responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
Adverse event and SAE collection is to begin from subject consenting, and continued 
until 30 days after the last zanubrutinib treatment, and until resolution of all treatment 
related AEs. 
10.1  Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product (zanubrutinib in combination with 
obinutuzumab). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study drug. 
Examples of an AE include: 
• 
Worsening of a chronic or intermittent pre-existing condition including an 
increase in severity, frequency, duration, and/or has an association with a 
significantly worse outcome. 
• 
New conditions detected or diagnosed after study drug administration even though 
it may have been present before the start of the study.  
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug or a concurrent medication.  
• 
Significant failure of expected pharmacological or biological action. See 
Section 10.3 for additional information. 
10.2  Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• 
Results in death. 
• 
Is life threatening.  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 81 of 122 
NOTE: The term “life threatening” in the definition of “serious” refers to an event 
in which the subject was at risk of death at the time of the event. It does not refer 
to an event, which hypothetically might have caused death, if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an SAE. 
• 
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. 
• 
Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  
10.3  Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE. The signs and symptoms or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the AE or SAE 
definition (including clarifications). 
10.4  Abnormal Assessments as AEs or SAEs 
Abnormal laboratory findings (eg, clinical chemistry, hematology, coagulation, 
urinalysis) or other abnormal assessments (eg, ECGs, chest X rays, vital signs, etc.) that 
are judged by the investigator as clinically significant will be recorded as AEs or SAEs if 
they meet the definition of an AE, as defined in Section 10.1, or an SAE, as defined in 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 82 of 122 
Section 10.2. Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected during the study or are present at baseline and significantly 
worsen following the start of the study will be reported as AEs or SAEs. However, 
clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more 
severe than expected for the subject’s condition, or that are present or detected at the start 
of the study and do not worsen, will not be reported as AEs or SAEs. They should be 
reported as AEs or SAEs if they induce clinical signs or symptoms, need active 
intervention, need dose interruption or discontinuation or are clinically significant in the 
opinion of the investigator. 
The investigator will exercise his/her medical and scientific judgment in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant. 
10.5 Time Period, Frequency, and Method of Detecting AEs and 
SAEs 
10.5.1 
Adverse Event Reporting Period  
After informed consent has been signed but prior to the administration of the study drug, 
only SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, 
will be reported until 30 days after the last study treatment of zanubrutinib or 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. 
10.5.2 
Eliciting Adverse Events  
The investigator or designee will ask about AEs by asking the following standard 
questions: 
• 
How are you feeling?  
• 
Have you had any medical problems since your last visit?  
• 
Have you taken any new medicines since your last visit?  
All AEs and SAEs will be recorded in the source documents. All AEs and SAEs will be 
reported in the eCRF. 
10.5.3 
Specific Instructions for Recording Adverse Events
 
and Serious Adverse Events 
10.5.3.1 
Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF (and 
SAE report, as applicable), rather than the individual signs and symptoms (eg, record only 
hepatitis rather than elevated transaminases, bilirubin or jaundice). However, if a 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 83 of 122 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual AE should be recorded as 
an SAE or AE on the eCRF (and SAE report, if applicable). If a diagnosis is subsequently 
established, it should replace the individual signs and/or symptoms as the AE term on the 
eCRF (and SAE report, if applicable), unless the signs/symptoms are clinically 
significant. 
10.5.3.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other AEs (eg, clinical sequelae or a cascade of 
AEs) should be identified by their primary cause. For example, if severe vomiting is 
known to result in dehydration, it is sufficient to record only vomiting as the SAE or AE 
on the eCRF (and SAE report, if applicable). However, if a subject initially has a non-
serious AE, and it subsequently becomes an SAE, both AEs should be reported separately 
on the eCRF. The onset date of the non-serious AE should be recorded as the start date of 
the non-serious AE. The onset date of the SAE should be recorded as the start date when 
the non-serious AE becomes an SAE. 
10.5.3.3 
Persistent or Recurring Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points. Such AEs should only be recorded once on the AE eCRF (and 
SAE report, if applicable). If a persistent AE worsens in grade, it should be recorded as a 
new AE on the eCRF (and a stop date should be recorded in the previous AE).  
A recurrent AE is one that occurs and resolves between subject evaluation time points, 
and subsequently recurs. All recurrent AEs should be recorded separately on the eCRF 
(and SAE report, if applicable). 
10.5.3.4 
Disease Progression  
Disease progression is expected in this study population, and the term “disease 
progression” should not be reported as an AE term.  When disease progression is 
identified, the AE that identifies the disease progression should be reported as the AE 
term. For instance, a subject with pleural effusion presents with shortness of breath.  The 
cause of the shortness of breath is a pleural effusion resulting from disease progression.  
The AE term should be reported as “pleural effusion” instead of disease progression or 
metastasis to lungs.  If a subject has a seizure that is determined to be associated with a 
brain metastasis, the term “seizure” should be recorded as the AE instead of disease 
progression or brain metastasis. If a subject experienced multi-organ failure due to 
disease progression, the term “multi-organ failure” should be reported as the AE instead 
of disease progression. Deaths that are assessed by the investigator as solely due to 
disease progression should be recorded on Study Completion or Early Discontinuation 
eCRF as efficacy data. They should not be reported as an SAE. If deaths are attributed by 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 84 of 122 
the investigator not solely due to disease progression, whether they are assessed as related 
or not related to the study drug, they should be reported as SAE immediately.  
If there is any uncertainty regarding whether an AE is due to disease progression, it 
should be reported as an AE. 
10.5.3.5 
Death 
When recording a death as an SAE, the AE that caused or contributed to fatal outcome 
should be recorded as the single medical concept.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “unexplained death”. 
10.6  Recording of Adverse Events and Serious Adverse Events 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) relative to 
the event. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. It is not acceptable for the investigator to send photocopies of the 
subject’s medical records to the Sponsor in lieu of completion of the appropriate AE or 
SAE eCRF pages. However, there may be instances when copies of medical records for 
certain cases are requested by the Sponsor. In this instance, all subject identifiers will be 
blinded on the copies of the medical records prior to submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE or SAE and not the individual signs/symptoms. Adverse events are 
independent components of the study. 
10.7  Evaluating Adverse Events and Serious Adverse Events 
10.7.1 
Assessment of Severity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study. When applicable, AEs and SAEs should be assessed and graded based upon the 
NCI CTCAE Version 4.03.18 Subjects who initiate treatment with an ANC <1000/μl will 
not be considered evaluable for neutrophil toxicity as outlined in the 2008 IWCLL 
guidelines. 15 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
 Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)  
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 85 of 122 
 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 10.2. 
10.7.2 
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 event to the 
study drug will be considered and investigated. The investigator will also consult the IB 
and/or Product 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 event prior to 
transmission of the SAE report to the Sponsor. The investigator may change his/her 
opinion of causality in light of follow up information, amending the SAE report 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
The investigator will provide the assessment of causality (zanubrutinib in combination 
with obinutuzumab) as per instructions on the SAE form. 
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: 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 86 of 122 
 There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
 There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
 There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the AE (eg, the subject’s 
clinical condition or other concomitant AEs). 
An AE should be considered ‘unrelated’ to study drug if any of the following are met: 
 An unreasonable temporal relationship between administration of the study drug and 
the onset of the AE (eg, the AE occurred either before or too long after 
administration of the product for it to be considered product-related) 
 A causal relationship between the study drug and the AE is biologically implausible 
(eg, death as a passenger in an automobile accident) 
 A clearly more likely alternative explanation for the AE is present (eg, typical 
adverse reaction to a concomitant drug and/or typical disease-related AE) 
10.8  Follow Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the Sponsor on the subject’s condition. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, 
will be reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow up. Once resolved, 
the appropriate AE or SAE eCRF page(s) will be updated. The investigator will ensure 
that follow up includes any supplemental investigations as may be indicated to elucidate 
the nature and/or causality of the AE or SAE. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
The Sponsor may request that the investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations to elucidate as fully as possible the nature 
and/or causality of the AE or SAE. The investigator is obligated to assist. If a subject 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 form. The 
updated SAE form should be resent to the Sponsor within the time frames outlined in 
Section 10.9. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 87 of 122 
10.9  Prompt Reporting of Serious Adverse Events 
10.9.1 
Timeframes for Submitting Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an 
SAE, the event must be reported promptly (within 24 hours) to the Sponsor or designee as 
described in Table 8. 
Table 8 Timeframes and Documentation for Reporting Serious Adverse Events to 
the Sponsor or Designee 
 
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 
the AE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Email or fax 
SAE form 
Abbreviations: SAE: serious adverse event 
10.9.2 
Completion and Transmission of the Serious Adverse 
Event Report 
Once an investigator becomes aware that an SAE has occurred in a subject, he/she will 
report the information to the Sponsor within 24 hours as outlined in Section 10.9.1. The 
SAE report will always be completed as thoroughly as possible with all available details 
of the event, and forwarded to the Sponsor 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 at the time of the initial 
report as described in Section 10.7.2. 
The Sponsor will provide a list of project contacts for SAE receipt, fax numbers, 
telephone numbers, and mailing addresses. 
10.10 
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 10.9.1. 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 subjects 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 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 88 of 122 
authorities and the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC).  
This protocol is being filed under an Investigational New Drug (IND) application with the 
FDA. 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. Such a report is prepared for an SAE that is 
both attributable to study drug and unexpected. The purpose of the report is to fulfill 
specific regulatory and GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow up report or other safety information (eg, 
revised IB) from the Sponsor, the responsible person according to local requirements is 
required to promptly notify his/her IRB or IEC. 
10.11 
Post Study Adverse Events and Serious Adverse 
Events 
A post study AE or SAE is defined as any event that occurs outside of the AE/SAE 
reporting period, defined in Section 10.5. 
Investigators are not obligated to actively seek AEs or SAEs in former subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably related to the 
study drug (zanubrutinib in combination with obinutuzumab), the investigator will 
promptly notify the Sponsor. 
10.12 
Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (eg, procedures, invasive tests), even if 
it occurs during the post treatment period, will be reported promptly to the Sponsor (see 
Section 10.9). 
10.13 
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 SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference documents: 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 89 of 122 
 Zanubrutinib Investigator’s Brochure  
 Obinutuzumab Investigator’s Brochure  
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 90 of 122 
11  DATA ANALYSIS AND STATISTICAL 
 CONSIDERATIONS 
11.1  Sample Size Considerations 
The number of dose regimens in the safety evaluation part and the emerging zanubrutinib 
and obinutuzumab toxicities will determine the sample size. It is anticipated that 
approximately 12 subjects will be required to establish the selected treatment regimen of 
zanubrutinib when administered in combination with obinutuzumab in the safety 
evaluation part. 
Approximately 120 subjects will be enrolled during the indication expansion period. 
Enrollment in certain arms may be closed prematurely due to safety intolerability to 
zanubrutinib at the discretion of Sponsor or SMC. 
11.2  General Considerations for Data Analysis 
The following descriptive statistics will be used to summarize the trial data on the basis of 
their nature unless otherwise specified: 
• 
Continuous variables:  number of non-missing observations, mean, standard 
deviation, coefficient of variation (CV%) as appropriate, median, minimum, and 
maximum. 
• 
Categorical variables:  frequencies and percentages. 
• 
Time to event variables:  number of non-missing observations (N), median, 
minimum and maximum. Kaplan Meier median times, 25th and 75th percentiles 
and associated 95% confidence intervals (CIs) will also be provided for specific 
time to event variables. 
Further description of the statistical methods and analyses will be provided in the SAP. 
11.2.1 
Analysis Populations  
All Subjects Enrolled Set:  
The all subjects enrolled set will include all subjects who provide informed consent for 
this study. The all subjects enrolled set will be used to summarize and describe the 
analysis set. 
Safety Analysis Set:  
The safety analysis set will include all subjects in the all subjects enrolled set who receive 
at least 1 administration of zanubrutinib and/or obinutuzumab. The safety analysis set will 
be used for all summaries, including efficacy analyses (except DLTs and PK/PD 
analyses). 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 91 of 122 
DLT Analysis Set:  
The DLT analysis set includes all subjects who experienced a DLT during Cycle 1 or 
subjects who received at least 80% of the planned doses of zanubrutinib and missed no 
more than one administration of obinutuzumab during the DLT observation period 
(Cycle 1). DLT summary will be performed for Part 1 only. 
PK Analysis Set:  
The PK analysis set will include subjects who have received at least the first 
administration of zanubrutinib and provided PK samples as per protocol (without 
significant protocol deviation affecting the PK blood sample) following the first treatment 
on Day 1 Cycle 1. 
PD Analysis Set: 
The PD analysis set will include subjects who have received at least the first 
administration of zanubrutinib and provided PD samples as per protocol (without any 
significant protocol deviation affecting the PD blood sample) following the first treatment 
on Day 1 Cycle 1. 
11.2.2 
Interim Analysis 
No interim analysis is planned for this study. Since this is a dose regimen safety 
evaluation study, safety, PK and PD data will be evaluated on an ongoing basis. 
11.2.3 
Withdrawal 
Subjects who drop out or are withdrawn for any reason which does not fall under DLT 
will be considered for replacement after due consideration from Sponsor and safety 
committee and will be replaced whenever possible. 
11.3  Pharmacokinetic Analysis 
Nominal sampling times will be used for interim PK parameter calculations, while actual 
sampling times will be used in the final PK parameter calculations.  
Plasma samples will be collected at the time points detailed in Table 3. 
Where possible, the following plasma PK parameters will be determined for zanubrutinib 
(Cycle 1 Day 1 and Cycle 2 Day 1) and obinutuzumab:  
AUC 
Area under the plasma concentration-time curve from zero 
extrapolated to infinity calculated using the linear up/log down 
trapezoidal method 
AUClast and 
AUClast,ss 
Area under the plasma concentration time-curve from zero to the 
last quantifiable concentration 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 92 of 122 
Cmax and Cmax,ss 
Maximum observed plasma concentration 
tmax and tmax,ss 
Time to maximum observed plasma concentration 
λz 
Terminal rate constant 
t1/2 
Terminal half life 
CL/F 
Apparent systemic plasma clearance 
Vzd/F 
Apparent volume of distribution during the terminal phase 
 
Where possible, the following diagnostic parameters of the plasma PK analysis will be 
calculated and listed, but not summarized: 
Interval 
The time interval (hours) of the log linear regression used to 
determine λz 
N 
Number of data points included in the log linear regression 
analysis to determine λz (a minimum of 3 points will be used) 
Rsq 
Rsquare; coefficient of determination for calculation of λz. If 
Rsq is less than 0.800, then λz and related parameters will not be 
reported 
%AUCex 
Percentage of AUC obtained by extrapolation; if greater than 
30% then AUC and related parameters will not be reported 
 
Additional PK parameters may be calculated if deemed appropriate.  
Plasma zanubrutinib concentration time data will be summarized and displayed in both 
tabular and graphical form. Predose samples that are below quantifiable limits (BQL) or 
missing will be assigned a numerical value of zero for the calculation of PK parameters. 
The BQL concentrations will be treated as zero for summary statistics. Concentration 
time data will be analyzed with standard non compartmental PK methods. The PK 
parameters for a single dose profile (AUClast, AUC, Cmax, tmax, t1/2, CL/F, and Vd/F) and 
after steady state (AUClast,ss, Cmax,ss, tmax,ss), will be calculated, if there are sufficient data. 
Individual subject parameter values, as well as a descriptive summary (N, mean, standard 
deviation, median, minimum, maximum, and the standard deviation, CV%, and geometric 
mean of log transformed parameters) by treatment group will be reported. Individual 
subject parameter values will be plotted against dose.  
Plasma obinutuzumab concentrations will be measured as detailed at the times in Table 3. 
Plasma obinutuzumab concentration time data will be summarized and displayed in 
tabular form. Limited PK parameters [AUClast, Cmax, and tmax) will be reported for 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 93 of 122 
obinutuzumab during Cycle 1 treatment. This is due to the long elimination half-life 
(about 29.7 hours) and sparse PK blood sampling schedule in this study. A pop-PK 
approach may be used for this analysis. 
11.4  Pharmacodynamic Analyses 
Pharmacodynamics is not a primary objective of this study. BTK occupancy in PBMCs 
will be summarized and listed if possible. 
11.5  Efficacy Analysis 
Response assessment will be performed per the standard International Working Group 
(IWG) Criteria for each disease as described in Appendix 16.3.  
ORR, MRD clearance rate, hematological improvement: 
The number and percentage of subject along with 95% exact binomial CIs will be 
presented for overall response (ORR defined as CR or PR [CR+PR]]), CR, PR, SD, 
progressive disease, MRD clearance rate and, for subjects with CLL, hematological 
improvement (HI). 
HI for subjects with CLL will be described by the frequency and number of subjects with: 
1. Erythroid response (HI-E) 
Major response: For subjects with pretreatment hemoglobin less than 9 g/dL, 
greater than 2 g/dL increase in hemoglobin; for RBC transfusion-dependent 
subjects, transfusion independence. The defined improvement in haemoglobin 
levels must be maintained for at least 2 months while on study treatment. 
Minor response: For subjects with pretreatment hemoglobin less than 9 g/dL, 1 to 
2 g/dL increase in hemoglobin; for RBC transfusion-dependent subjects, 50% 
decrease in transfusion requirements. The defined improvement in haemoglobin 
levels must be maintained for at least 2 months while on study treatment. 
2. Platelet response (HI-P) 
Major response: For subjects with pretreatment platelet count less than 
100,000/mm3, an absolute increase of 30,000/mm3 or more; for platelet 
transfusion-dependent patients, stabilization of platelet counts and transfusion 
independence. The defined improvement in platelet levels must be maintained for 
at least 2 months while on study treatment. 
Minor response: For subjects with pretreatment platelet count less than 
100,000/mm3, a 50% or more increase in platelet count with a net increase greater 
than 10,000/mm3 but less than 30,000/mm3. The defined improvement in platelet 
levels must be maintained for at least 2 months while on study treatment. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 94 of 122 
3. Neutrophil response (HI-N) 
Major response: For absolute neutrophil count (ANC) less than 1500/mm3 before 
therapy, at least a 100% increase or an absolute increase of more than 500/mm3, 
whichever is greater. The defined improvement in neutrophil levels must be 
maintained for at least 2 months while on study treatment. 
Minor response: For ANC less than 1500/mm3 before therapy, ANC increase of at 
least 100%, but absolute increase less than 500/mm3. The defined improvement in 
neutrophil levels must be maintained for at least 2 months while on study 
treatment. 
RBC and platelet transfusion dependence and independence are defined in Section 16.4. 
PFS and OS: 
Progression-free survival and OS will be analyzed by Kaplan Meier methodology to 
estimate median PFS and OS, and 95% CI. Kaplan Meier curves will be constructed to 
provide a visual description of the PFS and OS change with time. 
PFS is defined as the time from the date of first study treatment to disease progression or 
death whichever occurs first in subjects. As noted previously, it is the investigator’s 
responsibility to define the date of progression. Subjects without event (no disease 
progression or death) will be censored at the date of ‘last tumor assessment’. Subjects for 
whom no post baseline tumor assessments are available are censored at the time of first 
treatment.   
OS is defined as the time from the date of first study treatment to death (any cause). 
Subjects without death will be censored at the final known date of survival.  
Duration of Response: 
Duration of response for responders (CR or PR) is defined as the time interval between 
the date of the earliest qualifying response and the date of progressive disease or death for 
any cause, whichever occurs earlier. For subjects who are alive without progression 
following the qualifying response, duration of response will be censored on the date of 
last evaluable tumor assessment or last follow up for progression of disease.  
Duration of response will be analysed by Kaplan-Meier methodology to estimate median 
durations and 95% CI. 
This analysis is planned for the statistical analysis plan. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 95 of 122 
11.6  Safety Data Analysis 
11.6.1 
Dose Limiting Toxicity 
The number and proportion of subjects experiencing DLTs will be reported by dose 
level/regimen, based on DLT observations during the first cycle. The DLT analysis set 
will be used for this analysis. 
11.6.2 
Adverse Event 
Adverse events will be coded and grouped using MedDRA Version 17.0 or higher. 
Adverse events and toxicities will be graded according to NCI CTCAE, Version 4.03.18 
Subjects who initiate treatment with an ANC <1000/μl will not be considered evaluable 
for neutrophil toxicity as outlined in the 2008 IWCLL guidelines.15 Adverse events 
representing clear evidence of disease progression will not be considered relevant to the 
assessment of toxicity.  
Analyses will include but may not be restricted to: 
• 
All AEs 
• 
SAEs 
• 
AEs related to study treatment (zanubrutinib in combination with obinutuzumab) 
• 
AEs leading to withdrawal of study treatment 
• 
AEs leading to death 
• 
AEs with toxicity Grade ≥3 
• 
AEs of special interest: summarize by cycle (Cycles 1, 2, 3, 4, 5, 6 and Cycles >6) 
The number and percent of subjects will be summarized for above items, and also 
summarized according to MedDRA system organ classes (SOCs) and preferred terms 
(PTs). The toxicities and causality of AEs will be summarized. 
11.6.3 
Laboratory Assessments 
Hematology, clinical chemistry, coagulation, and urinalysis values will be listed for each 
subject and flagged as high or low relative to the normal range, where applicable. Predose 
values will be used to assess laboratory shifts occurring at postdose. A comparison of 
pre-study and post-study values will be performed to identify any parameters that have 
not returned to pre study levels. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 96 of 122 
Table 9 Safety Laboratory Assessments 
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Immunoglobulin 
Assessment and 
Serum 
Electrophoresis 
Alkaline 
phosphatase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Albumin 
Calcium 
Creatinine 
Glucose 
Lactate 
dehydrogenase 
Magnesium 
Total protein 
Potassium 
Sodium 
Total and direct 
bilirubin 
Urea 
Uric Acid 
Hemoglobin 
MCV 
Platelet counts 
WBC count with 
differential 
Neutrophil count 
Bands (optional) 
Lymphocyte 
count 
Eosinophil count 
Blasts 
 
Prothrombin time 
Partial 
thromboplastin time 
International 
normalized ratio 
pH  
Specific gravity 
Glucose 
Protein 
Ketones 
Blood 24 hour 
protein1 
Random urine 
protein to 
creatinine ratio1 
IgA  
IgG 
IgM 
Serum EPG 2 
Abbreviations: EPG: serum electrophoresis; Ig: Immunoglobulin;  MCV: mean corpuscular volume.  
1. 
On routine urinalysis, if urine protein is ≥2+ by dipstick, then obtain a 24 hour urine sample for 
total protein and a random urine sample for total protein and creatinine to determine a protein to 
creatinine ratio. 
2. 
Serum EPG on 1st test for WM subjects only, and if a paraprotein is present, repeated on all 
subsequent immunoglobulin assessments. 
11.6.4 
Electrocardiogram 
All ECG parameters, including the QT interval corrected for heart rate (QTc), will be 
listed for each subject and summarized by dose level and assessment time. Change from 
baseline will also be summarized. The clinical markedly abnormalities will be 
summarized. Relationship between dose level and QTc changes will be explored by 
graphs. QTc will be calculated using Bazett’s formula. 
11.6.5 
Vital Signs 
Blood pressure (SBP and DBP), pulse, respiratory, body temperature, and weight will be 
summarized and listed. The change from baseline will also be displayed. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 97 of 122 
11.6.6 
Extent of Exposure 
Extent of exposure to zanubrutinib in combination with obinutuzumab will be calculated 
for each subject. Overall exposure will also be summarized by treatment arms, as well as 
dose adjustment information. 
11.6.7 
Physical Examination 
Physical examination results will be listed and summarized. 
11.6.8 
Other Safety Endpoints 
B symptoms, including unexplained weight loss >10% over the previous 6 months, fever 
(>38°C), and/or drenching night sweats will be listed and summarized. 
Eastern Cooperative Oncology Group status, pregnancy test and viral serology will be 
listed. 
11.7  Other Explorative Endpoints 
Correlative blood samples will be collected as per Table 1 and Table 2. Clinical response 
to the zanubrutinib and obinutuzumab combination will be correlated with established 
prognostic and biological markers for the specific histology (eg, International Prognostic 
Index for DLBCL, adverse cytogenetics for CLL, and genomic alterations in non-GCB 
DLBCL).  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 98 of 122 
12  REGULATORY AND ETHICAL ISSUES 
12.1  Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country specific regulatory requirements before 
the study is initiated at a study center in that country. 
12.2  Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles 
of the “Declaration of Helsinki” International Conference of 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. 
Investigators and all subinvestigators must provide documentation of their financial 
interest or arrangements with BeiGene, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
subinvestigator. The investigator and subinvestigator agree to notify BeiGene or its 
authorized representative of any change in reportable interests during the study and for 
1 year following completion of the study. Study completion is defined as the date that the 
last patient has completed the protocol defined activities. 
12.3  Ethical Conduct of the Study and Ethics Approval 
This study will be conducted by the principal investigator and the study center in 
accordance with GCP and all applicable regulatory requirements, including, where 
applicable, 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 subjects (eg, advertisements or information that supports or 
supplements the informed consent) are reviewed and approved by the appropriate 
IEC/IRB. The investigator agrees to allow the IEC/IRB direct access to all relevant 
documents. 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 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 subjects. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has 
approved for presentation to potential subjects is amended during the study, the 
investigator (or Sponsor, where applicable) is responsible for ensuring the IEC/IRB 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 99 of 122 
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 subjects 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. 
12.4  Informed Consent 
The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and before undertaking any study-related 
procedures. The investigator must utilize an IRB/IEC-approved ICF for documenting 
written informed consent. Each ICF 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 subject can participate in the study. The 
contents and process of obtaining informed consent will be in accordance with all 
applicable regulatory requirements. 
12.5  Investigator Reporting Requirements 
As indicated in Section 10.10, 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. 
12.6  Confidentiality 
Information on maintaining patient confidentiality in accordance to individual local and 
national patient privacy regulations must be provided to each patient as part of the 
informed consent process, either as part of the ICF or as a separate signed document (for 
example, in the US, a study-center 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 patient initials, date of birth, and 
an identification code (ie, not names) should be recorded on any form or biological 
sample submitted to the sponsor, IRB, or laboratory. The investigator must keep a 
screening log showing codes, names, and addresses for all patients screened and for all 
patients enrolled in the study. 
The investigator agrees that all information received from BeiGene, including but not 
limited to the IB, this protocol, eCRFs, the IND, and any other study information, remain 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 100 of 122 
the sole and exclusive property of BeiGene during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents 
directly involved in the conduct of the study or as required by law) without prior written 
consent from BeiGene. The investigator further agrees to take all reasonable precautions 
to prevent the disclosure by any employee or agent of the study site to any third party or 
otherwise into the public domain. 
If a written contract for the conduct of the study includes confidentiality provisions 
inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
12.7  Indemnity and Compensation 
In accordance with Statutory Instrument 1031 and amendments section 15 (5i, j) and the 
EU Clinical Trials Directive 2000/20/EC Article 3 (2f), provision is to be made for: 
• 
The indemnity or compensation in the event of injury or death attributable to the 
clinical trial; and  
• 
Insurance or indemnity to cover the liability of the investigator or Sponsor. 
Therefore the Sponsor will indemnify the Investigators from all and any claims arising 
out of this study except for their negligence or malpractice and providing that the study is 
conducted according to the standards established by the protocol. 
In the event that it can be demonstrated that a subject suffers any significant deterioration 
in health or wellbeing or any harmful susceptibility or toxicity as a direct result of their 
participation in this study then the Sponsor will agree to abide by the current 
ABPI/FDA/Swedish Guidelines with regard to compensation payable to the subject. The 
amount of compensation will be calculated by reference to the level of damages 
commonly awarded in law for similar injuries at the time when such injury occurred. 
The investigators declare to having insurance cover for the malpractice and/or negligence 
of their employees and agents. 
12.8  Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the principal 
investigator or subinvestigator within a reasonable time period after data collection. This 
also applies to records for those patients who discontinue the study early. If a patient 
withdraws from the study, the reason must be noted on the 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 eCRFs exist within an EDC system with controlled access managed by BeiGene or 
its authorized representative for this study. Study staff will be appropriately trained in the 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 101 of 122 
use of eCRFs and applications of electronic signatures before the study start and before 
being given access to the EDC system. Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in 
an electronic audit trail. The investigator attests that the information contained in the 
eCRFs 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 on CD ROMs for 
archiving the data at the study center. 
12.9  Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of receipt 
of each shipment of study product (quantity and condition), patient dispensing records and 
returned or destroyed study product. Dispensing records will document quantities received 
from BeiGene, quantities dispensed to patients, and quantities destroyed or returned to 
BeiGene, including lot number, date dispensed, patient identifier number, patient initials, 
and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the study center’s standard operating 
procedure for study drug disposal/destruction in order to ensure that it complies with 
BeiGene requirements. At the end of the study, following final drug inventory 
reconciliation by the monitor, the study center will dispose of and/or destroy all unused 
study drug supplies, including empty containers, according to these procedures. If the study 
center cannot meet BeiGene’s requirements for disposal, arrangements will be made 
between the study center 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. 
12.10 
Inspections 
The investigator should understand that the facilities used for this trial and all source 
documents for this study should be made available to appropriately qualified personnel 
from BeiGene or its representatives, to IRBs/IECs, or to regulatory authority or health 
authority inspectors. 
12.11 
Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply 
due diligence to avoid protocol deviations and shall report all protocol deviations to 
sponsor. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 102 of 122 
12.12 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be initiated only by BeiGene. All protocol modifications must be submitted to 
regulatory authorities and the IRB/IEC together with, if applicable, a revised model ICF in 
accordance with local requirements. As applicable by local requirements, written 
documentation of regulatory authorities, IRB/IEC and required study center 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 his/her willingness to remain in the study. 
12.13 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the 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 eCRFs. The investigator agrees to cooperate with 
the monitor to ensure that any problems detected in the course of these monitoring visits 
are resolved. 
12.14 
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. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 103 of 122 
13  STUDY MANAGEMENT 
13.1  Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the investigator or study center personnel, as appropriate: 
• 
Return of all study data to the Sponsor 
• 
Data queries 
• 
Accountability, reconciliation, and arrangements for unused study drug(s) 
• 
Review of study records for completeness 
• 
Return of treatment codes to the Sponsor 
• 
Shipment of PK and PD samples to assay laboratories 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely 
discontinue this study either at a single study center or at all study centers at any time for 
reasons including, but not limited to, safety or ethical issues or severe non compliance 
with this protocol, GCP, the clinical study agreement, or applicable laws and regulations. 
If the Sponsor determines such action is needed, the Sponsor will discuss this with the 
investigator (including the reasons for taking such action) at that time. When feasible, the 
Sponsor will provide advance notification to the investigator of the impending action 
prior to it taking effect. 
The Sponsor will promptly inform all other investigators and/or institutions conducting 
the study if the study is suspended or terminated for safety reasons, and will also inform 
the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action. If required by applicable regulations, the investigator must inform the 
IEC/IRB promptly and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the 
Sponsor. In addition, arrangements will be made for all unused study drug(s) in 
accordance with the applicable Sponsor procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the Sponsor. 
13.2  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. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 104 of 122 
The investigator’s study file will contain the protocol/amendments, eCRF and query 
forms, IRB/IEC, and governmental approval with correspondence, ICF, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be 
limited to) the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment 
log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe 
and secure location. The records must be maintained to allow easy and timely retrieval, 
when needed (eg, audit or inspection), and, whenever feasible, to allow any subsequent 
review of data in conjunction with assessment of the facility, supporting systems, and 
personnel. Where permitted by local laws/regulations or institutional policy, some or all 
of these records can be maintained in a format other than hard copy (eg, microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is taken. 
The investigator must assure that all reproductions are legible, are a true and accurate 
copy of the original, and meet accessibility and retrieval standards, including re 
generating a hard copy, if required. Furthermore, the investigator must ensure there is an 
acceptable back up of these reproductions and that an acceptable quality control process 
exists for making these reproductions. 
The Sponsor will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to that study center for the study, as dictated by any 
institutional requirements or local laws or regulations, or the Sponsor’s 
standards/procedures; otherwise, the retention period will default to 15 years. 
The investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to, the following: archival at an off site facility, transfer of 
ownership or responsibility for 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, arrangements must be made between the investigator and BeiGene 
to store these in secure containers outside of the study center so that they can be returned 
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 study center. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 105 of 122 
Biological samples at the conclusion of this study may be retained as outlined in the 
agreement with the CRO managing the biological samples, for the shorter of: a period of 
up to 10 years or as allowed by your IRB/IEC. 
13.3  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 treatment 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 
subjects. 
The Sponsor will not routinely inform the investigator or subject 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. 
13.4  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 subject’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 subject’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. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 106 of 122 
• 
Information which is necessary to disclose in order to provide appropriate medical 
care to a subject. 
• 
Study results which may be published as described in Section 13.4.1.  
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. 
13.4.1 
Publication Policy 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry 
and regulatory guidance, and the need to protect the intellectual property of BeiGene 
(sponsor), regardless of the outcome of the study.  The data generated in this clinical 
study are the exclusive property of the sponsor and are confidential.  As this is a 
multicenter study, the first publication or disclosure of study results shall be a complete, 
joint multicenter publication or disclosure coordinated by the sponsor.  Thereafter, any 
secondary publications will reference the original publication(s).  Authorship will be 
determined by mutual agreement and all authors must meet the criteria for authorship 
established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors 201623). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation in 
accordance with the clinical study agreement.  This allows the sponsors to protect 
proprietary information, provide comments based on information from other studies that 
may not yet be available to the investigator, and ensure scientific and clinical accuracy. 
Each investigator agrees that, in accordance with the terms of clinical study agreement, a 
further delay of the publication/presentation may be requested by the sponsor to allow for 
patent filings and/or protection in advance of the publication/presentation. 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 107 of 122 
14  REFERENCES 
1. 
Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B-cell 
malignancies. Nat Rev Immunol. 2013;13(8):578-91. 
2. 
Ibrutinib approved for mantle cell lymphoma. Cancer Discov. 2014;4(1):OF1. 
3. 
Ibrutinib (Imbruvica) for chronic lymphocytic leukemia. Med Lett Drugs Ther. 
2014;56(1440):29-30. 
4. 
Advani RH et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has 
significant activity in patients with relapsed/refractory B-cell malignancies. J Clin 
Oncol. 2013;31(1):88-94. 
5. 
Byrd JC et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2013;369(1):32-42. 
6. 
Wang ML et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med. 2013;369(6):507-16. 
7. 
Kohrt HE et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated 
cytotoxicity. Blood. 2014;123(12):1957-60. 
8. 
Roit FD et al. Ibrutinib interferes with the cell-mediated anti-tumor activity of 
therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 
2015;100(1):77-86. 
9. 
Investigator’s Brochure Zanubrutinib (BGB-3111). Edition 5. February 2018. 
10. Clinical study protocol (BGB-3111 AU-003): A Phase I, Open Label, Multiple Dose, 
Dose Escalation and Expansion Study to Investigate the Safety and 
Pharmacokinetics of the BTK Inhibitor BGB-3111 in Subjects with B-Cell 
Lymphoid Malignancies. 
11. Gazyva® (obinutuzumab). Safety Information. 
12. GAZYVA® (obinutuzumab) Prescribing Information. Available at 
http://www.gene.com/download/pdf/gazyva_prescribing.pdf.  
13. Burger JA, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with 
rituximab is well tolerated and displays profound activity in high-risk chronic 
lymphocytic leukemia (CLL) patients. 2012 ASH Annual Meeting, December 8-11 
2012, Atlanta, GA, USA. Abstract 187. 
14. Holbrook E Kohrt et al. Ibrutinib (PCI-32765) Antagonizes Rituximab-Dependent 
NK-Cell Mediated Cytotoxicity. 2013 ASH Annual Meeting, Dec. 7-10 2013, New 
Orleans, LA, USA, Abstract 373. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 108 of 122 
15. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment 
of chronic lymphocytic leukemia: a report from the International Workshop on 
Chronic Lymphocytic Leukemia updating the National Cancer Institute Working 
Group 1996 guidelines. Blood. 2008;111(12):5446-5456. 
16. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-
586. 
17. Owen RG et al. Response assessment in Waldenström macroglobulinaemia: update 
from the VIth International Workshop. Br J of Haematol, 2013; 160:171-176. 
18. Common Toxicity Criteria for Adverse Events Version 4.03. Cancer Therapy 
Evaluation Program. 14 June 2010. 
19. Howard SC et al. The tumor lysis syndrome. N Engl J Med. 2011;364:1844-1854. 
20. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, 
indications for treatment, response assessment, and supportive management of CLL. 
Blood. 2018;131(25):2745-60. 
21. Rawstron AC, Fazi C, Agathangelidis A, et al. A complementary role of 
multiparameter flow cytometry and high-throughput sequencing for minimal residual 
disease detection in chronic lymphocytic leukemia: an European Research Initiative 
on CLL study. Leukemia. 2016;30(4):929-36. 
22. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine 
clinical end points in chronic lymphocytic leukemia. J. Clin. Oncol. 2012; 30: 2820. 
23. International Committee of Medical Journal Editors. Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals. 2016. Available online: http://www.icmje.org. 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 109 of 122 
15  PROTOCOL SIGNATURES 
 
 
INVESTIGATOR SIGNATURE 
 
 
PROTOCOL TITLE: 
A Phase 1b Study to Assess Safety, Tolerability and Antitumor 
Activity of the Combination of BGB-3111 with Obinutuzumab 
in Subjects with B-Cell Lymphoid Malignancies 
PROTOCOL NO: 
BGB-3111_GA101_Study_001 
 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study. I also acknowledge that the Sponsor of the study has the right 
to discontinue the study at any time. I have read the protocol and understand it and will 
work according to it and according to the principles of Good Clinical Practices, applicable 
laws and regulations, and the Declaration of Helsinki. 
 
 
 
____________________________________ 
 
           __________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
_______________________________ 
Printed Name 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 110 of 122 
SPONSOR SIGNATURE 
 
 
PROTOCOL TITLE: A Phase 1b Study to Assess Safety, Tolerability and Antitumor 
Activity of the Combination of BGB-3111 with Obinutuzumab 
in Subjects with B-Cell Lymphoid Malignancies 
PROTOCOL NO: 
BGB-3111_GA101_Study_001 
 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study. I also acknowledge that the Sponsor of the study has the right 
to discontinue the study at any time. I have read the protocol and understand it and will 
work according to it and according to the principles of Good Clinical Practices, applicable 
laws and regulations, and the Declaration of Helsinki. 
 
 
 
____________________________________ 
 
___________________ 
 
 
 
 
 
Date 
 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 111 of 122 
16  APPENDIX   
16.1 Appendix 1:  Blood Volume Requirements for the Subjects 
in Part 1 
Time point 
Assessment 
Total blood 
volume (mL) 
Screening 
 
 
Day -28 to Day -1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, IgM level and serum EPG 
5 
 
Pregnancy test 
3.5 
 
Virology 
5 
 
Total 
24 mL 
Cycle 1 Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
PK sampling for zanubrutinib (5 samples x 4 mL)  
20 
 
PD sampling (2 samples x 8 mL)  
16 
 
Total 
43.5 mL 
Cycle 1 Day 2 
 
 
 
PK sampling for zanubrutinib (1 sample x 4 mL)  
4 
 
PK sampling for obinutuzumab (2 samples x 5 mL)  
10 
 
PD sampling (1 sample x 8 mL)  
8 
 
Total 
22 mL 
Cycle 1 Day 3 
 
 
 
PK sampling for obinutuzumab (2 samples x 5 mL)  
10 
 
Total 
10 mL 
Cycle 1 Day 9 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
PK sampling for obinutuzumab (2 samples x 5 mL)  
10 
 
Total 
17.5 mL 
Cycle 1 Day 16 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
PK sampling for obinutuzumab (2 samples x 5 mL)  
10 
 
Total 
17.5 mL 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 112 of 122 
Time point 
Assessment 
Total blood 
volume (mL) 
Cycle 1 Day 23 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 
Cycle 2 to Cycle 6 Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
(where required as per Footnote 15 of Table 1 and 2) 
5 
 
PK sampling for zanubrutinib 
(only on Day 1 of Cycle 2; 5 samples x 4 mL) 
 
20 
 
PK sampling for obinutuzumab  
(only on Day 1 of Cycle 2, Cycle 4 and Cycle 6;  
2 samples x 5 mL) 
10 
 
PD sampling (only on Day 1 of Cycle 2;  
1 sample x 8 mL)     
8 
 
Total 
50.5 mL 
Cycle 2 to Cycle 6 Day 15 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 
Week 25 to Week 48 
 
 
(Every 12 weeks) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
(where required as per Footnote 15 of Table 1 and 2) 
5 
 
Total 
12.5 mL 
Week 48+ 
 
 
(Every 12 weeks1) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
(where required as per Footnote 15 of Table 1 and 2) 
5 
 
Total 
12.5 mL 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 113 of 122 
Time point 
Assessment 
Total blood 
volume (mL) 
Safety Follow-up 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
(where required as per Footnote 15 of Table 1 and 2) 
 
Post-progression Biomarker testing (optional) 
5 
 
 
10 
 
Total 
22.5 mL 
Follow-up Visit 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
(where required as per Footnote 15 of Table 1 and 2) 
5 
 
Total 
12.5 mL 
1. Immunoglobulins and serum EPG assessments will be conducted every 24 weeks until disease 
progression. 
Notes: 
Unscheduled blood samples for pharmacokinetic analysis may also be collected whenever any notable 
safety is seen, to evaluate if the observation is exposure related. 
Cannulation for blood sampling for PK and pharmacodynamics will be performed. Blood will be collected 
via the intravenous cannula predose and at the time points specified in Table 1 and Table 3. A 1 mL blood 
sample will be taken and discarded prior to each blood sample. 
Blood samples (4 mL) should be obtained, when possible, for analysis of plasma zanubrutinib in the event 
of a DLT.   
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.   
Additional blood PK samples will be taken to determine the plasma concentration of zanubrutinib if there is 
an intra-subject dose escalation. The investigator must record the time points for PK sampling and the time 
of dose administration before PK sampling in eCRFs.   


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 114 of 122 
16.2 Appendix 2:  Blood Volume Requirements for the Subjects 
in Part 2 
Time point 
Assessment 
Total blood 
volume (mL) 
Screening 
 
 
Day -28 to Day -1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, IgM level and serum EPG 
5 
 
Pregnancy test 
3.5 
 
Virology 
5 
 
Total 
24 mL 
Cycle 1 Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 
Cycle 1 Day 8 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 
Cycle 1 Day 15 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 
Cycle 2 to Cycle 6 Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
5 
 
PK sampling for zanubrutinib 
(only on Day 1 of Cycle 2; 5 samples x 4 mL) 
20 
 
PK sampling for obinutuzumab  
(only on Day 1Cycle 4 and Cycle 6; 2 samples x 5 mL) 
10 
 
Total 
42.5 mL 
Cycle 2 to Cycle 6 Day 15 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 mL 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 115 of 122 
Time point 
Assessment 
Total blood 
volume (mL) 
Week 25 to Week 48 
 
 
(Every 4 weeks) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
5 
 
Total 
12.5 mL 
Week 48+ 
 
 
(Every 12 weeks1) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
5 
 
Total 
12.5 mL 
Safety Follow-up 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
Post-progression Biomarker testing (optional) 
5 
10 
 
Total 
22.5 mL 
Follow-up Visit 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, IgM level and serum EPG 
5 
 
Total 
12.5 mL 
1. Immunoglobulins and serum EPG assessments will be conducted every 24 weeks until disease 
progression. 
Notes: 
Unscheduled blood samples for pharmacokinetic analysis may also be collected whenever any notable 
safety is seen, to evaluate if the observation is exposure related. 
Cannulation for blood sampling for PK and pharmacodynamics will be performed. Blood will be collected 
via the intravenous cannula predose and at the time points specified in Table 2 and Table 3. A 1 mL blood 
sample will be taken and discarded prior to each blood sample. 
Blood samples (4 mL) should be obtained, when possible, for analysis of plasma zanubrutinib in the event 
of a DLT.   
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.   
Additional blood PK samples will be taken to determine the plasma concentration of zanubrutinib if there is 
an intra-subject dose escalation. The investigator must record the time points for PK sampling and the time 
of dose administration before PK sampling in eCRFs.   


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 116 of 122 
16.3 Appendix 3:  Response Criteria 
Response Definition after Treatment for Patients with CLL 
Parameter 
CR* 
PR* 
PR-L: 
PD* 
Group A 
Lymphadenopathy† 
None > 1.5 cm 
Decrease ≥ 50% 
Decrease ≥ 50% 
Increase ≥ 50% or new lesion 
Hepatomegaly 
None 
Decrease ≥ 50% 
Decrease ≥ 50% 
Increase ≥ 50% 
Splenomegaly 
None 
Decrease ≥ 50% 
Decrease ≥ 50% 
Increase ≥ 50% 
Blood lymphocytes 
< 4000/μL 
Decrease ≥ 50% from baseline 
Decrease < 50% or increase from 
baseline 
** 
Marrow‡ 
Normocellular, < 30% 
lymphocytes, no B-lymphoid 
nodules. Hypocellular marrow 
defines CRi (5.1.6). 
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules 
50% reduction in marrow 
infiltrate, or B-lymphoid nodules 
Group B 
Platelet count 
> 100,000/μL 
> 100,000/μL or increase ≥ 
50% over baseline 
> 100,000/μL or increase ≥ 50% 
over baseline 
Decrease of ≥ 50% from 
baseline secondary to CLL 
Hemoglobin 
> 11.0 g/dL 
> 11 g/dL or increase ≥ 50% 
over baseline 
> 11 g/dL or increase ≥ 50% over 
baseline 
Decrease of > 2 g/dL from 
baseline secondary to CLL 
Neutrophils‡ 
> 1500/μL 
> 1,500/μL or > 50% 
improvement over baseline 
> 1,500/μL or > 50% 
improvement over baseline 
 
CLL = chronic lymphocytic leukemia; CR = complete remission (response); CRi = CR with incomplete bone marrow recovery; PD = progressive disease; PR = partial 
remission (response); PR-L = partial remission (response) with lymphocytosis; SD = stable disease. 
Group A criteria define the tumor load, Group B criteria define the function of the hematopoietic system (or marrow). 
CR*: all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR*: at least two of the criteria of group A (lymphadenopathy, 
splenomegaly, hepatomegaly, or lymphocytes) plus one of the criteria of Group B (platelets, hemoglobin, or neutrophils) have to be met (with the exception of patients who 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 117 of 122 
have only one abnormal group A criteria at baseline, who have to meet one of the criteria of group A plus one of the criteria of Group B); PR-L: presence of lymphocytosis, 
plus ≥ 50% reduction in lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for platelets, hemoglobin, or neutrophils have to be met; SD: is 
absence of progressive disease (PD) and failure to achieve at least a PR; PD: at least one of the above PD criteria has to be met. 
** Note: In the absence of other objective evidence of PD, lymphocytosis alone should not be considered an indicator of PD (Cheson, 2012). 
† Sum of the products of multiple lymph nodes (as evaluated by CT scans, or by physical examination) 
‡ These parameters are irrelevant for some response categories 
 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 118 of 122 
Non-Hodgkin Lymphoma (including SLL; excluding WM) 
 
 
 
 
 
 
Response Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
(a) FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET negative 
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT  
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
(a) FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site (b) Variably FDG-
avid or PET negative; 
regression on CT  
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no increase 
in size of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to 
attain CR/PR 
or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no 
new sites on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
Relapsed 
disease or 
PD 
Any new 
lesion or 
increase by ≥ 
50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s)  
> 1.5 cm in any axis, ≥ 50% 
increase in SPD of more than 
one node, or ≥ 50% increase in 
longest diameter of a previously 
identified node > 1 cm in short 
axis. Lesions PET positive if 
FDG-avid lymphoma or PET 
positive prior to therapy 
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 119 of 122 
Categorical Waldenström’s Macroglobulinemia Response Definitions (Modified Owen 2013) 
Response category 
Definition 
Complete response (CR) 
• Normal serum IgM values  
• Disappearance of monoclonal protein by immunofixation  
• No histological evidence of bone marrow involvement  
• Complete resolution of lymphadenopathy/splenomegaly (if 
present at baseline) a  
Very good partial response (VGPR) 
• Monoclonal IgM protein is detectable 
• ≥90% reduction in serum IgM level from baseline (or normal 
serum IgM level)a 
• Improvement in extramedullary disease,  
 lymphadenopathy/splenomegaly if present at baseline 
• No new signs or symptoms of active disease 
Partial response (PR) 
• ≥50% reduction of serum IgM from baseline 
• Reduction in lymphadenopathy/splenomegaly (if present at 
baseline) a  
Minor response (MR) 
• At least 25% but <50% reduction of serum IgM from baseline  
Stable disease (SD) 
• Not meeting criteria for CR, VGPR, PR, MR, or progressive 
disease  
Progressive disease (PD) 
At least one of the following:  
• Confirmed ≥25% increase in serum IgM and total increase of 
≥500 mg/dL from nadir (on treatment)b,c 
• New lymph nodes >1.5 cm, or ≥50% increase from nadir in SPD 
of >1 node, or ≥50% increase in longest diameter of a previously 
identified node >1 cm in short axis  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 120 of 122 
• New splenomegaly or ≥50% increase from nadir in enlargement  
• New extranodal disease 
• New or recurrent involvement in bone marrow 
• New symptomatic disease 
a For response assessments that occur during cycles where a CT scan is not required then results from prior scans (up to 12 weeks during the first 48 weeks and up to 24 
weeks thereafter) can be carried forward in those subjects with extramedullary disease at baseline 
b Sequential changes (separated by at least 4 weeks) in IgM levels should be determined by the IgM value from the quantitative serum immunoglobulin assay, unless for 
assay limitations this is not possible, in which case the M protein level by densitometry (SPEP) will be used 
c Isolated increase in serum IgM levels during periods of study drug withholding will not be considered as progressive disease unless confirmed by a repeat serum IgM level 
at least 6 weeks after restarting study drug administration and accompanied by a total increase of at least 500mg/dL from lowest nadir.  Please see Guidelines for specific 
clinical or laboratory circumstances below. 
 
Guidelines for specific clinical or laboratory circumstances: 
 
1. Baseline serum total IgM value above the local laboratory limit of quantitation. 
If the baseline local laboratory serum total IgM value exceeds the upper limit of quantitation, the M-protein value, by local assessment, 
will be used for response determination throughout the study. 
 
2. Baseline serum total IgM value, by local assessment, is not interpretable due to technical reasons. 
If the baseline local laboratory serum total IgM value is not interpretable due to technical reasons, the local laboratory serum M-protein 
value will be used of response determination throughout the study. In cases where both the local laboratory total serum IgM and M-protein 
values are not interpretable due to technical reasons, the local serum total IgM (or local M-protein value, in cases where the local serum 
total IgM value exceeds the upper level of quantitation) will be used for response assessment throughout the study.  
 
3. Subjects with documented cryoglobulinemia. 
For these subjects, serum quantitative immunoglobulin and serum immunoelectrophoresis assays should be conducted under warm 
conditions in the local laboratory. The local serum total IgM (or local M-protein value, in cases where the local serum total IgM value 
exceeds the upper level of quantitation) will be used for response assessment throughout the study.  
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 121 of 122 
 
4. Plasmapheresis 
Subjects may undergo plasmapheresis, when clinically indicated, during the first two cycles of study treatment. A pre-plasmapheresis 
serum total IgM and M-protein must be obtained during the screening period, and will serve as the baseline value for response assessment 
throughout the study. Response determination will commence 4 weeks following the last plasmapheresis procedure and will be based upon 
the baseline pre-plasmapheresis serum total IgM or M-protein value (according to the guidelines above). Subjects requiring plasmapheresis 
after cycle 2 will be adjudged to have progressive disease. 
 
5. Assigning Response in the Case of Drug Hold 
Isolated increase in serum IgM levels during periods of study drug withholding will not be considered as progressive disease unless 
confirmed by a repeat serum IgM level at least 10 weeks after restarting study drug administration and accompanied by a total increase of 
≥ 25% increase in serum IgM and at least 500mg/dL from lowest nadir.  Instead a response of “IgM Flare” (IgM-rise of undetermined 
significance) should be selected.  As IgM levels fall, response should be in comparison to the IgM at baseline 
 
6. Missing CT Scans 
During treatment cycles where CT scans are required for subjects with extramedullary disease at baseline that has not resolved, if a CT 
scan is missed it should be performed as soon as possible.  In cases where a single CT scan is missed and the findings remain the same or 
improved from the prior scan, response can be assessed for the intervening cycles using the CT scan obtained prior to the missed CT scan.   
If 2 consecutive CT scans are missed, then the best response that can be assessed during those cycles is an MR (minor response). 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Sponsor:  BeiGene AUS Pty Ltd.  
Version 6.0 
Date 03 January 2019 
 
Protocol Number: BGB-3111_GA101_Study_001 
IND Number:125326 
 
 
 
Page 122 of 122 
16.4 Appendix 4: Transfusion Dependence and Independence 
 

SAP_001.pdf: 
 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 1 of 37  
CONFIDENTIAL 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111_GA101_Study_001 
Study Protocol 
Title: 
A Phase 1b Study to Assess Safety, Tolerability and Antitumor 
Activity of the Combination of BGB-3111 with Obinutuzumab in 
Subjects with B-Cell Lymphoid Malignancies  
Date: 
03Aug2020 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
   


		




 


 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 2 of 37  
CONFIDENTIAL 
 
SIGNATURE PAGE 
Author:  
 
 
 
 
 
Signat
Date: 
 
 
 
 
Approval: 
 
 
 
Signature 
Date: ___
 
 
 
 
Signature 
Date: ___
 
 
 
 
 
Signature 
Date: ___
   


		









 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 3 of 37  
CONFIDENTIAL 
 
TABLE OF CONTENTS 
1 
INTRODUCTION 
9 
2 
STUDY OVERVIEW 
9 
3 
STUDY OBJECTIVES 
11 
3.1 
Part 1 
11 
3.2 
Part 2 
12 
4 
STUDY ENDPOINTS 
12 
4.1 
Part 1 
12 
4.2 
Part 2 
13 
4.3 
Efficacy endpoints for pooled part1 and part2 by disease type Error! Bookmark 
not defined. 
5 
SAMPLE SIZE CONSIDERATIONS 
15 
6 
STATISTICAL METHODS 
16 
6.1 
Analysis sets 
16 
6.2 
Data Analysis General Considerations 
16 
6.2.1 
Definitions and Computations 
18 
6.2.2 
Handling of Missing Data 
18 
6.2.3 
Adjustment for Covariates 
19 
6.2.4 
Multiplicity Adjustment 
19 
6.2.5 
Data Integrity 
19 
6.3 
Subject Characteristics 
19 
6.3.1 
Subject Disposition 
19 
6.3.2 
Protocol Deviations 
20 
6.3.3 
Demographic and Other Baseline Characteristics 
20 
6.3.4 
Disease History 
20 
6.3.5 
Medical History 
22 
6.3.6 
Prior Anti-Cancer Therapies, Radiotherapies, or Surgeries 
22 
6.3.7 
Prior and Concomitant Medications 
22 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 4 of 37  
CONFIDENTIAL 
 
6.4 
Efficacy Analysis 
22 
6.4.1 
Best Overall Response and Response Rates 
23 
6.4.2 
Progression-free Survival 
23 
6.4.3 
Duration of Response 
24 
6.4.4 
Time to Response 
25 
6.4.5 
Overall Survival 
25 
6.4.6 
Subgroup Analyses 
25 
6.4.7 
Other Endpoints 
25 
6.4.7.1 
Hematologic Improvement for CLL 
25 
6.4.7.2 
Minimal Residual Disease Clearance Rate for CLL 
25 
6.4.7.3 
Correlation of Clinical Response with Prognostic and 
Biological Markers 
25 
6.5 
Safety Analyses 
26 
6.5.1 
Extent of Exposure 
26 
6.5.2 
Adverse Events 
27 
6.5.3 
Laboratory Values 
30 
6.5.4 
Physical Examination 
31 
6.5.5 
Echocardiogram 
31 
6.5.6 
Electrocardiograms (ECG) 
31 
6.5.7 
Vital Signs 
31 
6.5.8 
ECOG 
31 
6.5.9 
New Anti-Cancer Therapy 
31 
6.6 
Pharmacokinetic Analyses 
32 
6.7 
Pharmacodynamics Analyses 
32 
6.8 
Other Analyses 
32 
7 
INTERIM ANALYSIS 
32 
8 
CHANGES IN THE PLANNED ANALYSIS 
32 
9 
REFERENCES 
32 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 5 of 37  
CONFIDENTIAL 
 
10 
APPENDIX 
34 
10.1 
Appendix A: Missing Data Imputation Rule 
34 
10.2 
Appendix B: Keyword list of identifying compliance-related zanubrutinib 
dose interruptions 
36 
 
 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 6 of 37  
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AEs 
Adverse events 
AUC 
Area under the plasma concentration-time curve 
BID 
Bis in die (twice a day) 
BMI 
Body mass index 
BTK 
Bruton tyrosine kinase 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed plasma concentration 
CR 
Complete response 
CT 
Computed tomography 
DBP 
Diastolic blood pressure 
DLBCL 
Diffuse large B-cell lymphoma 
DOR 
Duration of response 
eCRF 
Electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FL 
Follicular lymphoma 
GCB 
Germinal center B-cell-like 
GRK 
G-protein coupled receptor kinase 
HCV 
Hepatitis C virus 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 7 of 37  
CONFIDENTIAL 
 
HER 
Human epidermal growth factor receptor 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal residual disease 
MRR 
Major response rate 
MTD 
Maximal tolerated dose 
MZL 
Marginal zone lymphoma 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NHL 
Non-Hodgkin’s lymphoma 
NK 
Natural killer 
ORR 
Overall response rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PFS 
Progression-free survival 
PR-L 
Partial response with lymphocytosis 
QD 
Quaque die (once a day) 
RP2D 
Recommended phase 2 dose 
RT 
Richter’s transformation 
SAEs 
Serious adverse events 
SBP 
Systolic blood pressure 
SLL 
Small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 8 of 37  
CONFIDENTIAL 
 
t1/2 
Terminal half-life 
tmax 
Time to maximum observed plasma concentration 
Vd/F 
Apparent volume of distribution 
WHO-DD 
World Health Organization Drug Dictionary 
WM 
Waldenström’s macroglobulinemia 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 9 of 37  
CONFIDENTIAL 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the detailed plan for the analysis of data used for 
the evaluation of safety and efficacy for the zanubrutinib GA101 Study 001.  This document is 
based on version 6 of the protocol, dated 03 January 2019.   
  
2 
STUDY OVERVIEW 
This is a two-part, phase 1b, multi-center open-label study designed to determine the safety, 
tolerability, and clinical activity of zanubrutinib in combination with obinutuzumab.  The study 
is conducted in two sequential parts.  Part 1 evaluates the safety of two dose regimens of 
zanubrutinib in combination with obinutuzumab.  Part 2 evaluates the antitumor activity of the 
recommended phase 2 dose (RP2D) of zanubrutinib in combination with obinutuzumab in 
subjects with treatment-naïve (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic 
lymphoma (SLL), relapsed/refractory (R/R) CLL/SLL, R/R non-germinal center B-cell (non-
GCB) diffuse large B-cell lymphoma (DLBCL), R/R follicular lymphoma (FL), R/R mantle cell 
lymphoma (MCL), R/R Waldenström macroglobulinemia (WM), or R/R marginal zone 
lymphoma (MZL). 
The study consists of a screening period, treatment, a 28-day safety follow-up, and follow-up for 
disease status and survival.  Subjects who discontinue study drug due to reasons other than 
disease progression are to remain in the study and be followed every 3 months until the subject 
exhibits first progression, withdraws consent, death or study closure, whichever occurs first.  
Once a subject progresses or starts alternative anti-cancer therapy, he/she will be contacted every 
3 months, by telephone, to assess survival until death, withdrawal of consent or study closure, 
whichever occurs first. 
Part 1: Safety Evaluation  
This part of the study evaluated two dose regimens of orally administered zanubrutinib (320 mg 
QD and 160 mg BID [added per Amendment Version 3.0]) in combination with intravenously 
administered obinutuzumab (100 mg IV on Cycle 1 Day 2, 900 mg IV on Cycle 1 Day 3, 1000 
mg IV on Cycle 1 Days 9 and 16, and 1000 mg IV on Day 1 of cycles 2-6) in cohorts of 6 
subjects each.  If there were 2 or more dose-limiting toxicities (DLTs) in a 6-subject cohort in 
either regimen, the dose level was considered to have exceeded the maximum tolerated dose 
(MTD) and a reduced dose level of zanubrutinib (160 mg QD or 80 mg BID) was to be evaluated 
in combination with obinutuzumab in another cohort of 6 subjects.  Further reductions of 
zanubrutinib dose level were allowed until a safe dose combination was identified.  The period 
for DLT assessment was 29 days from first administration of zanubrutinib.  In the event that a 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 10 of 37  
CONFIDENTIAL 
 
MTD was not exceeded, both 320 mg QD and 160 mg BID were to be evaluated for Part 2 of the 
study. 
Zanubrutinib was administered orally with or without food every day in each cycle (29 days for 
Cycle 1 and 28 days for Cycles 2 and each cycle thereafter) until disease progression, death, 
unacceptable toxicity, other reasons for treatment discontinuation, or study closure, whichever 
occured first. 
The continuous safety evaluation was performed by a Safety Monitoring Committee (SMC) 
composed of the Sponsor, the Sponsor’s medical monitor, the coordinating investigator, and the 
contract research organization (CRO) medical monitor.  The SMC composition and 
responsibilities are detailed in the SMC charter.  The SMC was responsible for the determination 
of regimens to be administered during the study. 
At the time of approval of this document, enrollment and dose evaluation of Part 1 has been 
completed.  A cohort of 6 subjects were assigned to both regimens and no DLT was identified in 
either cohort.  
Part 2: Indication Specific Expansion 
In Part 2, the 2 zanubrutinib regimens (320 mg QD and 160 mg BID) were investigated in 5 
expansion cohorts (revised per Amendment Version 4.0) with histology type of tumor defined as 
below.  Based on the safety, tolerability, PK, and antitumor activity data from the safety 
evaluation part (Part 1) of the study: 
• 
Cohort 1: TN CLL/SLL subjects (approximately 20 subjects divided by the 2 regimens) 
• 
Cohort 2: R/R CLL/SLL subjects (approximately 20 subjects divided by the 2 regimens) 
• 
Cohort 3: R/R non-GCB DLBCL, defined by Hans algorithm (approximately 20 subjects 
divided by the 2 regimens)  
• 
Cohort 4: R/R FL, MCL, MZL, and WM (approximately of 20 subjects divided by the 2 
regimens) 
• 
Cohort 5: R/R FL (approximately 40 subjects in 160 mg BID.  About 10-15 of them were 
to meet double-refractory criterion, defined as refractoriness to both rituximab and an 
alkylating agent, whether administered together or in successive treatment regimens.  
Refractoriness was defined per protocol as less than a partial response or progression of 
disease within 6 months after completion of a prior therapy, added per Amendment 
Version 4.0).   
After the SMC confirmed that the 6 subjects in 160 mg BID regimen passed Part 1 DLT test, all 
new eligible subjects were enrolled into 160 mg BID regimen in each of the 5 cohorts until the 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 11 of 37  
CONFIDENTIAL 
 
total number of that cohort reached the pre-specified number.  Subjects enrolled in zanubrutinib 
320 mg QD dose regimen had the option to switch to 160 mg BID.  
Zanubrutinib was administered orally with or without food every day in each cycle (28 days for 
each cycle) until disease progression, death, unacceptable toxicity, other reasons for treatment 
discontinuation, or study closure, whichever occurs first. 
Obinutuzumab was administered intravenously for up to 6 cycles consistent with the 
U.S. label regimen: 
• Day 2 Cycle 1: 100 mg obinutuzumab 
• Day 3 Cycle 1: 900 mg obinutuzumab 
• Day 9 and Day 16 Cycle 1: 1000 mg obinutuzumab 
• Day 1 Cycles 2 to 6: 1000 mg obinutuzumab 
The safety evaluation by the SMC was to be performed on as needed basis (see the SMC 
Charter) but at a minimum of every 6 months to review all subjects enrolled, or when there was 
any significant safety finding. Any treatment-related death would also trigger review by the 
SMC. The SMC would determine whether it is safe to proceed with the study. Approximately 
120 subjects were to be enrolled and treated during Part 2. 
At the time of approval of this document, enrollment of subjects in the 5 expansion cohorts of 
Part 2 was complete and a total of 107 subjects were enrolled into one of the 5 cohorts.  
  
3 
 STUDY OBJECTIVES 
3.1 
PART 1   
Primary Objectives 
 
x To evaluate the safety and tolerability of zanubrutinib in combination with obinutuzumab. 
x To determine the MTD and/or the RP2D of zanubrutinib, in combination with 
obinutuzumab, when given continuously orally.  
Secondary Objectives  
x To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
x To characterize the pharmacokinetics (PK) of zanubrutinib and obinutuzumab when 
administered in combination. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 12 of 37  
CONFIDENTIAL 
 
Exploratory Objectives 
 
3.2 
PART 2 
Primary Objectives 
 
x To assess the preliminary antitumor activity of zanubrutinib in combination with 
obinutuzumab. 
Secondary Objectives  
x To further evaluate the safety and tolerability of zanubrutinib in combination with 
obinutuzumab. 
x To further characterize the PK of zanubrutinib and obinutuzumab when administered in 
combination. 
Exploratory Objectives 
 
4 
STUDY ENDPOINTS 
4.1 
PART 1 
Primary Endpoints 
x Incidence, nature, and severity of adverse events (AEs), serious adverse events (SAEs) 
per the NCI-CTCAE Version 4.03, clinical laboratory abnormalities, deaths and cause of 
death, and DLTs. 
x Incidence of DLTs in Part 1 of the study according to the MTD/RP2D evaluation process. 
Secondary Endpoints 
x For zanubrutinib, area under the plasma concentration-time curve from zero to the last 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 13 of 37  
CONFIDENTIAL 
 
measurable concentration (AUClast), area under the plasma concentration-time curve from 
zero to infinity (AUC), maximum observed plasma concentration (Cmax), time to 
maximum observed plasma concentration (tmax), terminal half-life (t1/2), apparent 
clearance (CL/F), and apparent volume of distribution (Vz/F) on Cycle 1 Day 1 and Cycle 
2 Day 1. 
x For zanubrutinib, after steady-state: AUClast,ss, Cmax,ss, and tmax,ss. 
x For obinutuzumab, plasma concentration prior to start of the infusion, and at 4 hours (end 
of infusion) on Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 9, Cycle 1 Day 16, as well as 
Day 1 Cycles 2, 4, and 6. 
Exploratory Endpoints 
4.2 
POOLED PART 1 AND PART 2 
Primary Endpoint 
x Frequency and durability of objective responses for each of the specified disease cohorts 
as per the standard International Working Group (IWG) Criteria for each diagnose in 
terms of BOR. 
Secondary Endpoints  
      Efficacy Secondary Endpoints 
x Frequency and durability of objective responses for each of the specified disease cohorts 
as per the standard International Working Group (IWG) Criteria for each diagnose in 
terms of PFS, DOR, TTR, and OS. 
      Safety Secondary Endpoints 
x AEs, SAEs per the NCI-CTCAE version 4.03 (or higher), physical examination, and 
laboratory measurements. 
x 
Pharmacokinetic parameters for zanubrutinib and obinutuzumab as described for Part 1, 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 14 of 37  
CONFIDENTIAL 
 
including AUClast, AUC, Cmax, tmax, t1/2, CL/F, Vd/F, AUClast,ss, Cmax,ss, and tmax,ss. 
Exploratory Endpoints 
In addition to the endpoints defined above, the following efficacy endpoints are defined for 
pooled Part 1 and Part 2 subjects for each disease type.  
WM 
Response criteria for subjects with WM are based on modified Response Assessment in WM: 
Update from the VIth International Workshop (Owen, 2013).   
Primary Efficacy Endpoint  
x Rate of VGPR or better  
Secondary Efficacy Endpoints  
x Rate of major response (PR or better)  
x Rate of overall response (MR or better)  
x Duration of VGPR or better, duration of major response, and duration of overall response  
x Time to VGPR or better, time to major response, and time to overall response  
CLL/SLL 
Response criteria for subjects with CLL/SLL are based on Guidelines for the Diagnosis and 
Treatment of CLL (Halleck, 2008) and Novel Targeted Agents and the Need to Refine Clinical 
Endpoints in CLL (Cheson, 2012) for CLL and Modified Lugano Classification for NHL 
(Cheson, 2014) for SLL. 
Primary Efficacy Endpoint  
x Rate of overall response (PR-L or better) 
Secondary Efficacy Endpoint  
x Rate of CR 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 15 of 37  
CONFIDENTIAL 
 
x Rate of PR or better 
x Duration of CR, duration of PR or better, duration of overall response 
x Time to CR, time to PR or better, time to overall response 
x Number and percentage of CLL subjects with anemia (hemoglobin ≤110 ݃/ܮ), 
neutropenia (neutrophil count ≤1.5 × 10ଽ/ܮ), or thrombocytopenia (platelet count ≤
100 × 10ଽ/ܮ) at baseline and among these subjects who achieved hematologic 
normalization after treatment , respectively. 
Exploratory Efficacy Endpoint  
FL and Other B-cell Lymphoid Malignancies (MCL, MZL, non-GCB DLBCL) 
Response criteria for subjects with MCL are based on Modified Lugano Classification for NHL 
(Cheson, 2014). Response criteria for other B-cell lymphoid malignancies are based on the 
modified Lugano classification for NHL (Cheson, 2014). 
Primary Efficacy Endpoint  
x Rate of overall response (PR or better) 
Secondary Efficacy Endpoint  
x Rate of CR 
x Duration of CR and duration of overall response 
x Time to CR and time to overall response 
 
5 
SAMPLE SIZE CONSIDERATIONS 
Part 1 
The number of dose regimens and the emerging zanubrutinib and obinutuzumab toxicities will 
determine the sample size.  It is anticipated that approximately 12 subjects are required to 
establish the selected treatment regimen of zanubrutinib when administered in combination with 
obinutuzumab in Part 1. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 16 of 37  
CONFIDENTIAL 
 
Part 2 
Approximately 120 subjects will be enrolled in the five disease cohorts in Part 2.  The number of 
subjects in each cohort is described in Section 2. Enrollment in certain arms may be closed 
prematurely due to safety intolerability to zanubrutinib at the discretion of Sponsor or SMC. 
 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
Safety Analysis Set 
The safety analysis set will include all subjects who receive at least 1 dose of zanubrutinib and/or 
obinutuzumab.  The safety analysis set will be the primary analysis set for the efficacy and safety 
analyses unless otherwise noted.  
DLT Evaluable Set 
The DLT Evaluable set will include all subjects who experienced a DLT during Cycle 1, or 
subjects who received at least 80% of the planned doses (80%*29*320 mg) of zanubrutinib and 
missed no more than one administration (one full dose) of obinutuzumab during Cycle 1 
(interruption of obinutuzumab infusion does not count as long as the full dose was administered).  
DLT summary will be performed for Part 1 only. 
PK Analysis Set 
The PK analysis set will include all subjects who have received at least the first administration of 
zanubrutinib and provided PK samples as per protocol (without any significant protocol 
deviation affecting the PK blood sample)1 following the first treatment of zanubrutinib on Cycle 
1 Day 1. 
PD Analysis Set 
The PD analysis set will include all subjects who have received at least the first administration of 
zanubrutinib and provided PD samples as per protocol following the first treatment of 
zanubrutinib on Cycle 1 Day 1. 
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
Limited safety and efficacy analysis will be performed by Part 1 and Part 2 separately.    
                                                 
1 Listings of significant protocol deviations affecting the PK blood sample will be provided separately. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 17 of 37  
CONFIDENTIAL 
 
For Part 1, limited safety analyses will be summarized by the following dose level/schedule of 
zanubrutinib administration: 
x 160 mg BID 
x 320 mg QD 
x Part 1 overall. 
For Part 2, limited safety and efficacy analysis by disease type may be performed similarly to the 
pooled part 1 and part 2 set as described below. 
 
Complete safety and efficacy analyses will be performed for the pooled Part 1 and Part 2 set.  
Efficacy and safety will be summarized by the following disease type and status: 
x CLL/SLL 
o R/R 
o TN 
o Overall 
x WM 
x MCL 
x FL 
x MZL 
x DLBCL (including all non-GCB DLBCL and one GCB DLBCL) 2 
x Overall. 
Moreover, for the pooled Part 1 and Part 2 set, safety will be summarized by the following dose 
level/schedule of zanubrutinib administration as well: 
x 160 mg BID 
x 320 mg QD 
                                                 
2 While the disease type GCB DLBCL was not allowed by the protocol, one subject with this diagnosis was enrolled, treated, and 
followed for efficacy and safety. This subject will be combined with non-GCB DLBCL subjects in the efficacy and safety 
analyses and specified in a footnote.  
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 18 of 37  
CONFIDENTIAL 
 
x Part 1 and Part 2 overall. 
A subject will be included in the dose level/schedule group per the first dose received unless 
otherwise specified. 
Descriptive statistics include n, mean, standard deviation, median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum for continuous variables and n (%) for categorical 
variables.  
DLT (if any) will be summarized by dose schedule.  
All calculations and analyses will be conducted using SAS® (SAS Institute Inc., Cary, NC, 
USA) version 9.3 or above. 
6.2.1 Definitions and Computations 
Study treatment for this study is zanubrutinib and/or obinutuzumab. 
Study day is calculated relative to the date of the first administration of either study treatment.  
For assessments conducted on or after the date of the first administration of study treatment, 
study day will be calculated as assessment date – date of first administration + 1.  For 
assessments conducted before the date of the first administration of study treatment, study day is 
calculated as assessment date – date of first administration.  There is no study day 0.  
Treatment duration is calculated as (date of end of treatment – date of first administration of 
study treatment + 1). 
Baseline is defined as the last non-missing value collected on or before the first administration of 
study drug unless otherwise specified.  
Study follow-up time is defined as the time from first dose date to the death date or end of study 
date for patients discontinued from study (whichever occurs first), or the database cutoff date for 
ongoing patients.  
Definitions of efficacy variables are provided in Section 6.4 and definitions of safety variables 
are provided in Section 6.5. 
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 and 
prior/concomitant medications/procedures.  Specific rules for handling of missing or partially 
missing dates for diagnosis, progression/relapse to prior therapy, adverse events, and 
prior/concomitant medications/procedures are provided in the Appendix A: Missing Data 
Imputation Rule.   
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 19 of 37  
CONFIDENTIAL 
 
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 
calculations unless otherwise specified. 
No imputation of AE grades will be performed. TEAEs with missing CTCAE grade will only be 
summarized in the all-grades column. 
If the assessment of the relationship of an AE to study treatments is missing, then the AE is 
assumed to be related to the study treatment in the safety analysis summary. No imputation will 
be done in the AE listings. 
6.2.3 Adjustment for Covariates 
With possible exception of exploratory analyses, no adjustments for covariates are planned for 
this study. Baseline factors may be included in the models used for these exploratory analyses. 
6.2.4 Multiplicity Adjustment 
No formal hypothesis testing is planned for this study.  Adjustment for multiplicity is not 
planned.   
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 subjects’ relevant outcomes from the clinical database.  All essential data 
should be complete 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. 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The following subject disposition information will be summarized: 
x Number of treated subjects who received any amount of zanubrutinib or obinutuzumab. 
x Number (%) of treated subjects who remained on treatment 
x Number (%) of treated subjects who discontinued treatment 
o Reasons for treatment discontinuation 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 20 of 37  
CONFIDENTIAL 
 
x Number (%) of treated subjects who discontinued study 
o Reasons for study discontinuation 
x Number (%) of treated subjects who remained on study 
The number (%) of treated subjects by country and site, and the study follow-up time will also be 
summarized.   
6.3.2 Protocol Deviations 
Criteria for important protocol deviations will be identified and documented before the database 
lock.  Important protocol deviations will be summarized by deviation category.  A listing of 
important protocol deviations will also be provided.   
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics including the following will be summarized using 
descriptive statistics:  
x Age (years) and age group (<65 vs. ≥65 and <75 vs. t75) 
x Gender 
x Race and ethnicity 
x Height (cm), weight (kg), and body mass index (BMI, kg/m2) 
x Vital signs (blood pressure, pulse, and temperature) 
x Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2) 
6.3.4 Disease History 
The disease characteristics at baseline including the following will be summarized if data 
permits: 
x Prior treatment status (treatment naïve, relapsed/refractory) 
x Time (months) since the initial diagnosis to first dose 
x Bulky disease 
x Disease-related B symptoms 
x Bidimensional measurement of nodal, liver, and spleen 
x Tumor or lymphoid cell infiltration  
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 21 of 37  
CONFIDENTIAL 
 
x Serum immunoglobulin (IgM, IgA, IgG, Serum EPG, Monoclonal IgM by IFE) 
x IgM category (< 40 g/L, ≥ 40 g/L) 
x Hemoglobin and category (≤ 110 g/L, > 110 g/L) 
x Platelet count and category (≤100 x109/L, > 100 x109/L) 
x Absolute neutrophil count and category (≤1.5 x109/L, > 1.5 x109/L) 
x Absolute lymphocytes count 
x For CLL:  
o RAI and Binet clinical stage 
o IgHV mutational status (mutated/unmutated) 
o P53 mutational status (negative, positive [wild type, mutant, unknown, other]) 
o Positive chromosomal abnormalities (17p, 11q, 13q, +12, complex karyotype 
[defined as 3 or more unrelated chromosome abnormalities]) 
x For FL:  
o International Prognostic Index for Follicular Lymphoma risk factors and risk 
category 
o Rituximab-refractory status (refractory, not refractory or unknown) 
o Refractory status to the most recent line of therapy (refractory, not refractory or 
unknown) 
o Progression of disease within 24 months of starting the first line of therapy (yes, 
no or unknown) 
o Progression of disease within 6 months of starting any prior therapy (yes, no or 
unknown) 
o Progression of disease within 12 months of starting any prior therapy (yes, no or 
unknown) 
Refractoriness (including rituximab-refractory) is defined as less than a partial response or 
progression of disease within 6 months after completion of the prior therapy.  
x For DLBCL: International Prognostic Index risk factors and risk category 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 22 of 37  
CONFIDENTIAL 
 
6.3.5 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(version 20.0 or higher).  The number (%) of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by system organ class (SOC) and 
preferred term (PT).   
6.3.6 Prior Anti-Cancer Therapies, Radiotherapies, or 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 2017 or later) preferred 
name: 
x Number of regimens of prior anti-cancer therapies 
x Time (months) from the end of the last line of prior anti-cancer therapy to first dose of 
study drug   
x Best response to the last line of prior anti-cancer therapy 
x Prior anti-cancer radiotherapy  
x Prior anti-cancer surgeries 
6.3.7 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes version March 2017 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.  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 patient’s last dose or 
initiation of a new anti-cancer therapy.  For the purpose of determining if a medication should be 
noted as a concomitant medication, the imputation rules stated in Appendix A: Missing Data 
Imputation Rule will be used.   
The number (%) of subjects reporting prior medications and concomitant medications will be 
summarized by ATC medication class Level 2 and WHO DD preferred name. 
6.4 
EFFICACY ANALYSIS 
The primary summaries of the efficacy data will be performed in the safety analysis set.  The 
response and progression status will be determined by the investigator using the appropriate 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 23 of 37  
CONFIDENTIAL 
 
disease-specific criteria defined in the protocol.  The efficacy endpoints for pooled Part 1 and 
Part 2 by disease type are listed in Section Error! Reference source not found.. 
6.4.1 Best Overall Response and Response Rates 
A subject’s best overall response (BOR) is the best response recorded throughout the study (prior 
to data cutoff).  Subjects without post-baseline disease assessment will be considered as non-
responders. Response rate is a crude proportion of patients with best overall responses in the 
corresponding response categories. Responses after the initiation of any new anti-cancer therapy, 
rollover to LTE or the first occurrence of disease progression will not be considered for the 
analysis of response rate.   
The best overall response (number [%]) will be summarized. Moreover, each response rate with 
corresponding two-sided 95% exact binomial confidence interval (Clopper-Pearson method) will 
also be calculated.     
6.4.2 Progression-free Survival 
Progression-free survival (PFS) is defined as time (in months) from the start of study treatment 
to the first documented disease progression or death (due to any cause), whichever occurs first. 
PFS will be right-censored for subjects who met one of the following conditions: 1) alive and no 
post-baseline disease assessment; 2) disease progression or death after one year since last disease 
assessment; 3) rollover to LTE and 4) alive without disease progression.  For such subjects, the 
primary analysis of PFS will be right-censored according to the convention described in Table 1. 
The censoring rule is based on FDA Guidance for Industry, ‘Clinical Trial Endpoints for the 
Approval 
of 
Cancer 
Drugs 
and 
Biologics’ 
(2018, 
https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-
biologics). 
Table 1: Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression Event 
Outcome 
Alive and no post-baseline disease 
assessment 
Date of the first dose of study drug 
Censored 
Alive and no PD before study 
discontinuation or rollover to LTE 
Date of last disease assessment before 
study discontinuation or rollover to LTE 
Censored 
Death or PD after one year since last 
disease assessment 
Date of last disease assessment 
Censored 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 24 of 37  
CONFIDENTIAL 
 
Death or PD between 2 planned 
disease assessments 
Date of death or PD, whichever occurs 
first 
Event 
Death and no post-baseline disease 
assessment 
Date of death 
Event 
 
Date of last disease assessment is defined as below: 
x For CLL/SLL: date of the last response assessment3, radiographic scan, targeted physical 
exam (liver, spleen, or lymph node), B symptoms assessment, or local hematology lab 
assessment (hemoglobin, platelet, neutrophil, or lymphocyte), whichever is the latest. 
x For WM: date of the last response assessment3 or IgM level test, whichever is later. 
x For all other disease types (FL, MCL, MZL, and non-GCB DLBCL): date of the last 
response assessment3, radiographic scan, or targeted physical exam (liver, spleen, or 
lymph node), whichever is the latest. 
The distribution of PFS, including median and other quartiles and PFS rate at selected timepoints 
such as 12, 24, 36, 48 months, will be estimated using the Kaplan-Meier method.  The 95% 
confidence interval for median and other quartiles of PFS will be generated by using 
Brookmeyer method, whereas the 95% confidence interval for PFS event free rate at landmark 
times will be generated by using the Greenwood formula.  Duration of follow-up for PFS will be 
estimated by the reverse Kaplan-Meier method. Kaplan-Meier curves for PFS will also be 
generated. 
6.4.3 Duration of Response 
Duration of response (DOR) for responders (those whose best response was CR, VGPR, PR, or 
PR-L  depending on the disease type, or other targeted responses) is defined as the time (in 
months) from the date of the earliest qualifying response to the date of PD or death due to any 
cause (whichever occurs earlier).  The dates of progression and censoring will be determined as 
described in Section 6.4.2.  DOR will be analyzed using the same methods as in the analysis of 
PFS. Responses after the initiation of new anti-cancer therapy, rollover to LTE or the first 
occurrence of disease progression will not be considered for the analysis of DOR. 
                                                 
3 Prior to the protocol amendment 6, response assessment frequency after week 48 was at the discretion of the treating 
investigator when there was no sign of disease progression. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 25 of 37  
CONFIDENTIAL 
 
6.4.4 Time to Response 
Time to response (TTR) for responders is defined as time (in months) from the start of the study 
treatment to the date of the earliest qualifying response.  TTR will be summarized by descriptive 
statistics. Responses after the initiation of new anti-cancer therapy, rollover to LTE or the first 
occurrence of disease progression will not be considered for the analysis of TTR. 
6.4.5 Overall Survival 
Overall survival (OS) is defined as the time (in months) from the date of the start of the study 
treatment to death due to any cause.  Subjects who remained alive before data cutoff or 
discontinuation of the study (discontinued study due to reasons other than death) will be 
censored at subject’s last known alive date on or prior to data cutoff. OS will be analyzed using 
the same methods as in the analysis of PFS.      
6.4.6 Subgroup Analyses 
The primary and selected secondary endpoints for each disease type may be summarized in 
selected subgroups described in Section 6.3.3 and 6.3.4 as appropriate (i.e. when there is 
sufficient number of patients in the subgroup, otherwise relevant subgroups may be combined).   
6.4.7 Other Endpoints 
The following analyses may be performed if found to be necessary and data permits. 
6.4.7.1 Hematologic Improvement for CLL 
Number and percentage of CLL subjects with anemia (hemoglobin ≤110 ݃/ܮ), neutropenia 
(absolute neutrophil count ≤1.5 × 10ଽ/ܮ), or thrombocytopenia (platelet count ≤100 ×
10ଽ/ܮ) at baseline and among these subjects who achieved hematologic normalization after 
treatment will be estimated respectively along with corresponding 95% exact binomial CI. 
Hematologic normalization refers to hemoglobin, absolute neutrophil count, or platelet count 
goes beyond 110 ݃/ܮ, 1.5 × 10ଽ/ܮ, 100 × 10ଽ/ܮ, respectively. 
6.4.7.2 Minimal Residual Disease Clearance Rate for CLL 
The minimal residual disease (MRD) clearance rate, defined as the proportion of subjects who 
achieved negative MRD status after treatment, will be estimated with 95% exact binomial 
confidence interval for CLL/SLL subjects who achieved a CR and had MRD tested.   
6.4.7.3 Correlation of Clinical Response with Prognostic and Biological Markers 
The correlation of clinical response to zanubrutinib in combination with obinutuzumab with 
established prognostic (e.g., International Prognostic Index for DLBCL, adverse cytogenetics for 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 26 of 37  
CONFIDENTIAL 
 
CLL) and biological markers (genomic alterations in non-GCB DLBCL) for the specific 
histology may be explored using logistic regression.   
Other exploratory efficacy analyses will be based on review of the available efficacy, 
pharmacokinetic (PK), and pharmacodynamic (PD) data.  Further analyses to the PK, PD, and 
biomarkers data will be specified in a separate analysis plan. 
6.5 
SAFETY ANALYSES 
All safety analyses will be provided for the safety analysis set.  In addition to the study groups 
described in Section 6.2 summaries will be provided for the overall group combining all subjects 
in Part 1 and 2. 
6.5.1 Extent of Exposure 
The following measures of the extent of study drug exposure will be summarized: 
x Starting dose and schedule of zanubrutinib 
x Number (%) of subjects with dose reduced, drug interrupted (due to compliance issues, 
due to non-compliance issues4), and the corresponding reasons for zanubrutinib 
x Number (%) of subjects with dose interrupted (full dose administered, full dose not 
administered) and the corresponding reasons for obinutuzumab  
x Number of treatment cycles for zanubrutinib and obinutuzumab respectively 
x Duration of study treatment in week for zanubrutinib, obinutuzumab, and a combination 
of zanubrutinib and obinutuzumab, respectively 
x Cumulative dose of study treatment (mg) administered for zanubrutinib and 
obinutuzumab respectively 
x Actual dose intensity (ADI, mg/day) and relative dose intensity (RDI, mg/day) of 
zanubrutinib  
x ADI (mg/infusion) and RDI (mg/infusion) of obinutuzumab  
Number of treatment cycles for zanubrutinib is defined as (duration of zanubrutinib treatment in 
days)/29 if duration of zanubrutinib treatment in days <= 29, and 1 + (duration of zanubrutinib 
treatment in days-29)/28 if duration of zanubrutinib treatment in days > 29. Duration of 
                                                 
4 A list of key word search will be used to identify whether the interruption of zanubrutinib was due to compliance issues or not. 
The list of key words will be provided in the appendix. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 27 of 37  
CONFIDENTIAL 
 
zanubrutinib treatment in days is defined as the last zanubrutinib administration date – the first 
zanubrutinib administration date + 1. 
Number of treatment cycles for obinutuzumab is defined as the number of cycles where patients 
received any amount of obinutuzumab.  
Duration of zanubrutinib/obinutuzumab/combination in week is defined as (the last zanubrutinib/ 
obinutuzumab/ combination administration date – the first zanubrutinib/ obinutuzumab/ 
combination administration date + 1)/7. 
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 ADI of obinutuzumab is defined as the cumulative dose (mg) of obinutuzumab divided by 
the actual number of infusions of obinutuzumab.  
The RDI of obinutuzumab is defined as the ratio of ADI (mg/infusion) of obinutuzumab and the 
PDI (mg/infusion) of obinutuzumab, which is (8000/9) mg/infusion. 
6.5.2 Adverse Events  
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 and within 30/90 days after the 
last dose of zanubrutinib/obinutuzumab or prior to the initiation of new anti-cancer therapy, 
whichever is sooner.   
A treatment-related adverse event is an adverse event that is noted by the investigator as related 
to zanubrutinib or obinutuzumab. 
AEs will be graded by the investigators using CTCAE v4.03.  The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events will be coded to 
the MedDRA (Version 20.0 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database.   
TEAE will be summarized based on the number (%) of subjects experiencing events by 
MedDRA SOC and PT.  A subject reporting the same AE more than once will be counted only 
once when calculating incidence 1) within a given SOC, and 2) within a given SOC and PT 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 28 of 37  
CONFIDENTIAL 
 
combination.  For such cases, the maximum CTCAE toxicity grade and strongest causal 
relationship to zanubrutinib for the event will be used in the incidence calculations.  
An overall summary of the number and percentage of subjects will be presented for the 
following categories: 
x With at least one TEAE 
x With at least one grade 3 or higher TEAE  
x With at least one treatment-related TEAE, defined as related to zanubrutinib or 
obinutuzumab by the investigator 
x With at least one zanubrutinib-related TEAE 
x With at least one obinutuzumab-related TEAE 
x With at least one infusion-related TEAE 
x With at least one treatment-related grade 3 or higher TEAE 
x With at least one zanubrutinib-related grade 3 or higher TEAE 
x With at least one obinutuzumab-related grade 3 or higher TEAE 
x With at least one infusion-related grade 3 or higher TEAE 
x With at least one fatal TEAE 
x With at least one treatment-related fatal TEAE 
x With at least one zanubrutinib -related fatal TEAE 
x With at least one obinutuzumab-related fatal TEAE 
x With at least one infusion-related fatal TEAE 
x With at least one SAE 
x With at least one treatment-related SAE 
x With at least one zanubrutinib-related SAE 
x With at least one obinutuzumab-related SAE 
x With at least one infusion-related SAE 
x With TEAE leading to dose reduction of zanubrutinib 
x With TEAE leading to dose interruption of zanubrutinib 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 29 of 37  
CONFIDENTIAL 
 
x With TEAE leading to dose interruption of obinutuzumab 
x With TEAE leading to discontinuation of zanubrutinib 
x With TEAE leading to discontinuation of obinutuzumab 
x With at least one instance of DLT (no reported) 
Summaries of all above TEAEs will also be provided by SOC and PT. 
Moreover, summaries of all TEAEs, grade 3 or higher TEAEs, treatment-related TEAEs, and 
SAEs will also be provided by PT only and maximum severity. 
An overall summary of the number and percentage of subjects will be presented for the 
following categories: 
x With at least one AE of special interest (AESI) 
x With at least one treatment-related AESI 
x With at least one grade 3 or higher AESI 
x With at least one treatment-related grade 3 or higher AESI 
x With at least one serious AESI 
x With at least one serious treatment-related AESI 
Summaries of all above AESIs will also be provided by SOC and PT. Moreover, summaries of 
all AESIs will also be provided by PT only, and maximum severity.  
Although Protocol V.6 stated that AESIs will be summarized by cycle, but this will not be done 
as it is not part of BeiGene normal procedures and standards. 
An overall summary of death will be presented for the following categories: 
x Total deaths  
x Deaths within 30 days of last dose of study drug 
x Deaths more than 30 days of last dose of study drug 
Causes of death will also be summarized. 
Listings of deaths, SAEs, TEAEs leading to zanubrutinib discontinuation and TEAEs leading to 
obinutuzumab discontinuation will be provided. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 30 of 37  
CONFIDENTIAL 
 
6.5.3 Laboratory Values 
All hematology, serum chemistry, coagulation, and urinalysis results for each subject will be 
presented in data listings.  The baseline value, post-baseline value and change from baseline for 
all hematology, serum chemistry, and coagulation parameters will be summarized at each 
scheduled visit. 
Selected laboratory test results will be assigned toxicity grades using the IWCLL 2008 Grading 
Scale (Hallek et al 2008) for hematological toxicity in CLL/SLL patients and NCI CTCAE 4.03 
for hematological toxicities in non-CLL/SLL patients and non-hematological toxicities of all 
patients.  The laboratory parameters of interest for these summaries are (if available): 
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. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 31 of 37  
CONFIDENTIAL 
 
Shift tables assessing the toxicity grade at baseline versus worst toxicity recorded post-baseline 
will be presented.  A summary of the number (%) of subjects 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 will 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.   
6.5.4 Physical Examination 
Physical examination results will be listed without summary.   
6.5.5 Echocardiogram  
The overall evaluation and left ventricular ejection fraction (LVEF, %) at screening will be listed 
without summary.   
6.5.6 Electrocardiograms (ECG) 
The baseline value, post-baseline value and change from baseline for the PR, QRS, and QTc-B 
interval will be summarized at each scheduled visit.   If triplicate readings are recorded at one 
visit the average of the readings for the visit will be used for the summary. It’s expected that 
there may be a decrease in ECG testing implemented, based on the reduced ECG requirements in 
Protocol Amendment 6. 
6.5.7 Vital Signs 
The baseline value, post-baseline value and change from baseline for vital sign results including 
blood pressure, pulse, and temperature will be summarized at each scheduled visit. If triplicate 
readings are recorded at one visit the average of the readings for the visit will be used for the 
summary. Any clinically significant values will be reported by the investigator as AEs in the 
clinical study database. 
6.5.8 ECOG 
ECOG performance status will be summarized and listed at each visit.  Shift tables assessing the 
ECOG performance status at baseline versus worst performance status post-baseline will be 
presented.   
6.5.9 New Anti-Cancer Therapy 
The number and percentage of subjects with at least one new anti-cancer therapy, and number of 
new anti-cancer treatments will be summarized. The initiation date of new anti-cancer therapy 
will be the earliest date of any new anti-cancer treatment, any new anti-cancer radiology, and any 
new anti-cancer surgery, taking from these 3 CRF forms: “Anti-cancer treatment on 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 32 of 37  
CONFIDENTIAL 
 
(SURVIVAL) follow up”, “Anti-cancer Radiology on (SURVIVAL) follow up”, and “Anti-
cancer Surgery on (SURVIVAL) follow up”. 
6.6 
PHARMACOKINETIC ANALYSES 
Calculations of pharmacokinetic parameters will be delivered separately.  
6.7 
PHARMACODYNAMICS ANALYSES 
A pharmacodynamics report with raw and analyzed data will be provided separately.  
6.8 
OTHER ANALYSES 
The methods for the summary and analysis of the BTK inhibition activity of zanubrutinib in 
PBMCs via BTK occupancy assay will be provided in a separate document.   
The methods for the summary and analysis of the BTK inhibition activity of obinutuzumab in 
PBMCs via BTK occupancy assay will be provided in a separate document.   
The methods for the summary and analysis of potential resistance biomarkers will be provided in 
a separate document.   
7 
Interim Analysis 
No formal interim analyses are planned for this study.  Data from the individual dose escalation 
cohorts in Part 1 of the study were reviewed by the study monitoring committee at the end of the 
DLT observation period for each cohort. No DLT was found in either regimen.  Summaries and 
analyses of subsets of the study data were performed on a periodic basis for submission to 
professional meetings and for internal decision-making.   
8 
Changes in The Planned Analysis 
This SAP provides more detail on the statistical methods than is provided in the protocol. The 
efficacy endpoints for combined Part 1 and Part 2 cohorts which were not defined in the protocol 
were added to the SAP.  
9 
References 
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. 
Cheson, B.D., et al. Novel Targeted Agents and the Need to Refine Clinical End Points in 
Chronic Lymphocytic Leukemia. Journal of Clinical Oncology, 2012; 30(23): 2820-2822. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 33 of 37  
CONFIDENTIAL 
 
Fleiss, J.L.  Statistical Methods for Rates and Proportions, Second Edition, 1981, New 
York: John Wiley & Sons, Inc. 
Hallek, B.D., et.al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute–Working Group 1996 guidelines. Blood, 2008; 
111(12):  5446–5456. 
Owen, R.G., et.al. Response assessment in Waldenström Macroglobulinaemia: Update from 
the VIth International Workshop, British Journal of Haematology, 2013; 160(2): 171-176. 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 34 of 37  
CONFIDENTIAL 
 
10 Appendix 
10.1 APPENDIX A: MISSING DATA IMPUTATION RULE  
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: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
If end date of a medication is missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x 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 adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent.  When in doubt, the adverse event 
will be considered treatment emergent by default.  The following rules will be applied to impute 
partial dates for adverse events: 
If start date of an adverse event is missing, impute as follows: 
x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 35 of 37  
CONFIDENTIAL 
 
x If day is missing and month and year = month and year of treatment start date, then set to 
treatment start date 
x If day is missing and month and year ≠ month and year of treatment start date, then set to 
first day of the month 
x If start date is completely missing, set to treatment start date as long as adverse event end 
date is not before treatment start date. 
If end date of an adverse event is missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If end date is completely missing, do not impute. 
A.3 Deaths 
In case only the day of a death date is missing, the death will be assumed to be on the 1st date of 
the month if the last date of subject known to be alive is earlier that the 1st date of the month, 
otherwise the death date will be assumed to be on 1 day after the last date of subject known to be 
alive. 
A.4 New Anti-Cancer Therapy 
If the start day of a new anti-cancer treatment, radiotherapy, or surgery is incomplete or missing, 
impute as follows: 
x If only day is missing, then the imputed day will be the first day of the month. 
x 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: 
x If both month and day are missing, then set to January 01. 
x If only day is missing, then set to the first of the month. 
x If a diagnosis date or progression date is completely missing, do not impute. 
A.6 Prior Therapies, Radiotherapies, or Surgeries 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 36 of 37  
CONFIDENTIAL 
 
If a prior therapy, radiotherapy, or surgery date is missing, impute as follows:  
x If only day is missing, then set to the 15th of the month.  
x No imputation will be performed for all other types of missing dates. 
10.2 APPENDIX B: KEYWORD LIST OF IDENTIFYING COMPLIANCE-RELATED ZANUBRUTINIB 
DOSE INTERRUPTIONS   
The following keywords will be used in the search of the “Dose Adjustment Reason” field (free-
text) on the “BGB-3111 Administration” CRF when “Drug interrupted” was selected in the 
previous field in order to identify zanubrutinib interruptions due to compliance issues. Since the 
list was created by examining the real data, it may be modified until the final database lock.  
 COMPLIANCE 
 ERROR 
 
MISS 
 MISSING 
 MISSED 
o But if the words “MISS/MISSING/MISSED” and “ELECTIVE” are in the same 
phrase this is not a compliance issue and should not be included 
o But if the words “MISS/MISSING/MISSED” and “INFECTION” are in the same 
phrase this is not a compliance issue and should not be included 
 SKIP 
 SKIPPED 
 FORGOT 
 FORGOTTEN 
 
DID NOT TAKE 
 DIDN’T TAKE 
 NOT TAKEN 
o But if the words “DID NOT TAKE/DIDN’T TAKE/NOT TAKEN” and 
“CONSTIPATION” are in the same phrase this is not a compliance issue and 
should not be included 
 ACCIDENTALLY TOOK 
 RAN OUT 
 RUN OUT 
 RUNNING OUT 
 SELF ADMINISTER 
 SELF ADMINISTERED 
 TRAVELING 
   


		






 
BeiGene USA, Inc 
BGB-3111_GA101_Study_001 
(Statistical Analysis Plan) 
 
 
Version Draft: 03Aug2020 
 
 
Page 37 of 37  
CONFIDENTIAL 
 
 OUT OF TOWN 
 
The following are to be picked out as compliance issues if they match exactly: 
 PATIENT TOOK MORNING DOSE 
 PATIENT ONLY TOOK MORNING DOSE 
 PATIENT TOOK EVENING DOSE 
 PATIENT ONLY TOOK EVENING DOSE 
 
 
 
   


		



