Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma CLL SLL relapsed refractory
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 652
Healthy volunteers: no

Brief summary:
This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed description:
This is a global, Phase 3, randomized study of zanubrutinib versus ibrutinib in 652 participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

The primary efficacy endpoint is overall response rate determined by investigator assessment. Participants were randomized in a 1:1 manner to either zanubrutinib or ibrutinib. Treatment with zanubrutinib and ibrutinib was open label.

Arms:
arm 1: Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy. arm 2: Participants received Ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

Interventions: intervention 1: Zanubrutinib intervention 2: Ibrutinib
Intervention descriptions: intervention 1: 160 mg orally twice daily intervention 2: Ibrutinib 420 mg orally once daily

Protocol document:
SAP_002.pdf: 
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CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-305 
Study Protocol 
Title: 
A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) 
Compared with Ibrutinib in Patients with Relapsed/Refractory 
Chronic Lymphocytic Leukemia or Small Lymphocytic 
Lymphoma 
Date: 
March 12, 2021  
Version: 
Final 1.0 
NCT Number
NCT03734016


 
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SIGNATURE PAGE 
 
 
 
Approval 
 
 
Director, Biostatistics 
 
 
 
 
Signature
Date: __
 
Vice President, Global Statistics and 
Data Science 
 
 
 
 
Signatur
Date: __
 
Chief Medical Officer 
 
 
 
 
Signature
Date: ___
 
Medical Director 
 
 
 
 
Signature
Date: ___


 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
10 
2 
STUDY OVERVIEW 
10 
3 
STUDY OBJECTIVES 
12 
3.1 
Primary Objective 
12 
3.2 
Secondary Objectives 
12 
3.3 
Exploratory Objectives 
12 
4 
STUDY ENDPOINTS 
13 
4.1 
Primary Endpoint 
13 
4.2 
Secondary Endpoints 
13 
4.3 
Exploratory Endpoints 
14 
5 
SAMPLE SIZE CONSIDERATIONS 
14 
6 
STATISTICAL METHODS 
15 
6.1 
Analysis Sets 
15 
6.2 
Data Analysis General Considerations 
15 
6.2.1 
Definitions and Computations 
15 
6.2.2 
Handling of Missing Data 
16 
6.2.3 
Adjustment for Covariates 
16 
6.2.4 
Multiplicity Adjustment 
16 
6.2.5 
Data Integrity 
19 
6.3 
Patient Characteristics 
20 
6.3.1 
Patient Disposition 
20 
6.3.2 
Protocol Deviations 
20 
6.3.3 
Randomization Stratification Factors 
21 
6.3.4 
Demographics and Other Baseline Characteristics 
21 
6.3.5 
Disease History and Baseline Disease Characteristics 
22 
6.3.6 
Medical History 
23 
6.3.7 
Prior Systemic Anti-Cancer Therapies 
23 


 
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6.3.8 
Prior and Concomitant Medications, Procedures and Surgeries 
23 
6.4 
Efficacy Analyses 
23 
6.4.1 
Primary Efficacy Analyses 
24 
6.4.2 
Secondary Efficacy Analyses 
27 
6.4.2.1 
Key secondary endpoint: Progression-free Survival per 
investigator assessment 
27 
6.4.2.2 
Key secondary endpoint: Atrial fibrillation/flutter 
incidence 
30 
6.4.2.3 
Other secondary endpoints 
30 
6.4.3 
Sensitivity Analyses 
33 
6.4.4 
Subgroup Analyses 
34 
6.4.5 
Exploratory Efficacy Analyses 
35 
6.5 
Safety Analyses 
35 
6.5.1 
Extent of Exposure 
35 
6.5.2 
Adverse Events 
36 
6.5.3 
Laboratory Values 
38 
6.5.4 
Vital Signs 
39 
6.5.5 
Electrocardiograms (ECG) 
39 
6.5.6 
ECOG Performance Status 
39 
6.6 
Pharmacokinetic Analyses 
40 
7 
INTERIM ANALYSIS 
40 
8 
CHANGES IN THE PLANNED ANALYSIS 
40 
9 
REFERENCES 
41 
10. 
APPENDIX 
43 
Appendix A: Imputation of Missing or Partially Missing Dates 
43 
Appendix B: Derivation of Investigator Disease Assessment Dates 
44 
Appendix C: Derivation of Best Overall Response for CLL 
45 
Appendix D: EORTC QLQ-C30 Scoring 
47 


 
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 LIST OF TABLES  
Table 1.  ORR Monitoring Boundaries 
25 
Table 2.  Date of Progression or Censoring for Progression-free Survival 
28 
Table 3.  Assessment Dates used for Investigator Disease Assessment Date Derivation 
45 
 
 LIST OF FIGURES  
Figure 1.  Flowchart for the Multiplicity Adjustment 
17 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADaM 
Analysis data model 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma concentration time curve 
BID 
Twice a day 
BMI 
Body mass index 
BOR 
Best overall response 
BTK 
Bruton’s tyrosine kinase 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed plasma concentration 
CR 
Complete response 
CRi 
Complete response with incomplete bone marrow recovery 
CSR 
Clinical study report 


 
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CT 
Computed tomography 
DBP 
Diastolic blood pressure 
DIPP 
Data integrity protection plan 
DOR 
Duration of response 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
EDC 
Electronic data capture 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal residual disease 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 


 
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PK 
Pharmacokinetic  
PR 
Partial response 
PR-L 
Partial response with lymphocytosis 
PT 
Preferred term 
Q1, Q3 
First quartile, third quartile 
QD 
Once daily 
QT 
Electrocardiographic interval  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SE 
Standard error 
SLL 
Small lymphocytic lymphoma 
SOC 
System organ class 
SPD 
Sum of products of the perpendicular diameters 
SD 
Stable disease 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event  
tmax 
Time to maximum observed plasma concentration 


 
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TTR 
Time to response 
ULN 
Upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 


 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the detailed plans for the analysis of safety and 
efficacy data for study BGB-3111-305: A Phase 3, Randomized Study of Zanubrutinib (BGB-
3111) Compared with Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic 
Leukemia or Small Lymphocytic Lymphoma.  This SAP describes analyses for Europe and other 
regions outside of the United States and China; analyses for the United States and China will be 
covered in a separate SAP.   
This document is based on the protocol version 3.0 dated 31JAN2020.  The analysis plan for the 
pharmacokinetic and exploratory biomarker analyses are not included in this SAP.   
 
2 
STUDY OVERVIEW 
This is a Phase 3, randomized open-label study of zanubrutinib versus ibrutinib in approximately 
600 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic 
lymphoma (SLL).  The primary efficacy endpoint is overall response rate (ORR), defined as a 
best overall response of partial response (PR) or higher, per investigator assessment.  Disease 
response will be assessed per the “modified” 2008 International Workshop on Chronic 
Lymphocytic Leukemia guidelines (Hallek et al 2008), with modification for treatment-related 
lymphocytosis (Cheson et al 2012) for patients with CLL, and per Lugano Classification for non-
Hodgkin lymphoma (Cheson et al 2014) for patients with SLL.  Rate of response for partial 
response with lymphocytosis (PR-L) or higher will be assessed as a secondary efficacy endpoint.   
The study is broken into three periods for every patient: 
x Screening Period 
x Treatment Period 
x Post-Treatment Period 
o 
End of Treatment Visit 
o 
Long-Term Follow-up 
o 
Survival Follow-up 
Patients will be randomized in a 1:1 manner to one of the following treatment arms: 


 
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x Arm A: Zanubrutinib 160 mg orally twice daily 
x Arm B: Ibrutinib 420 mg orally once daily 
Randomization will be stratified by age (<65 years versus ≥ 65 years), geographic region (China 
versus non-China), refractory status (yes or no), and del17p/TP53 mutation status (present or 
absent).   
Study treatment will be open-label and should continue until disease progression is confirmed by 
independent central review.  The study duration is estimated to be approximately 51 months.   
Assessments to be performed during the study include pharmacokinetics of zanubrutinib; 
disease-related constitutional symptoms; physical examination of the liver, spleen and lymph 
nodes; computed tomography (CT) or protocol allowed alternative imaging modality scan of 
neck, chest, abdomen and pelvis with contrast; bone marrow examination at screening, for 
patients with baseline marrow involvement who meet clinical and laboratory criteria for CR or 
CRi and at time of suspected cytopenic progression; patient-reported outcomes (PRO; European 
quality of life 5-dimensions 5-levels health questionnaire [EQ-5D-5L], European Organisation 
for Research and Treatment of Cancer quality of life cancer core questionnaire [EORTC QLQ-
C30], and, in select countries, an optional device-based evaluation of quality of life and activity 
that patients may consent to); laboratory studies; bone marrow examination; genetic alterations 
in the tumor cells (eg, del 17p, TP53, del 11q, del 13q, trisomy 12 and immunoglobulin variable 
region heavy chain [IGHV] mutation analysis).   
Assessments of safety will include adverse events (AEs), serious adverse events (SAEs), clinical 
laboratory tests, physical examinations, electrocardiograms, ECOG performance status, and vital 
signs. Adverse events will be graded for severity per the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the Grading Scale 
for Hematologic Toxicities in CLL Studies according to Hallek 2008.  An independent Data 
Monitoring Committee will periodically monitor safety data and perform the interim efficacy 
analysis.   
 


 
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3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE 
x To compare the efficacy of zanubrutinib versus ibrutinib as measured by ORR 
determined by investigator 
3.2 
SECONDARY OBJECTIVES 
x To compare the efficacy of zanubrutinib versus ibrutinib as measured by: 
o Progression-free survival (PFS) determined by investigator assessment and 
independent central review 
o ORR determined by independent central review 
o Duration of response (DOR) determined by independent central review 
o DOR determined by investigator assessment 
o Time to treatment failure 
o Rate of PR-L or higher determined by independent central review 
o Overall survival 
o Health Related Quality of Life (HRQoL) 
x To compare the safety of zanubrutinib versus ibrutinib 
3.3 
EXPLORATORY OBJECTIVES 
x To evaluate the correlation between clinical outcomes (eg, ORR, PFS, DOR, overall 
survival, rate of partial response) and the prognostic and predictive biomarkers, including 
minimal residual disease (MRD) 
x To characterize the pharmacokinetics (PK) of zanubrutinib 
 


 
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4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINT 
The primary endpoint is ORR (PR or higher, defined as CR/CRi + PR + nodular PR) per 
investigator assessment using the “modified” 2008 IWCLL guidelines (Hallek et al 2008) with 
modification for treatment-related lymphocytosis (Cheson et al 2012) for patients with CLL and 
per Lugano Classification for non-Hodgkin lymphoma (NHL) (Cheson et al 2014) for patients 
with SLL.   
4.2 
SECONDARY ENDPOINTS 
Key Secondary Endpoints: 
The key secondary endpoints are PFS per investigator assessment and atrial fibrillation/flutter 
incidence.   
PFS is defined as the time from randomization to the date of first documentation of disease 
progression or death, whichever comes first.   
For atrial fibrillation/flutter incidence, patients will be considered as having an atrial 
fibrillation/flutter event if they have a treatment-emergent AE of either “atrial fibrillation” or 
“atrial flutter”.   
Other Secondary Endpoints: 
x ORR by independent central review 
x PFS by independent central review 
x DOR, defined as the time from the date that response criteria are first met to the date that 
disease progression is objectively documented or death, whichever comes first, 
determined by independent central review 
x DOR by investigator assessment 
x Time to treatment failure, defined as the time from randomization to discontinuation of 
study drug due to any reason 
x Rate of PR-L or higher, defined as the proportion of patients who achieve a CR/CRi + PR 
+ nodular PR + PR-L determined by independent central review 


 
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x Rate of PR-L or higher determined by investigator assessment 
x Overall survival, defined as the time from randomization to the date of death due to any 
cause 
x HRQoL measured by the EQ-5D-5L and EORTC QLQ-C30 questionnaires 
x Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and 
vital signs 
4.3 
EXPLORATORY ENDPOINTS 
x Correlation between clinical outcomes (eg, ORR, PFS, DOR, OS) and the prognostic and 
predictive biomarkers 
x MRD negativity rate 
x PK parameters 
x Self-administered Activity and Quality of Life questionnaire 
 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the primary efficacy analyses for the primary endpoint of 
ORR per investigator assessment.  Assuming a response ratio (zanubrutinib arm / ibrutinib arm) 
of 1.03 (72% / 70%), 600 patients will provide more than 90% power to demonstrate the 
noninferiority of zanubrutinib to ibrutinib at the noninferiority margin of 0.8558 (response ratio) 
and a 1-sided alpha level of 0.025 when there is 1 interim analysis at 69% information fraction.  
The response rate for ibrutinib is approximated from published clinical data (Byrd et al 2019).   
Assuming a hazard ratio (HR) of 0.9 (zanubrutinib arm / ibrutinib arm), 205 PFS events are 
required to achieve 80% power at a 1-sided alpha of 0.025 to demonstrate the noninferiority of 
zanubrutinib to ibrutinib at the noninferiority margin of 1.3319 (HR) for the key secondary 
endpoint of PFS per investigator assessment.  If the 600 patients are randomized in a 1:1 ratio to 
the 2 arms over a 24-month period, including a 9-month ramp-up period before reaching peak 
enrollment of 33 patients/month with a 0.0017/month hazard rate for dropout, 205 PFS events 
are expected to accumulate in 45 months from study start.  A median PFS of 47 months for 
ibrutinib and an exponential distribution for PFS are also assumed.   


 
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6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
The Intent to Treat (ITT) Analysis Set includes all randomized patients.   
The Safety Analysis Set includes all patients who received any dose of study drug.  The Safety 
Analysis Set will be used for all safety analyses.   
The Per-protocol Analysis Set includes patients who received any dose of study drug and had no 
critical protocol deviation.  Categories of critical protocol deviations are defined in Section 6.3.2.   
Criteria for exclusion from the Per-protocol Analysis Set will be determined and documented 
before the database lock for the interim analysis of the primary endpoint.   
The PK Analysis Set includes all zanubrutinib-treated patients who have at least one post dose 
drug concentration measured.   
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
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.   
If an event date (eg, AE onset date) is partial or missing, the date will appear partial or missing in 
the listings.   
All calculations and analyses will be conducted using SAS version 9.2 or higher. 
6.2.1 Definitions and Computations 
Study treatment (study drug): Study drug for this study is zanubrutinib or ibrutinib. 
Study day: Study day will be calculated relative to the date of the first dose of study drug (study 
day 1).  For patients not dosed, the randomization date will be used instead of the first dose date.  
For assessments conducted on or after the date of first dose of study drug, study day will be 
calculated as (assessment date – date of first dose of study drug + 1).  For assessments conducted 
before the date of the first dose of study drug, study day is calculated as (assessment date – date 
of first dose of study drug).  There is no study day 0.   


 
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Treatment duration: The treatment duration will be calculated as (date of last dose of study drug 
– date of first dose of study drug + 1).   
Baseline: the baseline value or assessment is defined as the last non-missing value or assessment 
before the first dose of study drug or before randomization for patients not dosed.   
Postbaseline: a postbaseline value or assessment is defined as a value or assessment after the first 
dose of study drug or after randomization for patients not dosed.   
6.2.2 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified.  Missing dates or partially missing 
dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures as provided in Appendix A: Imputation of Missing or Partially Missing 
Dates.  Missing data for the health-related quality-of-life (HRQoL) data will be handled 
according to each PRO instrument manual (Fayers & Machin, 2000 in The EORTC QLQ-C30 
(Third Edition), 2001; https://euroqol.org/publications/user-guides/).   
Missing longitudinal data analyses may employ the missing-at-random (MAR) assumption such 
as described for QLQ-C30 scores over time in Section 6.4.2.3.9.   
Time-to-event data analyses will have associated censoring rules as described for PFS in Section 
6.4.2.1.   
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.   
6.2.3 Adjustment for Covariates 
Stratified analysis will be performed to adjust for important baseline covariates for the primary 
and some secondary endpoints. Details of the stratified analyses are provided in Section 6.4. 
6.2.4 Multiplicity Adjustment 
To control the study-wide type I error, individual significance levels will be adjusted for the tests 
of the primary endpoint of ORR per investigator assessment (noninferiority and superiority), and 


 
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the key secondary endpoint of PFS per investigator assessment (noninferiority and superiority).  
Multiplicity due to multiple endpoints and multiple tests will be handled per the graphical 
approach by Maurer and Bretz (2013) utilizing fixed sequence hierarchical testing.  Under this 
procedure, secondary endpoints will be tested only if the primary endpoint is significant.   
If the noninferiority of ORR per investigator assessment is statistically significant, the key 
secondary endpoint of atrial fibrillation/flutter incidence will be tested at the interim and final 
analyses of ORR with the same 1-sided significance levels as ORR but will be tested separately 
from the fixed sequence hierarchical testing.   
Hypothesis testing will be performed according to the multiplicity adjustment flowchart shown 
in Figure 1.   
Figure 1.  Flowchart for the Multiplicity Adjustment 
 
Per the testing sequence in Figure 1, the study-wide 1-sided significance level of 0.025 will be 
passed to subsequent hypothesis tests in the sequence and will be distributed for each of the 
following potential analysis timepoints based on the known correlation of the interim and final 
test statistics and corresponding alpha spending function: 
x interim analysis of ORR 
o 
noninferiority of ORR per investigator assessment is tested at a 1-sided 
significance level of 0.005 based on the O’Brien-Fleming alpha spending function 


 
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with an information fraction of 64% (415 divided by 652, total number of 
randomized patients); if this is not statistically significant, do not conduct any of 
the remaining hypothesis tests at this analysis timepoint and continue to the final 
analysis of ORR 
o 
if the noninferiority of ORR per investigator assessment is statistically significant, 
the superiority of ORR per investigator assessment will be tested at a 1-sided 
significance level of 0.005 based on the O’Brien-Fleming alpha spending function 
with an information fraction of 64%; if this is not statistically significant, continue 
to the final analysis of ORR for additional hypothesis testing starting with the 
superiority of ORR per investigator assessment 
o 
if the superiority of ORR per investigator assessment is statistically significant at 
the interim analysis, PFS per investigator assessment will be compared between 
the two treatment arms for descriptive purposes only, but not for statistical 
inference (for either non-inferiority or superiority) at this interim analysis.  A 1-
sided 0.00001 significance level will be spent to account for the increased false 
positive rate due to this descriptive analysis.   
x final analysis of ORR 
o 
if the noninferiority of ORR per investigator assessment was not statistically 
significant at the interim analysis of ORR,  
1. 
noninferiority of ORR per investigator assessment will be tested at a 1-
sided significance level of 0.0235; if this is not statistically significant, the 
study does not meet the primary objective and no additional hypothesis 
testing will be performed in this study 
2. 
if the noninferiority of ORR per investigator assessment is statistically 
significant, the superiority of ORR per investigator assessment will be 
tested at a 1-sided significance level of 0.0235; if this is not statistically 
significant, no additional hypothesis testing will be performed in this study 
3. 
if the superiority of ORR per investigator assessment is statistically 
significant, PFS per investigator assessment will be compared between the 
two treatment arms for descriptive purposes only, but not for statistical 


 
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inference (for either non-inferiority or superiority).  A 1-sided 0.00001 
significance level will be spent to account for the increased false positive 
rate due to this descriptive analysis.   
o 
if the noninferiority of ORR per investigator assessment was statistically 
significant but the superiority of ORR per investigator assessment was not 
significant at the interim analysis of ORR 
1. 
the superiority of ORR per investigator assessment will be tested at a 1-
sided significance level of 0.0235; if this is not statistically significant, no 
additional hypothesis testing will be performed in this study 
2. 
if the superiority of ORR per investigator assessment is statistically 
significant, PFS per investigator assessment will be compared between the 
two treatment arms for descriptive purposes only, but not for statistical 
inference (for either non-inferiority or superiority).  A 1-sided 0.00001 
significance level will be spent to account for the increased false positive 
rate due to this descriptive analysis. 
x final analysis of PFS 
o 
if the superiority of ORR per investigator assessment is statistically significant at 
either the interim or final analysis of ORR, PFS per investigator assessment will 
be followed further until 205 PFS events per investigator assessment have 
occurred for the final PFS analysis; noninferiority of PFS per investigator 
assessment will be first tested at a 1-sided significance level of 0.02498 
o 
if the noninferiority of PFS per investigator assessment is statistically significant, 
the superiority of PFS per investigator assessment will be tested at a 1-sided 
significance level of 0.02498.   
   
6.2.5 Data Integrity 
Before pre-specified statistical analysis begins, the integrity of the data should be reviewed to 
assure fit-for-purpose.  The data set for analysis should be an accurate and complete 
representation of the patients’ relevant outcomes from the clinical database.   All essential data 


 
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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.   
Though the study is open-label, access to study data is controlled for specific sponsor study team 
members overseeing the conduct of the study or analyzing study data. The sponsor will not have 
access to aggregated efficacy or safety data summaries by treatment arm according to the study’s 
Data Integrity Protection Plan (DIPP).   
6.3 
PATIENT CHARACTERISTICS 
6.3.1 Patient Disposition 
The following patient disposition information will be summarized by treatment arm: 
x 
Number of randomized patients 
x 
Number (%) of treated patients 
x 
Number (%) of treated patients still receiving treatment as of the data cutoff 
x 
Number (%) of treated patients who discontinued treatment and reasons for treatment 
discontinuation 
x 
Number (%) of randomized patients still on study as of the data cutoff 
x 
Number (%) of randomized patients who discontinued study and reasons for study 
discontinuation 
Study follow-up time is defined as the time from the randomization to the death date or the end 
of study date for the patients who discontinued from study (whichever occurs first), or the data 
cutoff date for patients still on study.  Study follow-up time will be summarized descriptively.   
6.3.2 Protocol Deviations 
Important protocol deviations are protocol deviations designated as “Major” or “Significant” per 
the China and the Rest of the World protocol deviation data, respectively.   
Critical protocol deviations will also be identified and used to define the Per-protocol Analysis 
Set.  Critical protocol deviations will be identified before the database lock.  The critical protocol 


 
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deviations will include but are not limited to selected protocol deviations from the following 
categories: 
x Patient randomized even though he/she did not satisfy study eligibility criteria 
x Patient developed study drug withdrawal criteria but was not withdrawn 
x Patient received wrong study treatment or incorrect dose 
x Patient received prohibited concomitant treatment 
Important protocol deviations and critical protocol deviations will be summarized by deviation 
category and by treatment arm. COVID-19-related protocol deviations will be summarized.  A 
listing will also be provided.   
6.3.3 Randomization Stratification Factors 
The number of patients with each of the IRT randomization stratification factors will be 
summarized by treatment arm.  The randomization stratification factors include age (< 65 years 
versus ≥ 65 years), geographic region (China versus non-China), refractory status (yes or no), and 
del17p/TP53 mutation status (present or absent).  In addition, stratification errors (defined as IRT-
based strata vs clinical data-based strata inconsistencies) will be summarized.   
6.3.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics including the following will be summarized by 
treatment arm using descriptive statistics:  
x 
Age (years);  
x 
Age group (< 65 vs  ≥ 65 years); 
x 
Sex; 
x 
Race and ethnicity; 
x 
Geographic region (Asia vs Australia/New Zealand vs Europe vs North America); 
x 
Height (cm), weight (kg), and body mass index (BMI, kg/m2); 
x 
Eastern Cooperative Oncology Group (ECOG) performance status. 


 
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6.3.5 Disease History and Baseline Disease Characteristics 
Baseline disease characteristics including the following will be summarized by treatment arm 
using descriptive statistics: 
x 
Time since initial CLL/SLL diagnosis; 
x 
Disease type (CLL vs SLL); 
x 
Disease stage (Binet stage for CLL; Ann Arbor stage for SLL) at study entry; 
x 
Bulky disease (any target lesion longest diameter ≥ 5 cm; ≥ 10 cm); 
x 
Serum immunoglobulin (IgM, IgA and IgG); 
x 
β2 microglobulin (quantitative and categorical: ≤ 3 mg/L vs  > 3 mg/L); 
x 
Hepatitis B core antibody and hepatitis C virus antibody statuses (positive vs negative); 
x 
Coagulation parameters of prothrombin time, international normalized ratio, and aPTT (< 
LLN vs normal vs > ULN); 
x 
Mutation statuses: del 17p, TP53, trisomy 12, del 11q, del 13q, IGHV; 
x 
Splenomegaly (yes vs no); 
x 
Hepatomegaly (yes vs no); 
x 
Bone marrow involvement (< 30% vs  ≥ 30%); 
x 
ALC; 
x 
Hemoglobin (quantitative and categorical: ≤ 110 g/L vs.  > 110 g/L); 
x 
Platelet (quantitative and categorical: ≤ 100 x 109/L vs.  > 100 x 109/L); 
x 
ANC (quantitative and categorical: ≤ 1.5 x 109/L vs.  > 1.5 x 109/L); 
x 
Any cytopenia (yes: hemoglobin ≤ 110 g/L or platelet count ≤ 100 x 109/L or ANC ≤ 1.5 x 
109/L vs no); 
x 
LDH; 
x 
Prior radiotherapy and prior transplants (yes vs no);  
x 
Disease-related constitutional symptoms. 
Categories of baseline characteristics can be modified depending on the availability of data 
and/or percentage of categories.   


 
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6.3.6 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 20.0 or higher).  The number and percentage of patients reporting a history of any 
medical condition, as recorded on the CRF, will be summarized by system organ class (SOC) 
preferred term (PT), and treatment arm.  A listing of medical history will be provided.   
6.3.7 Prior Systemic Anti-Cancer Therapies 
Number of prior lines of systemic anti-cancer therapies, duration of last therapy, best response of 
last therapy, and time since the end of last therapy will be summarized for prior anti-cancer 
therapy by treatment arm using descriptive statistics.  The therapies with the same sequence/line 
number are counted as one prior line of therapy.  A listing of these therapies will be provided.  
6.3.8 Prior and Concomitant Medications, Procedures and Surgeries 
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 are defined as medications that (1) started before the first dose of the study drug and 
were continuing at the time of the first dose of the study drug, or (2) started on or after the first 
dose date of the study drug up to 30 days after the last dose date or the day prior to initiation of a 
new CLL/SLL therapy, whichever occurs first.   
The number and percentage of patients reporting prior medications and concomitant medications 
will be summarized by ATC medication class Level 2, WHO DD preferred name, and treatment 
arm.  A listing of the prior and concomitant medications will be provided.   
In addition, the number and percentage of patients reporting postbaseline anti-cancer therapies 
will be summarized by WHO DD preferred name, and treatment arm.  The number and 
percentage of patients reporting postbaseline cancer-related surgery or procedures will be 
summarized by treatment arm.  A listing of procedures and surgeries will be provided.   
6.4 
EFFICACY ANALYSES 
Statistical testing will be performed to compare the efficacy of zanubrutinib (Arm A) and 
ibrutinib (Arm B).  For all efficacy analyses, patients will be analyzed according to the treatment 


 
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arm to which they were randomized, and unless otherwise specified, efficacy analyses will be 
performed on the ITT Analysis Set.  At the interim analysis of ORR, ORR, DOR and associated 
descriptive analyses will be performed on the first 415 randomized patients in the ITT Analysis 
Set.   
Dates for investigator disease assessments are derived according to Appendix B, and best overall 
response derivation rules for CLL are derived according to Appendix C.   
ORR, rate of PR-L or higher and rate of CR/CRi will be based on the best overall response 
(BOR), and BOR per investigator assessment and per independent central review will be subject 
to confirmation for CLL patients as detailed in Appendix C and in the separate independent 
review charter.  BOR is defined as the best response from the randomization date to the data 
cutoff date, disease progression or the start of new CLL/SLL therapy, whichever comes first.  
Patients without any postbaseline disease assessment (regardless of the reason) will be 
considered as non-responders.   
Stratified analyses will be based on the randomization stratification factors per IRT unless 
otherwise specified.   
6.4.1 Primary Efficacy Analyses 
The primary hypothesis testing for the primary endpoint of ORR per investigator assessment will 
be to demonstrate the noninferiority of zanubrutinib to ibrutinib.   
Noninferiority testing for ORR 
The null and alternative hypotheses for the noninferiority test are as follows: 
x H0NI: Response ratio (zanubrutinib/ibrutinib) ≤ 0.8558 
x HaNI: Response ratio (zanubrutinib/ibrutinib) > 0.8558 
One interim analysis of ORR will occur approximately 12 months after 415 patients have been 
randomized, and the final analysis of ORR will occur approximately 12 months after 600 
patients have been randomized.   
The monitoring boundaries for the noninferiority test are based on the O’Brien Fleming 
boundary approximated by the Lan-DeMets spending function with an overall 1-sided level of 
0.025.  Hypothesis testing for the noninferiority of ORR at the interim analysis will be based on 


 
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the first 415 randomized patients only and will have a 1-sided significance level of 0.005.  
Hypothesis testing for the noninferiority of ORR at the final analysis will be based on the entire 
ITT Analysis Set and will have a 1-sided significance level based on the actual information 
fraction (or covariance) of the interim and final test statistics.  With 652 patients in the ITT 
Analysis Set at the final analysis, the actual information fraction is 64% (415/652), and the 1-
sided significance level for the final analysis will be 0.0235.   
The noninferiority hypothesis of ORR will be tested at each analysis using a stratified Wald test 
against a null response ratio of 0.8558, and the noninferiority of zanubrutinib to ibrutinib in ORR 
will be considered statistically significant if the 1-sided p-value is less than the 1-sided 
significance level at either the interim or the final analysis of ORR.  The form of the Wald 
statistic (Z) will be as follows: 
ܼ= log (ρ) −log(0.8558)
SE(log (ρ))
 
 
where log(ρ) is the log of the stratified Mantel-Haenszel response ratio estimate and  
SE(log(ρ)) is its corresponding standard error estimate (Greenland and Robins 1985) 
 
Table 1 summarizes the interim and final analysis monitoring boundaries for ORR noninferiority 
and superiority testing with 64% information fraction.   
Table 1.  ORR Monitoring Boundaries 
Analysis Timepoint 
ORR Noninferiority 
ORR Superiority 
1-sided p-value 
boundary 
Approximate 
response ratio 
boundary [1] 
1-sided p-value 
boundary 
Approximate 
response ratio 
boundary [1] 
Interim Analysis of ORR 
0.005 
1.01 
0.005 
1.176 
Final Analysis of ORR 
0.0235 
0.952 
0.0235 
1.105 
[1] Approximate boundary based on assumed ibrutinib ORR of 70%.   
 
Justification of the noninferiority margin for ORR 


 
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A non-inferiority margin of 0.8558 in response ratio was derived using the 95% to 95% fixed 
margin approach (FDA Guidance for Industry Non-Inferiority 2016). In the RESONATE trial 
(Byrd et al 2014), the ibrutinib effect over ofatumumab represented by the ratio of response rate 
(PR or higher) was 10.43 with a 95% CI of (5.2, 21.0) based on the independent review 
committee assessment. Thus, M1 is 5.2, the lower bound of the 95% CI. Since the effect size of 
ibrutinib is versus an active control (ofatumumab), rather than placebo, the choice of M1 is 
conservative, and a non-inferiority margin of 0.8558 (for the response ratio) retains over 90% of 
M1 (on the log scale).   
Superiority testing for ORR 
As described in Section 6.2.4, if the noninferiority in ORR per investigator assessment is 
statistically significant, then the superiority of zanubrutinib to ibrutinib in ORR will be tested.  
The null and alternative hypotheses for the superiority test are as follows: 
x H0SUP: Response ratio (zanubrutinib/ibrutinib) ≤ 1 
x HaSUP: Response ratio (zanubrutinib/ibrutinib) > 1 
The monitoring boundaries for the superiority test are based on the O’Brien Fleming boundary 
approximated by the Lan-DeMets spending function with an overall 1-sided level of 0.025.  If 
hypothesis testing for the superiority of ORR is performed at the interim analysis, it will be 
based on the first 415 randomized patients only and will have a 1-sided significance level of 
0.005.  If hypothesis testing for the superiority of ORR is performed at the final analysis, it will 
be based on the entire ITT Analysis Set and will have a 1-sided significance level that depends 
on the actual information fraction (or covariance) of the interim and final test statistics and will 
be the same 1-sided significance level used for the noninferiority ORR testing (0.0235, 
equivalent to a chi-squared p-value cutoff of 0.0469).   
The superiority hypothesis of ORR will be tested using a stratified Cochran-Mantel-Haenszel 
test, and the superiority of zanubrutinib to ibrutinib in ORR will be considered statistically 
significant if the 1-sided p-value is less than the 1-sided significance level at either the interim or 
the final analysis of ORR.   
Additional descriptive analyses 


 
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The 95% confidence interval (CI) for the response ratio will be constructed using a normal 
approximation.  ORR will be summarized for each treatment arm along with its corresponding 
95% CI.   
Time to response, defined as the time from randomization to the earliest qualifying response, will 
be summarized descriptively for responders only.   
Best overall response (BOR) will be summarized as well.  In addition, the concordance between 
independent central review and investigator assessment of BOR will be summarized.   
The rate of CR/CRi will be summarized for each treatment arm along with its corresponding 
95% CI.   
At the interim analysis of ORR only, the above descriptive analyses will be performed on the 
first 415 randomized patients in the ITT Analysis Set and BOR will also be summarized for the 
entire ITT Analysis Set.   
6.4.2 Secondary Efficacy Analyses  
The key secondary endpoints are PFS per investigator assessment and atrial fibrillation/flutter 
incidence.  For the other secondary endpoints, the tests will be descriptive without multiplicity 
adjustment.   
6.4.2.1 Key secondary endpoint: Progression-free Survival per investigator assessment 
Hypothesis testing for the key secondary endpoint of PFS will first be to demonstrate the 
noninferiority of zanubrutinib to ibrutinib.   
There will be a single analysis of PFS for the purpose of inference when approximately 205 PFS 
events have occurred; however, a 1-sided significance level of 0.00001 will be applied to each of 
the two descriptive analyses of PFS for the interim and final analyses of ORR to compensate for 
the potential type I error increase from the descriptive analysis.  From the time of the ORR 
analyses to the analysis of PFS after 205 events have occurred, the sponsor will continue to 
maintain trial integrity according to the DIPP.   
PFS will be right-censored for patients who meet one of the following conditions: 1) no baseline 
disease assessments; 2) PD or death more than 6 months from the last disease assessment (more 
than 12 months if a patient is on the disease assessment schedule of every 24 weeks); and 3) 
alive without documentation of PD.  The censoring convention generally follows the FDA 


 
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Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(2018) and references within the guidance document. The censoring rules are summarized in 
Table 2.   
 
Table 2.  Date of Progression or Censoring for Progression-free Survival 
Situation 
Date of Progression or Censoring 
Outcome 
Death or PD between the planned 
disease assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Event 
Death before the first disease assessment Date of death 
Event 
No baseline/postbaseline disease 
assessments (and no death) 
Date of randomization  
Censored 
Death or PD more than 6 months [1] 
from the last disease assessment 
Date of the last disease assessment 
before death or PD  
Censored 
Alive without documentation of PD  
Date of last disease assessment  
Censored 
[1] 12 months if a patient is on the assessment schedule of every 24 weeks.   
 
Noninferiority testing for PFS per Investigator Assessment 
The null and alternative hypotheses for the noninferiority test are as follows: 
x H0NI: HR (zanubrutinib/ibrutinib) ≥ 1.3319 
x HaNI: HR (zanubrutinib/ibrutinib) < 1.3319 
At the final analysis of PFS, hypothesis testing for the noninferiority of PFS per investigator 
assessment will be based on the entire ITT Analysis Set using a stratified Wald test and will have 
a 1-sided significance level of 0.02498.  The form of the Wald statistic (Z) will be as follows: 


 
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ܼ= β −log(1.3319)
SE(β)
 
 
where β is the log of the hazard ratio estimate from the stratified Cox proportional  
hazards model and SE(β) is its corresponding standard error estimate 
 
Justification of the noninferiority margin for PFS 
A non-inferiority margin of 1.3319 was derived using the 95% to 95% fixed margin approach 
based on the RESONATE study.  In the updated RESONATE results (Brown et al 2014), the 
estimated PFS HR for ibrutinib versus ofatumumab was 0.106 with a 95% CI of (0.073, 0.153).  
Therefore, the control arm effect (M1) is 0.153 in HR and -1.877 in log HR.  A noninferiority 
margin of 1.3319 for the HR (zanubrutinib/ibrutinib) retains approximately 85% of M1 (on the 
log scale).   
Superiority testing for PFS per Investigator Assessment 
If the noninferiority of zanubrutinib to ibrutinib in PFS per investigator assessment is statistically 
significant, then the superiority in PFS per investigator assessment will be tested.  The null and 
alternative hypotheses for the superiority test are as follows: 
x H0SUP: HR (zanubrutinib/ibrutinib) ≥ 1 
x HaSUP: HR (zanubrutinib/ibrutinib) < 1 
Hypothesis testing for the superiority of PFS per investigator assessment will be based on the 
entire ITT Analysis Set using a stratified log-rank test and will have the same 1-sided 
significance level of 0.02498 (equivalent to a chi-squared p-value cutoff of 0.04996) used for the 
noninferiority PFS testing.   
Additional descriptive analyses 
The HR for PFS and its 95% CI will be estimated from a stratified Cox regression model.   
The distribution of PFS, including the median and other quartiles, and the PFS rate at selected 
timepoints such as 12, 18 and 24 months, will be estimated using the Kaplan-Meier method for 
each treatment arm.  The 95% CI for the median and the other quartiles of PFS will be estimated 
using the Brookmeyer-Crowley method (Brookmeyer and Crowley 1982).  The 95% CI for the 


 
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PFS rate at the selected timepoints will be estimated using the Greenwood formula (Greenwood 
1926).  The duration of follow-up for PFS will be estimated using the reverse Kaplan-Meier 
method (Schemper and Smith 1996).   
Kaplan-Meier curves for PFS will be presented for each treatment arm.  A listing of PFS-related 
information, eg, the date of the progression or censoring and the corresponding reasons, will also 
be provided.   
6.4.2.2 Key secondary endpoint: Atrial fibrillation/flutter incidence 
As described in Section 6.2.4, if the noninferiority of zanubrutinib to ibrutinib in ORR is 
statistically significant, then the superiority of zanubrutinib to ibrutinib in the key secondary 
endpoint of atrial fibrillation/flutter will be tested but separately from the fixed sequence 
hierarchical testing that includes ORR and PFS.  The interim analysis will be performed on the 
Safety Analysis Set restricted to the first 415 randomized patients and according to the actual 
treatment received.  The final analysis will be performed on the Safety Analysis Set according to 
the actual treatment received.   
The monitoring boundaries for the superiority test are based on the O’Brien Fleming boundary 
approximated by the Lan-DeMets spending function with an overall 1-sided level of 0.025.  If 
hypothesis testing for the superiority of the rate of atrial fibrillation/flutter is performed at the 
interim analysis, it will have a 1-sided significance level of 0.005 (equivalent to a chi-squared p-
value cutoff of 0.0099).  If hypothesis testing for the superiority of the rate of atrial 
fibrillation/flutter is performed at the final analysis, it will have a 1-sided significance level of 
0.0235 (equivalent to a chi-squared p-value cutoff of 0.0469).   
Hypothesis testing on the rate of atrial fibrillation/flutter will be performed using an unstratified 
chi-squared test if the expected counts in the 2 x 2 contingency table (treatment arm by atrial 
fibrillation/flutter status) are at least 5 patients.  If any expected count in the 2 x 2 contingency 
table is less than 5 patients, then hypothesis testing will be performed using Fisher’s exact test.   
6.4.2.3 Other secondary endpoints  
6.4.2.3.1 ORR per Independent Central Review 
ORR per independent central review will be summarized and analyzed using the same methods 
used for ORR per investigator assessment.   


 
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6.4.2.3.2 PFS per Independent Central Review 
PFS per independent central review will be summarized and analyzed using the same methods 
used for PFS per investigator assessment.   
6.4.2.3.3 Duration of Response (DOR) by Independent Central Review 
DOR by independent central review will be analyzed only for patients in the ITT Analysis Set 
who achieved a response (PR or higher) per independent central review.  At the interim analysis 
of ORR only, DOR by independent central review will be analyzed only for the first 415 
randomized patients in the ITT Analysis Set who achieved a response (PR or higher) per 
independent central review.   
The censoring conventions and the analyses of DOR by independent central review will be the 
same as those of PFS with the exception that treatment arm comparisons will not be performed, 
ie, no HR or corresponding CI or testing will be calculated or performed.   
6.4.2.3.4 DOR by Investigator Assessment 
DOR by investigator assessment will be analyzed only for patients in the ITT Analysis Set who 
achieved a response (PR or higher) per investigator assessment.  At the interim analysis of ORR 
only, DOR by investigator assessment will be analyzed only for the first 415 randomized patients 
in the ITT Analysis Set who achieved a response (PR or higher) per investigator assessment.   
Analyses of DOR will be repeated based on the investigator assessment with the same methods 
as those for DOR by independent central review.   
6.4.2.3.5 Time to Treatment Failure 
The HR for time to treatment failure and its 95% CI will be estimated from a stratified Cox 
regression model.   
The distribution of time to treatment failure, including the median and other quartiles, and the 
on-treatment rate (ie, no treatment failure) at selected timepoints such as 12, 18 and 24 months, 
will be estimated using the Kaplan-Meier method for each treatment arm.  The 95% CI for the 
median and the other quartiles of time to treatment failure as well as the on-treatment rate at the 
selected timepoints will be estimated as for PFS.  Time to treatment failure will be censored at 
the data cutoff for patients who did not discontinue.   
6.4.2.3.6 Rate of PR-L or Higher by Independent Central Review 


 
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The rate of PR-L or higher by independent central review will be summarized for each treatment 
arm along with its corresponding 95% CI.  At the interim analysis of ORR only, the rate of PR-L 
or higher by independent central review will be analyzed only for the first 415 randomized 
patients in the ITT Analysis Set.   
6.4.2.3.7 Rate of PR-L or Higher per Investigator Assessment 
The rate of PR-L or higher per investigator assessment will be summarized for each treatment 
arm along with its corresponding 95% CI.  At the interim analysis of ORR only, the rate of PR-L 
or higher per investigator assessment will be analyzed only for the first 415 randomized patients 
in the ITT Analysis Set.   
6.4.2.3.8 Overall Survival 
Patients who remained alive as of the data cutoff or discontinued study due to reasons other than 
death will be right censored at the date on which the patient was last known to be alive.  The 
methods and analyses for overall survival will be the same as those described for PFS.   
6.4.2.3.9 Health Related Quality of Life 
The scoring of the EORTC QLQ-C30 and EQ-5D-5L will follow their corresponding manuals 
(Fayers et al. 2001;  EuroQol Group 1990; Herdman et al 2011).   
EORTC QLQ-C30 
The scores of the EORTC QLQ-C30 questionnaire will be summarized at each assessment 
timepoint for each treatment arm.  Summaries will include: scores and changes from baseline in 
the QLQ-C30 global health status/QoL (GHS/QoL) scale and the five functional scales (Physical 
Functioning, Role Functioning, Emotional Functioning, Cognitive Functioning, and Social 
Functioning), three Symptom scales (fatigue, pain, and nausea and vomiting), and six single 
items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).   
Higher QLQ-C30 symptom scales and single item scores indicate worse HRQoL.  Higher scores 
in the functional scales and GHS/QoL scale indicate better HRQoL.   
In addition, the change from baseline in QLQ-C30 GHS/QoL scale scores will be compared 
between treatment arms using a linear mixed model for repeated measures (MMRM) at the 
predefined timepoints of Cycle 7 (24 weeks) and Cycle 13 (48 weeks).  The model will include 
the repeated measurement (for Cycles 4, 7, 10 and 13) of the change from baseline in QLQ-C30 


 
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GHS/QoL score as the dependent variable, and the treatment arm by assessment timepoint 
interaction, and baseline score as a covariate with either an unstructured covariance matrix 
(Mallinckrodt 2018) or a simpler covariance structure, eg, heterogeneous Toeplitz.  The 
difference between treatment arms in change from baseline score at Cycles 7 and 13 as well as 
their 95% CIs will be estimated, and the corresponding p-values will be presented.   
EQ-5D-5L 
The EQ-5D-5L comprises a descriptive system and an EQ Visual Analogue Scale (EQ VAS) 
with the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression.  Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems.  The EQ VAS records the respondent’s self-
rated health on a 0 to 100 scale, with 100 labelled ‘the best health you can imagine’ and 0 ‘the 
worst health you can imagine’.   
EQ VAS will be summarized descriptively by treatment arm at each assessment timepoint.  
Descriptive statistics will also be provided by treatment arm at each assessment timepoint 
including the number and percentage of patients reporting each level of problem on each 
dimension of the EQ-5D-5L.   
6.4.3 Sensitivity Analyses  
Primary endpoint of ORR 
The noninferiority of the primary endpoint of ORR will also be analyzed in the Per-protocol 
Analysis Set.   
A sensitivity analysis of ORR using an alternative set of response confirmation rules (see 
Appendix C) will be performed that allows PR-L to be subsequently confirmed as a best overall 
response of PR.   
To account for disease progression due to study drug interruption, ORR and BOR will be 
summarized based on all disease assessments through the data cutoff date, disease progression or 
the start of new CLL/SLL therapy, whichever comes first; however, disease progression that 
occurs within 6 weeks of a study drug interruption of at least 7 days will not be counted as 
disease progression for the purpose of this sensitivity analysis.    


 
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To account for the impact of COVID-19, ORR will be summarized for each treatment arm 
excluding patients who have died due to COVID-19.   
Key secondary endpoint of PFS 
The non-inferiority of the key secondary endpoint of PFS will also be analyzed in the Per-
protocol Analysis Set.   
Alternative censoring rules such as censoring for new CLL/SLL therapies will be applied as 
another sensitivity analysis of PFS.   
To account for disease progression due to study drug interruption, PFS will also be summarized 
where disease progression that occurs within 6 weeks of a study drug interruption of at least 7 
days will not be counted as disease progression for the purpose of this sensitivity analysis.   
To account for the impact of COVID-19, PFS will be summarized for each treatment arm while 
additionally censoring deaths due to COVID-19.   
6.4.4 Subgroup Analyses 
The primary and selected secondary endpoints will be summarized, as appropriate, in the 
following subgroups (if collected in both IRT and in the clinical data, clinical data including 
EDC will be used to define subgroups): 
x Age group (< 65 vs  ≥ 65 years); 
x Sex; 
x Geographic region (Asia vs Australia/New Zealand vs Europe vs North America); 
x Prior lines of therapy (1-3 vs > 3); 
x Baseline ECOG performance status (0 vs ≥ 1); 
x Baseline del17p/TP53 mutation status (present or absent); 
x Bulky disease (yes: any target lesion longest diameter ≥ 5 cm vs no); 
x Baseline β2 microglobulin (≤ 3 mg/L vs > 3 mg/L); 
x Baseline IGHV mutation status (unmutated vs mutated); 
x Disease stage (Binet stage of A/B and Ann Arbor stage I-II bulky vs Binet stage C and 
Ann Arbor stage III/IV) at study entry 


 
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When the sample size of a subgroup is too small, the subgroup may be omitted from the analyses 
or be combined with other subgroups if appropriate.  Forest plots for the subgroup analyses will 
be provided with 95% CIs based on unstratified methods.   
6.4.5 Exploratory Efficacy Analyses 
Cox and/or logistic regression models, as well as descriptive comparisons, may be used to 
explore the association between the prognostic, predictive biomarkers, as well as MRD and the 
clinical outcomes.   
MRD 
The percentage of CLL cells amongst leukocytes will be provided in a listing.   
Self-administered Activity and Quality of Life Questionnaire 
The self-administered activity and quality-of-life questionnaire data consist of the following and 
may be provided in listings if appropriate: 
x 10 questions dealing with symptoms, activity and general well-being 
x 3 questions related to contact with physician, study drug compliance and mobile device 
usage 
x 6-minute walk test 
6.5 
SAFETY ANALYSES 
All safety analyses will be performed in the Safety Analysis Set.   
Safety will be assessed by the monitoring and recording of all adverse events (AEs) graded by 
NCI-CTCAE v4.03.  Laboratory values (complete blood count [CBC], serum chemistry, and 
coagulation), vital signs, physical exams, ECOG performance status and ECGs findings will also 
be used to assess safety.  Descriptive statistics will be used to summarize the safety data by 
treatment arm.   
For all safety analyses by treatment arm, patients will be analyzed according to the actual 
treatment received.   
6.5.1 Extent of Exposure 
The extent of exposure to study drug will be summarized descriptively by treatment arm as the 
number of cycles received (number and percentage of patients), treatment duration (months), 


 
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cumulative total dose received per patient (g), actual dose intensity (mg/day) and relative dose 
intensity (%).   
The number and percentage of patients with dose reductions, dose interruption, and drug 
discontinuation will be summarized with the respective reasons.   
The actual dose intensity is defined as the actual cumulative dose (mg) taken based on the total 
dose per day divided by the treatment duration (days).  The relative dose intensity is defined as 
the ratio of the actual dose intensity to the planned dose intensity as a percentage where the 
planned dose intensity is 320 mg/day for zanubrutinib and 420 mg/day for ibrutinib.   
Patient data listings will be provided for all dosing records.   
6.5.2 Adverse Events  
The AE verbatim descriptions (terms as recorded by the investigator on the eCRF) will be 
classified into standardized medical terminology using Medical Dictionary for Regulatory 
Activities (MedDRA).  AEs will be coded to 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) will also be captured in the database.   
A treatment-emergent adverse event (TEAE) is defined as an AE that has an onset date on or 
after the first dose of study drug up to 30 days after the last dose of study drug or the day prior to 
initiation of a new CLL/SLL therapy, whichever occurs first. If a TEAE worsens to grade 5 more 
than 30 days after last dose of study drug and prior to initiation of a new CLL/SLL therapy, the 
grade 5 AE will be treatment-emergent.  Only TEAEs will be included in summary tables.  All 
AEs, treatment-emergent or otherwise, will be presented in patient data listings.   
TEAEs will be summarized by treatment arm as the number and percentage of patients reporting 
TEAEs by SOC and PT.  A patient will be counted only once within a system organ class and 
preferred term.  TEAEs will also be summarized by grade and by the relationship to study drug 
assessed by the investigator, ie, treatment-related or not.  A treatment-related AE is an AE that is 
assessed by the investigator as related to the study drug or is missing an assessment of the causal 
relationship.  TEAEs summarized by grade or by relationship to study drug will be summarized 
at the maximum severity grade or strongest causal relationship to study drug, respectively.   
No imputation of AE grades will be performed.  Treatment-emergent adverse events (TEAEs) 
with missing CTCAE grade will only be summarized in the total column.   


 
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An overall summary of TEAEs will include the number and percentage of patients with at least 
one: 
x 
TEAE; 
x 
treatment-related TEAE; 
x 
grade 3 or higher TEAE;  
x 
treatment-related grade 3 or higher TEAE; 
x 
TEAE leading to death; 
x 
treatment-related TEAE leading to death; 
x 
serious TEAE; 
x 
treatment-related serious TEAE; 
x 
TEAE leading to treatment discontinuation; 
x 
treatment-related TEAE leading to treatment discontinuation; 
x 
TEAE leading to dose modification; 
x 
treatment-related TEAE leading to dose modification; 
x 
TEAE leading to dose reduction; 
x 
treatment-related TEAE leading to dose reduction; 
x 
TEAE leading to dose interruption; 
x 
treatment-related TEAE leading to dose interruption. 
The summaries of the TEAEs will be provided by PT only, by SOC and PT, and by SOC, PT and 
maximum severity grade.   
The adverse events of special interest (AESIs) will be defined and summarized by AESI category 
and PT for the following: 
x treatment-emergent AESIs; 
x grade 3 or higher treatment-emergent AESIs; 
x serious treatment-emergent AESIs; 
x treatment-emergent AESIs leading to treatment discontinuation; 
x treatment-emergent AESIs leading to dose modification; 


 
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x treatment-emergent AESIs leading to dose reduction; 
x treatment-emergent AESIs leading to dose interruption; 
x treatment-emergent AESIs by maximum severity.  
Time to first AESI along with cumulative event rates at milestone timepoints as well as patient 
incidence in 3-month intervals over time may be presented for selected AESIs.   
TEAEs related to liver, arrythmia and diarrhea will be defined and summarized by category and 
PT for all such events, grade 3 or higher, serious and by maximum severity.   
Incidence and time to diarrhea (grade 3 or higher), severe bleeding (defined as grade 3 or higher 
bleeding of any site or central nervous system bleeding of any grade), and atrial fibrillation (both 
new onset and exacerbation of existing atrial fibrillation) will also be summarized.   
A summary of the number of deaths and the cause of death, classified by deaths within 30 days 
of last dose of study drug and deaths more than 30 days after the last dose, will be provided.   
Listings of deaths, AEs, serious AEs, AEs leading to death, and AEs leading to dose 
modification or discontinuation of the study drug will be provided.  In addition, a listing of 
serious AEs for patients with COVID-19 infection will be provided.  No imputation will be done 
in the AE listings.   
6.5.3 Laboratory Values 
The values and changes from baseline for selected CBC components, serum chemistry and serum 
immunoglobulin parameters will be summarized by treatment arm at each assessment timepoint 
and for the worst postbaseline assessment.   
Certain laboratory parameters can come from central or local laboratories (eg, hematology, 
chemistry).  Summaries of laboratory parameters will be based on the preferred laboratory 
(central or local, not both) for each patient, and the preferred laboratory will be the central 
laboratory if central laboratory data are available and the local laboratory if central laboratory 
data are not available.   
Laboratory parameters that are graded in NCI-CTCAE v4.03 will be summarized by the CTCAE 
grade and laboratory parameters that are graded per Hallek (2008) including platelets, 
hemoglobin and absolute neutrophil count will be summarized by the Hallek toxicity grade.  In 
the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading in 


 
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both high and low directions (eg, calcium, glucose, magnesium, phosphorus, potassium, sodium) 
will be summarized separately.   
A summary of the number and percentage of patients with grade 3 or higher toxicity will be 
provided for selected laboratory parameters of interest.  Shift tables assessing the toxicity grade 
at baseline versus the worst postbaseline toxicity grade recorded will be presented.   
Hematology, serum chemistry, serum immunoglobulin and coagulation results for each patient 
will be presented in data listings.  A listing of all grade 3 or higher laboratory values will also be 
provided.   
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 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
temperature, weight) and changes from baseline will be presented by assessment timepoint.  A 
listing by patient and assessment timepoint will be generated.   
6.5.5 Electrocardiograms (ECG) 
The QTc-Fridericia (QTcF) interval values and changes from baseline will be summarized by 
treatment arm for each assessment timepoint.  If triplicate readings (eg, screening) are recorded, 
the average of the readings for the assessment timepoint will be used for the summary.   
The number and percentage of patients satisfying the following QTcF conditions at any time 
postbaseline will be summarized: 
x > 450, > 480, or > 500 msec; 
x ≤ 30 msec maximum increase from baseline, > 30 and ≤ 60 msec maximum increase 
from baseline, or > 60 msec maximum increase from baseline.  
A listing of abnormal ECG by patient and assessment timepoint will be generated.   
6.5.6 ECOG Performance Status 
ECOG performance status will be summarized by treatment arm at each assessment timepoint.   


 
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6.6 
PHARMACOKINETIC ANALYSES 
A population PK analysis may be performed to include plasma concentrations of zanubrutinib 
from this trial in an existing model.  PK parameters such as apparent systemic clearance and AUC 
may be derived from the population PK analysis if supported by data.   
An exposure-response (efficacy or safety endpoints) analysis may be performed if supported by 
data.  The results from the population PK and exposure-response analyses may be reported 
separately from the Clinical Study Report.   
Further PK analyses will be described in a separate analysis plan.   
7 
INTERIM ANALYSIS 
There will be one interim analysis for the noninferiority (and superiority if noninferiority is met) 
testing of ORR.  The interim analysis will be performed approximately 12 months after the 
randomization of 415 patients.  The monitoring boundaries for the interim and the final analyses 
for the nonferiority and superiority tests are based on the O’Brien-Fleming boundary 
approximated by the Lan-DeMets spending functions.   
8 
 CHANGES IN THE PLANNED ANALYSIS 
Not applicable. 
 
 


 
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9 
REFERENCES 
Brookmeyer, R.  and Crowley, J.  (1982) A confidence interval for the median survival time.  
Biometrics, 38, 29-41.   
Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic 
lymphoid leukemia. N Engl J Med. 2014;371(3):213-23. 
Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of 
ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-42. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
endpoints in chronic lymphocytic leukemia. J Clin Oncol. 2012;30:2820-2. 
EMA guidance on points to consider on switching between superiority and noninferiority, 2000. 
Fayers, P. M., N. K. Aaronson, K. Bjordal, M. Groenvold, D. Curran, A. Bottomley, and on 
behalf of the EORTC Quality of Life Group. 2001. The EORTC QLQ-C30 Scoring Manual. 3rd 
ed. Brussels: European Organization for Research and Treatment of Cancer. 
Food and Drug Administration Center for Drug Evaluation and Research (CDER). FDA 
Guidance for Industry: Non-Inferiority Clinical Trials to Establish Effectiveness. (2016). 
Food and Drug Administration Center for Drug Evaluation and Research (CDER) & Center for 
Biologics Evaluation and Research (CBER). FDA Guidance for Industry: Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics. (2018) 
Greenland, S. and Robins, J. M. (1985), Estimation of a Common Effect Parameter from Sparse 
Follow-Up Data. Biometrics, 41, 55–68. 
Greenwood, M.  (1926) The natural duration of cancer.  Public health and medical subjects, 33: 
1-26.   
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukaemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute - Working Group 1996 guidelines. Blood. 
2008;111(12):5446-56. 
Herdman, M et al, Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L). Qual Life Res (2011) 20:1727–1736. 
Mallinckrodt, C. H., Lane, P. W., Schnell, D., Peng, Y., & Mancuso, J. P. (2008). 
Recommendations for the Primary Analysis of Continuous Endpoints in Longitudinal Clinical 
Trials. Drug Information Journal, 42(4), 303–319.  
Mantel, N and Haenszel, W. (1959), Statistical Aspects of Analysis of Data from Retrospective 
Studies of Disease. Journal of the National Cancer Institute. 22, 719–748. 


 
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Maurer, W and Bretz, B. Multiple testing in group sequential trials using graphic approaches.  
Statistics in Biopharmaceutical Research. 2013; 5:4, 311-320.   
NCI-CTCAE v4.03 
http://www.oncology.tv/SymptomManagement/NationalCancerInstituteUpdatesCTCAEtov403.a
spx. Accessed 23 May 2019. 
Schemper, M, and Smith, T.L. (1996). A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials, 17:343-346 
Szende A, Oppe M, Devlin N. (Eds.) EQ-5D Value Sets: Inventory, Comparative Review and 
User Guide. Springer 2007. 
The EuroQol Group, 1990. EuroQol – a new facility for the measurement of health-related 
quality of life. Health Policy, 16, pp.199-208.  
 
 
 


 
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10. APPENDIX 
APPENDIX A: IMPUTATION OF MISSING OR PARTIALLY MISSING DATES 
In general, missing or partial dates will be imputed at the ADaM dataset level.  The following 
rules will apply to the specific analysis and summary purposes mentioned below only.  Date of 
death, discontinuation from study and analysis data cutoff will be accounted for in the date 
imputations as applicable.   
A.1 Prior/Concomitant Medications/Procedures/Surgeries 
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 partially 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 partially 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 
If start date or end date of a medication is completely missing, do not impute. 
A.2 Adverse Events 
When the start date or end date of an AE is partially missing, the date will be imputed to 
determine whether the AE is treatment-emergent.  When in doubt, the AE will be considered 
treatment-emergent by default.  The following rules will be applied to impute partial dates for 
AEs: 
If start date of an AE is partially missing, impute as follows: 
x 
If both month and day are missing, then the imputed month and day will be January 01 or the 
date of first dose of study drug if they have the same year 
x 
If only day is missing, then the imputed day will be the first day of the month or the date of 
first dose of study drug if they have the same month and year 


 
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x 
If the start date is completely missing, the imputed date will be the date of first dose of study 
drug as long as the AE end date is not before the date of first dose of study drug.   
If the end date of an AE is partially 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 
If the end date is completely missing, do not impute.   
A.3 Deaths 
For partial death dates, impute as follows: 
x If both month and day are missing, then the imputed month and day will be 01Jan or the last 
date the patient was known to be alive + 1, whichever is later 
x If only day is missing, then the imputed day will be the first day of the month or the last date 
the patient was known to be alive +1, whichever is later 
A.4 New Anti-cancer therapy 
For partial dates of new anti-cancer therapies, dates will be imputed as for concomitant 
medication start dates.     
A.5 Diagnosis 
If a diagnosis date is partially 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 a diagnosis date is completely missing, do not impute. 
 
APPENDIX B: DERIVATION OF INVESTIGATOR DISEASE ASSESSMENT DATES 
Dates corresponding to each investigator disease assessment (eg, CR, PR, PR-L) will be derived 
for disease assessments other than PD.  Investigator assessments of PD will use the PD date 
provided directly by the investigator in the eCRF.   


 
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The investigator disease assessment is based on several individual assessments, eg, target and 
non-target lesions, liver/spleen and CBCs, and the disease assessment date derivation will be 
computed as the latest of the applicable individual assessments, which differ by investigator 
disease assessment and disease type (ie, CLL vs SLL) and are described in Table 3.   
Table 3.  Assessment Dates used for Investigator Disease Assessment Date Derivation 
Assessment 
Investigator Disease Assessment 
CR, CRi 
nPR 
PR, PR-L, SD, NE 
Target and non-target lesion 
imaging 
Y 
Y 
Y 
Liver / spleen imaging 
Y 
Y 
Y 
Physical exam of liver/spleen, 
lymph nodes 
Y 
Y 
Y 
CBC collection (CLL only) 
Y 
Y 
Y 
Bone marrow biopsy 
N [1] 
N [1] 
N 
Constitutional symptoms check 
(CLL only) 
Y 
Y 
N 
Y = assessment and corresponding date accounted for when determining investigator disease assessment date for given 
investigator disease assessment (eg, CR, PR); N = assessment not used for given investigator disease assessment.  The latest 
of all dates with “Y” for the given investigator disease assessment will be the derived disease assessment date.   
[1] bone marrow biopsy is relevant for certain disease assessments but will not be used to derive the assessment date.   
APPENDIX C: DERIVATION OF BEST OVERALL RESPONSE FOR CLL 
For CLL patients, the best overall response will require two assessments at least 8 weeks apart to 
confirm a best overall response of PR-L, PR, nPR, CRi or CR that meet the following criteria: 


 
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x To confirm a response of CR, there must be one CR and another CR or CRi in any order 
and can only have intervening responses of non-PD or NE and at most one intervening PR 
or nPR; 
x To confirm a response of CRi, there must be two CRis and can only have intervening 
responses of non-PD or NE and at most one intervening PR or nPR; 
x To confirm a response of nPR, confirmed CR or CRi must not be met and there must be 
EITHER an nPR with a subsequent nPR or higher OR an nPR or higher with a subsequent 
nPR, and can have intervening responses of PR-L, PR, non-PD, NE or SD; 
x To confirm a response of PR, confirmed CR, CRi or nPR must not be met and there must 
be a PR or higher with a subsequent PR or higher and can have intervening responses of 
PR-L, non-PD, NE or SD; 
x To confirm a response of PR-L, confirmed CR, CRi, nPR or PR must not be met and there 
must be a PR-L with a subsequent PR-L or higher or a PR-L or higher with a subsequent 
PR-L and can have intervening responses of non-PD, NE or SD; 
x No other best overall response category requires confirmation. 
Time to response will be the first PR or higher that is subsequently confirmed as a PR or higher.   
For a sensitivity analysis of ORR with an alternative response confirmation, the best overall 
response will require two assessments at least 8 weeks apart to confirm a best overall response of 
PR-L, PR, nPR, CRi or CR that meet the following criteria: 
x To confirm a response of CR, there must be one CR and another CR or CRi in any order 
and can only have intervening responses of non-PD or NE and at most one intervening PR 
or nPR; 
x To confirm a response of CRi, there must be two CRis and can only have intervening 
responses of non-PD or NE and at most one intervening PR or nPR; 
x To confirm a response of nPR, confirmed CR or CRi must not be met and there must be 
EITHER an nPR with a subsequent nPR or higher OR an nPR or higher with a subsequent 
nPR, and can have intervening responses of PR-L, PR, non-PD, NE or SD; 


 
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x To confirm a response of PR, confirmed CR, CRi or nPR must not be met and there must 
be a PR-L or higher with a subsequent PR or higher and can have intervening responses of 
PR-L, non-PD, NE or SD; 
x To confirm a response of PR-L, confirmed CR, CRi, nPR or PR must not be met and there 
must be a PR-L or higher with a subsequent PR-L and can have intervening responses of 
non-PD, NE or SD; 
x No other best overall response category requires confirmation. 
For this sensitivity analysis, if a PR or higher is subsequently confirmed as PR or higher, then the 
date of first response will be the first PR or higher that is subsequently confirmed as a PR or higher, 
and if a PR-L is subsequently confirmed as PR, the date of first response will be the last PR-L or 
higher that is subsequently confirmed as a PR.  If both scenarios apply, the date of first response 
will be the earlier of the two. 
 
APPENDIX D: EORTC QLQ-C30 SCORING 
The principle for scoring the QLQ-C30 applies to all scales/scores: raw scores are calculated as 
the average of the items that contribute to the scale.   
A linear transformation to standardize the raw scores is utilized, so that the scores are ranged 
from 0 to 100.  Increases in scores for functional domains (e.g., physical, role, social, emotional, 
etc.) are improvements while increases in scores for symptoms (e.g., fatigue, vomiting and 
nausea, diarrhea, pain, etc.) are deteriorations. 
Missing Items 
If at least half of the items for a scale are answered, then all the completed items are used to 
calculate the score.  Otherwise, the scale score is set to missing. 
In practical terms, if items I1, I2, ... In are included in a scale, the procedure is as follows: 
Raw Score 
For all scores, the raw score (RS), is the mean of the component items 
RS = (I1+I2+…+In)/n 
 
Derived Scale 


 
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The derived scales are obtained from the raw scores as defined in the EORTC manual. The 
derived scales have a more intuitive interpretation: larger function scale or global health status / 
QoL are improvements while larger symptom scales (e.g., pain, nausea, etc.) are deteriorations.  
The derivation formulas are as follows: 
 
 
Scales of QLQ-C30 
 
Scale 
Number 
of items 
Item 
range 
Item 
Numbers 
Global health status/ QoL 
 Global health status/QOL 
QL2 
2 
6 
29,30 
Functional Scales 
 
 
 
 
Physical functioning  
PF2 
5 
3 
1, 2, 3, 4, 5  
Role functioning  
RF2 
2 
3 
6, 7  
Emotional functioning  
EF 
4 
3 
21, 22, 23, 24  
Cognitive functioning  
CF 
2 
3 
20, 25  
Social functioning  
SF 
2 
3 
26, 27  
Symptom Scales/ items 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 


 
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EQ-5D-5L: for the 5 level Dimensions, scores on a 5-point Likert scale of 1 to 5, with level 1 
indicating no problem and level 5 indicating extreme problems. The Health State is defined by 
combining one level from each dimension. Lower scores indicate better health. 
VAS includes a scale of 0 to 100 with higher scores indicating better health status.   
Scales of EQ-5D-5L 
MOBILITY 
I have no problems in walking about  
 
 
 
 
I have slight problems in walking about  
 
 
 
 
I have moderate problems in walking about   
 
 
 
I have severe problems in walking about  
 
 
 
 
I am unable to walk about  
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
 
I have slight problems washing or dressing myself   
 
 
I have moderate problems washing or dressing myself  
 
 
I have severe problems washing or dressing myself   
 
 
I am unable to wash or dress myself  
 
 
 
 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial Difficulties 
FI 
1 
3 
28 


 
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USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
 
 
I have slight problems doing my usual activities  
 
 
 
I have moderate problems doing my usual activities  
 
 
I have severe problems doing my usual activities  
 
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
 
I have moderate pain or discomfort   
 
 
 
 
I have severe pain or discomfort  
 
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
 
I am moderately anxious or depressed  
 
 
 
 
I am severely anxious or depressed   
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 


 
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Prot_001.pdf: 
BGB-3111-305 
BeiGene 
Protocol Amendment 4.0 
03 April 2023 
CONFIDENTIAL 
Page 1 
CLINICAL RESEARCH PROTOCOL 
Protocol Title: 
A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) 
Compared with Ibrutinib in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia or 
Small Lymphocytic Lymphoma 
Protocol Identifier: 
BGB-3111-305 
Phase: 
3 
Investigational Product: 
Zanubrutinib (BGB-3111) 
Indication: 
Chronic Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Dr., 3rd Floor 
San Mateo, California 94404, USA 
Reference Number: 
EudraCT 2018-001366-42 
Sponsor Medical Monitor 
 
Telephone: 
 
Email: 
 
Original Protocol: 
09 July 2018 
Protocol Amendment 1.0: 
04 August 2018 
Protocol Amendment 1.1 (Spain) 
07 December 2018 
Protocol Amendment 1.2 (Czech 
Republic) 
06 February 2019 
Protocol Amendment 1.3 
(Germany) 
31 May 2019 
Protocol Amendment 2.0: 
Protocol Amendment 3.0 
Protocol Amendment 4.0 
29 August 2019 
31 January 2020 
03 April 2023 
Confidentiality Statement 
This Document is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene Ltd.  This document is 
for use by individuals and their designated representatives for their confidential review, consideration, and/or 
participation in investigational trial(s).  This document may not be copied or distributed for review by any 
unauthorized individuals without the prior written authorization of BeiGene Ltd.  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without the prior written 
authorization from BeiGene Ltd. 
NCT Number:
NCT03734016


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Protocol Amendment 4.0 
03 April 2023 
 
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Page 2 
FINAL PROTOCOL APPROVAL SHEET  
A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared with Ibrutinib in Patients 
with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma 
 
 
BeiGene, Ltd. Approval: 
 
 
See electronic signature approval 


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Protocol Amendment 4.0 
03 April 2023 
 
CONFIDENTIAL 
Page 3 
SYNOPSIS  
Name of Sponsor/Company:  BeiGene USA, Inc. 
Investigational Product:  zanubrutinib (BGB-3111) 
Title of Study:  A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared with Ibrutinib 
in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic 
Lymphoma 
Protocol Identifier:  BGB-3111-305 
Phase of Development:  3 
Number of Patients:  Approximately 600 
Study Centers:  Approximately 150 
Study Objectives: 
Primary 
• 
To compare the efficacy of zanubrutinib (also known as BGB-3111) versus ibrutinib as measured 
by overall response rate determined by investigator assessment 
Secondary 
• 
To compare the efficacy of zanubrutinib versus ibrutinib as measured by: 
o Progression-free survival determined by investigator assessment and independent central 
review 
o Overall response rate determined by independent central review 
o Duration of response determined by independent central review  
o Duration of response determined by investigator assessment 
o Time to treatment failure 
o Rate of partial response with lymphocytosis or higher determined by independent central 
review  
o Overall survival  
o Patient-reported outcomes 
• 
To compare the safety of zanubrutinib versus ibrutinib  
Exploratory 
• 
To evaluate the correlation between clinical outcomes (eg, overall response rate, progression-free 
survival, duration of response, overall survival, rate of partial response) and the prognostic and 
predictive biomarkers, including minimal residual disease (MRD)  
• 
To evaluate the pharmacokinetics of zanubrutinib 


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Page 4 
Study Design: 
This is a Phase 3, randomized study of zanubrutinib versus ibrutinib in approximately 600 patients with 
relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).  The 
primary efficacy endpoint is overall response rate (ORR) determined by investigator assessment. While 
the primary efficacy endpoint is per investigator assessment, ORR per independent central review will 
also be analyzed to support the primary analysis. In the United States, ORR assessed by independent 
central review will be the basis for regulatory decisions.  Disease response will be assessed per the 
“modified” 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines (Hallek M et 
al 2008), with modification for treatment-related lymphocytosis (Cheson et al 2012) for patients with 
CLL (Appendix 2), and per Lugano Classification for non-Hodgkin lymphoma (Cheson et al 2014) for 
patients with SLL (Appendix 3).  Rate of response for partial response with lymphocytosis (PR-L) or 
higher will be assessed as a secondary efficacy endpoint. 
The study is broken into three periods for every patient: 
• 
Screening Period (Section 5.2) 
• 
Treatment Period (Section 5.11) 
• 
Post-Treatment Period 
o End of Treatment Visit (Section 5.12.1) 
o Long-Term Follow-up (Section 5.12.2)  
o Survival Follow-up (Section 5.12.3)  
Patients will be randomized in a 1:1 manner to one of the following treatment arms: 
• 
Arm A: Zanubrutinib 160 mg orally twice daily  
• 
Arm B: Ibrutinib 420 mg orally once daily  
Randomization will be stratified by age (< 65 years versus ≥ 65 years), geographic region (China 
versus non-China), refractory status (yes or no), and del17p/TP53 mutation status (present or absent).   
Treatment with zanubrutinib and ibrutinib will be open label.  Study treatment will continue until 
disease progression, or any of the events outlined in Section 6.7.  The study duration is estimated to be 
approximately 51 months (see Section 3.5). 
Study Assessments 
Assessments to be performed during the study include pharmacokinetics; disease-related constitutional 
symptoms; physical examination of liver, spleen, and lymph nodes; computed tomography (CT) scan 
of neck, chest, abdomen, and pelvis with contrast; bone marrow examination at screening, for patients 
with baseline marrow involvement who meet clinical and laboratory criteria for CR or CRi and at time 
of suspected cytopenic progression; patient-reported outcomes (PRO; European quality of life 5-
dimensions 5-levels health questionnaire [EQ-5D-5L], European Organisation for Research and 
Treatment of Cancer quality of life cancer core questionnaire [EORTC QLQ- C30], and, in select 
countries, an optional device-based evaluation of quality of life and activity that patients may consent 
to); laboratory studies; bone marrow examination; genetic alterations in the tumor cells (eg, del 17p, 
del11q, 12q+ and immunoglobulin variable region heavy chain (IGHV) mutation analysis).  
Patients should remain on study treatment until disease progression is confirmed by independent 
central review (as described in Section 6.7). 
Assessments of safety will include adverse events (AEs), serious adverse events (SAEs), clinical 
laboratory tests, physical examinations, electrocardiograms, and vital signs (Section 5.5).  Adverse 


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events will be graded for severity per the current version of National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 and the Grading Scale for Hematologic 
Toxicities in CLL Studies (see Section 8.1.1.1).  An independent Data Monitoring Committee will 
periodically monitor safety data and also perform the interim efficacy analysis. 
Efficacy (Section 5.6) will be assessed locally by the investigator as well as by independent central 
review (Section 10.3). Progression must be confirmed by independent central review (Section 6.7). 
Key Eligibility Criteria: 
The patients to be included in this trial will have a confirmed diagnosis of CLL or SLL that meets the 
International Workshop on Chronic Lymphocytic Leukemia criteria and requiring treatment as defined 
by at least 1 of the following: progressive marrow failure; massive, progressive, or symptomatic 
splenomegaly; massive, progressive, or symptomatic lymphadenopathy; progressive lymphocytosis 
with rapid doubling time;  or constitutional symptoms.  Patients must be 18 years or older, relapsed or 
refractory to at least 1 prior systemic therapy for CLL/SLL, with the last dose of prior therapy for 
CLL/SLL > 14 days before randomization, and have measurable disease (defined as ≥ 1 lymph node 
> 1.5 cm in longest diameter, and measurable in 2 perpendicular diameters or an extranodal lesion must 
measure > 10 mm in longest perpendicular diameter).  Note: A line of therapy is defined as completing 
at least 2 cycles of treatment of standard regimen according to current guidelines, or of an 
investigational regimen on a clinical trial.  Patients will have no history of prolymphocytic leukemia or 
Richter’s transformation, no currently active clinically significant cardiovascular disease, and no HIV 
infection or active infection with hepatitis B or C. 
Test Product, Dose, and Mode of Administration:   
Zanubrutinib (160 mg twice daily) will be administered orally. 
Reference Therapy, Dose, and Mode of Administration:   
Ibrutinib (420 mg once daily) will be administered orally.  
Statistical Methods: 
Efficacy Analyses 
The primary analysis set for all efficacy analyses is the Intent-to-Treat Analysis Set (all patients 
randomized).  For the non-inferiority testing for the primary endpoint of ORR, the analysis will also be 
performed using the Per-protocol Analysis Set.  
Primary Efficacy Endpoint Analysis: 
The primary efficacy analysis of ORR (PR or higher, defined as CR/CR with incomplete bone marrow 
recovery + PR + nodular PR) will be conducted as assessed by the investigator, using the “modified” 
2008 International Workshop on Chronic Lymphocytic Leukemia guidelines (Hallek Met al 2008), 
with modification for treatment-related lymphocytosis (Cheson et al 2012) for patients with CLL 
(Appendix 2) and per Lugano Classification for non-Hodgkin lymphoma (Cheson et al 2014) for 
patients with SLL (Appendix 3). While the primary efficacy endpoint is per investigator assessment, 
ORR per independent central review will also be analyzed to support the primary analysis. In the 
United States, ORR assessed by independent central review will be the basis for regulatory decisions. 
The primary hypothesis testing for ORR is for non-inferiority.  The non-inferiority of zanubrutinib to 
ibrutinib will be tested for the Intent-to-Treat Analysis Set under the pre-specified margin of 0.8558 
(response ratio of zanubrutinib to ibrutinib).  The primary objective of the study is met if the 
non-inferiority is demonstrated.  The null and alternative hypotheses for testing ORR non-inferiority 
are as follows: 


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• 
H0NI: Response Ratio (zanubrutinib/ibrutinib) ≤ 0.8558 
• 
HaNI: Response Ratio (zanubrutinib/ibrutinib) > 0.8558 
There will be 1 interim analysis approximately 12 months after 415 patients (69% information fraction) 
have been randomized.  The final analysis will occur approximately 12 months after 600 patients have 
been randomized.  Based on the assumption to randomize 600 patients in 24 months, the final analysis 
is expected to occur 36 months after the study start.  
A Cochran-Mantel-Haenszel test for response ratio adjusting for the 4 randomization stratification 
factors will be performed for hypothesis testing.  The Cochran-Mantel-Haenszel response ratio will be 
estimated along with its 95% Wald confidence interval (CI).  Clopper-Pearson 95% CI will be 
calculated for ORR for each treatment group. 
If non-inferiority is demonstrated at either interim or final analysis, superiority of zanubrutinib to 
ibrutinib will be tested next (Brannath et al 2003).  The monitoring boundaries for the non-inferiority 
and superiority tests are based on O’Brien Fleming type alpha spending function and depicted in 
Table 8 and Table 9. 
Justification of Non-inferiority Margin 
The non-inferiority margin was derived using the 95%-95% fixed margin method 
(FDA Guidance for Industry: Non-Inferiority Clinical Trials to Establish Effectiveness 2016).  The 
efficacy of ibrutinib (M1) in response ratio scale was estimated as 2.1781 from the results of 
RESONATE and RESONATE2 trials by a fixed-effect meta-analysis.  Requiring 80% of M1 to be 
retained in zanubrutinib, a non-inferiority margin of 0.8558 is generated.  The margin is within the 
clinically acceptable limit. 
Secondary Efficacy Endpoint Analyses 
Key secondary efficacy endpoint 
If the primary objective of demonstrating non-inferiority of zanubrutinib to ibrutinib in ORR is met, the 
key secondary efficacy endpoint of progression-free survival (PFS) by investigator assessment will be 
tested for non-inferiority under hierarchical testing to control study-wide type I error. There will be a 
single analysis of PFS when approximately 205 PFS events have occurred, and PFS will be 
summarized descriptively at the time ORR is significant. While the key secondary efficacy endpoint is 
per investigator assessment, PFS per independent central review will also be analyzed to support the 
key secondary endpoint analysis. In the United States, PFS assessed by independent central review will 
be used to support regulatory decisions. 
PFS will be compared between the 2 arms using a stratified log-rank test based on the 4 randomization 
stratification factors.  The non-inferiority margin for the test is 1.3319 in hazard ratio (HR; 
zanubrutinib/ibrutinib).  If the p-value from the stratified log-rank test for non-inferiority is significant, 
the non-inferiority of zanubrutinib to ibrutinib in PFS is demonstrated, and further testing of superiority 
will be performed.  The HR (zanubrutinib/ibrutinib) and its 95% CI will be estimated from a stratified 
Cox regression model.  The distribution of PFS, including median and other quartiles, and PFS rate at 
selected timepoints will be estimated using the Kaplan-Meier method for each arm. 
Other secondary efficacy endpoints:  
No hypothesis testing will be performed for other secondary efficacy endpoints. 
• 
The distribution of duration of response (DOR) by independent central review including median 
and other quartiles, will be estimated using the Kaplan-Meier method for each treatment group.  
The same analysis will be performed for DOR by investigator assessment.  
• 
The HR for time to treatment failure and its 95% CI will be estimated from a stratified Cox 
regression using the 4 randomization stratification factors.  Kaplan-Meier method will be used to 


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estimate the distribution of time to treatment failure for each treatment group.  
• 
Rate of response for partial response with lymphocytosis or higher by independent central review 
will be analyzed using the Cochran-Mantel-Haenszel response ratio along with its 95% Wald CI.  
Clopper-Pearson 95% CI for the estimate will be calculated for each treatment group. 
• 
Overall survival will be analyzed using the same methods employed for PFS by investigator 
assessment. 
• 
Patient-reported outcomes:  The EORTC QLQ-C30 questionnaire will be summarized for each 
assessment timepoint for each treatment group.  Change of EQ-5D-5L score will be summarized 
for each treatment group.  
Safety Analyses 
The Safety Analysis Set (all patients who received any dose of study drug) will be used for all safety 
analyses.  
Drug exposure will be summarized by treatment group, including duration, dosage, and dose intensity.   
All treatment-emergent AEs will be summarized.  Serious adverse events, deaths, treatment-emergent 
AEs ≥ Grade 3, study drug-related treatment-emergent AEs, treatment-emergent AEs that led to 
treatment discontinuation, and dose reductions or dose interruptions will be summarized. 
Sample Size Considerations 
The sample size calculation is based on the primary efficacy analyses for the primary endpoint of ORR.  
Assuming a response ratio (zanubrutinib arm/ibrutinib arm) of 1.03 (72%/70%), 600 patients will 
provide more than 90% power to demonstrate the non-inferiority of zanubrutinib to ibrutinib at the 
non-inferiority margin of 0.8558 (response ratio) and a 1-sided alpha level of 0.025 when there is 1 
interim analysis at 69% information fraction (415 out of 600 patients).  The response rate for ibrutinib 
is approximated from published clinical data (Byrd et al 2019).   
If the primary objective of non-inferiority of ORR is met, the study will continue until 205 PFS events 
have occurred.  At a 1-sided alpha of 0.025 and a non-inferiority margin of 1.3319 (HR), the power to 
demonstrate the non-inferiority of zanubrutinib to ibrutinib in PFS is 80%.  If the 600 patients are 
randomized in a 1:1 ratio to the 2 arms over a 24-month period, including a 9-month ramp-up period 
before reaching peak enrollment of 33 patients/month, with a 0.0017/month hazard rate for drop-out, 
205 events are expected to be accumulated at 45 months from study start.  A median PFS of 47 months 
for ibrutinib, an HR of 0.9, and an exponential distribution for PFS are also assumed.  


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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ...........................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
SYNOPSIS 3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
LIST OF ABBREVIATIONS AND TERMS ................................................................................15 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ............................17 
1.2. 
B-cell Receptor Signaling ...........................................................................................18 
1.2.1. 
Ibrutinib ......................................................................................................................19 
1.2.2. 
Zanubrutinib ...............................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................24 
3. 
STUDY DESIGN .......................................................................................................25 
3.1. 
Summary of Study Design ..........................................................................................25 
3.2. 
Study Schema .............................................................................................................27 
3.3. 
Blinding ......................................................................................................................27 
3.4. 
Study Rationale ...........................................................................................................27 
3.5. 
Duration of Study .......................................................................................................28 
3.5.1. 
Study Drug Access at Study Closure ..........................................................................28 
4. 
ELIGIBILITY CRITERIA .........................................................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................30 
5. 
ENROLLMENT AND STUDY PROCEDURES ......................................................33 
5.1. 
Study Visit Schedule ...................................................................................................33 
5.2. 
Screening ....................................................................................................................33 
5.2.1. 
Females of Childbearing Potential and Contraception ...............................................34 
5.2.2. 
Patient Numbering ......................................................................................................34 
5.2.3. 
Demographics .............................................................................................................35 
5.2.4. 
Medical and Cancer History .......................................................................................35 
5.2.5. 
Confirmation of Eligibility .........................................................................................35 


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5.2.6. 
Enrollment/Randomization .........................................................................................36 
5.3. 
Study Drug Dispensation ............................................................................................36 
5.4. 
Pharmacokinetics ........................................................................................................36 
5.5. 
Safety Assessments .....................................................................................................37 
5.5.1. 
Cardiac Function .........................................................................................................37 
5.5.2. 
Physical Examination and Vital Signs ........................................................................37 
5.5.3. 
ECOG Performance Status .........................................................................................37 
5.5.4. 
Electrocardiogram .......................................................................................................37 
5.5.5. 
Concomitant Medications Review ..............................................................................37 
5.5.6. 
Adverse Events Review ..............................................................................................37 
5.6. 
Efficacy Assessments .................................................................................................38 
5.6.1. 
Disease-Related Constitutional Symptoms.................................................................38 
5.6.2. 
Physical Examination of Liver, Spleen, and Lymph Nodes .......................................38 
5.6.3. 
Computed Tomography ..............................................................................................38 
5.6.4. 
Bone Marrow Examination .........................................................................................40 
5.6.5. 
Survival Status ............................................................................................................40 
5.7. 
Patient-Reported Outcomes ........................................................................................41 
5.7.1. 
EQ-5D-5L ...................................................................................................................41 
5.7.2. 
EORTC QLQ-C30 ......................................................................................................41 
5.7.3. 
Self-administered Activity and Quality of Life Evaluation (Optional) ......................41 
5.8. 
Laboratory Assessments .............................................................................................42 
5.8.1. 
Hematology .................................................................................................................43 
5.8.2. 
Serum Chemistry ........................................................................................................43 
5.8.3. 
Serum Immunoglobulins ............................................................................................43 
5.8.4. 
Coagulation .................................................................................................................43 
5.8.5. 
Hepatitis B and C testing ............................................................................................43 
5.8.6. 
Pregnancy Test ............................................................................................................45 
5.8.7. 
HIV Testing ................................................................................................................45 
5.9. 
Biomarkers ..................................................................................................................45 
5.9.1. 
Del17p and Cytogenetics ............................................................................................45 
5.9.2. 
Flow Cytometry for MRD ..........................................................................................45 
5.9.3. 
TP53 Mutation and Other Molecular Analysis ...........................................................45 


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5.10. 
Unscheduled Visits .....................................................................................................46 
5.11. 
Treatment Period ........................................................................................................46 
5.12. 
Post-Treatment Period ................................................................................................46 
5.12.1. 
End of Treatment ........................................................................................................46 
5.12.2. 
Long-term Follow-up ..................................................................................................46 
5.12.3. 
Survival Follow-up .....................................................................................................47 
5.13. 
End of Study ...............................................................................................................47 
5.14. 
Lost to Follow-up .......................................................................................................47 
5.15. 
Future Research (Optional) .........................................................................................47 
6. 
STUDY TREATMENT ..............................................................................................49 
6.1. 
Study Treatment Preparation and Dispensation .........................................................49 
6.1.1. 
Packaging and Labeling ..............................................................................................49 
6.1.2. 
Handling and Storage .................................................................................................49 
6.1.3. 
Study Drug Supply .....................................................................................................49 
6.1.4. 
Study Drug Dispensation Procedures .........................................................................49 
6.1.5. 
Compliance and Accountability .................................................................................50 
6.1.6. 
Disposal and Destruction ............................................................................................50 
6.2. 
Dosage and Administration ........................................................................................50 
6.2.1. 
Zanubrutinib ...............................................................................................................50 
6.2.2. 
Ibrutinib ......................................................................................................................51 
6.3. 
Overdose .....................................................................................................................51 
6.4. 
Precautions ..................................................................................................................51 
6.4.1. 
Surgery and Procedures ..............................................................................................51 
6.5. 
Dose Interruption and Modification ...........................................................................52 
6.5.1. 
Zanubrutinib ...............................................................................................................52 
6.5.2. 
Ibrutinib ......................................................................................................................54 
6.6. 
Toxicity Management Recommendations ..................................................................56 
6.7. 
Discontinuation from Study Treatment ......................................................................56 
7. 
CONCOMITANT THERAPY ...................................................................................58 
7.1. 
Concomitant Therapy .................................................................................................58 
7.1.1. 
Permitted Medications ................................................................................................58 
7.1.2. 
Prohibited Medications ...............................................................................................58 


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7.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................59 
7.2.1. 
CYP-Inhibiting/Inducing Drugs .................................................................................59 
8. 
SAFETY MONITORING AND REPORTING .........................................................61 
8.1. 
Adverse Events ...........................................................................................................61 
8.1.1. 
Definitions and Reporting ...........................................................................................61 
8.1.2. 
Laboratory Test Abnormalities ...................................................................................63 
8.1.3. 
Lack of Efficacy .........................................................................................................64 
8.2. 
Serious Adverse Events ..............................................................................................64 
8.2.1. 
Definitions ..................................................................................................................64 
8.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................65 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................65 
8.4.1. 
Adverse Event Reporting Period ................................................................................65 
8.4.2. 
Eliciting Adverse Events ............................................................................................65 
8.5. 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events .........................................................................................................................65 
8.5.1. 
Disease Progression ....................................................................................................65 
8.5.2. 
Death ...........................................................................................................................66 
8.6. 
Prompt Reporting of Serious Adverse Events ............................................................66 
8.6.1. 
Time Frames for Submitting Serious Adverse Events ...............................................66 
8.6.2. 
Regulatory Reporting Requirements for Serious Adverse Events .............................66 
8.7. 
Pregnancy Reporting ..................................................................................................67 
8.8. 
Post-Study Adverse Event ..........................................................................................67 
8.9. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................67 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................68 
9.1. 
Study Endpoints ..........................................................................................................68 
9.1.1. 
Primary Endpoint ........................................................................................................68 
9.1.2. 
Secondary Endpoints ..................................................................................................68 
9.1.3. 
Exploratory Endpoints ................................................................................................69 
9.2. 
Statistical Analysis ......................................................................................................69 
9.2.1. 
Randomization Methods .............................................................................................69 
9.2.2. 
Analysis Sets ...............................................................................................................69 


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9.2.3. 
Subject Disposition .....................................................................................................69 
9.2.4. 
Demographics and Other Baseline Characteristics .....................................................69 
9.2.5. 
Prior and Concomitant Therapy ..................................................................................70 
9.2.6. 
Efficacy Analysis ........................................................................................................70 
9.2.7. 
Pharmacokinetics Analyses ........................................................................................74 
9.3. 
Safety Analyses ..........................................................................................................74 
9.3.1. 
Extent of Exposure .....................................................................................................74 
9.3.2. 
Adverse Events ...........................................................................................................74 
9.3.3. 
Laboratory Analyses ...................................................................................................75 
9.3.4. 
Vital Signs ..................................................................................................................75 
9.3.5. 
Electrocardiogram .......................................................................................................75 
9.4. 
Sample Size Consideration .........................................................................................75 
9.5. 
Interim Analysis ..........................................................................................................76 
9.6. 
Final Analysis .............................................................................................................76 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................77 
10.1. 
Steering Committee ....................................................................................................77 
10.2. 
Data Monitoring Committee .......................................................................................77 
10.3. 
Independent Central Review .......................................................................................77 
10.4. 
Provision of Study Results and Information to Investigators .....................................77 
11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ..........................78 
11.1. 
Regulatory Authority Approval ..................................................................................78 
11.2. 
Investigator Responsibilities .......................................................................................78 
11.2.1. 
Good Clinical Practice ................................................................................................78 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................78 
11.2.3. 
Informed Consent .......................................................................................................79 
11.2.4. 
Investigator Reporting Requirements .........................................................................79 
11.2.5. 
Confidentiality ............................................................................................................79 
11.2.6. 
Data Collection ...........................................................................................................80 
11.2.7. 
Data Management/Coding ..........................................................................................80 
11.2.8. 
Data Integrity and In-house Blinding .........................................................................81 
11.2.9. 
Drug Accountability at Site ........................................................................................81 
11.2.10. 
Inspections, Audits, and Monitoring Visits ................................................................82 


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11.2.11. 
Protocol Adherence ....................................................................................................82 
11.2.12. 
Financial Disclosure ...................................................................................................82 
11.3. 
Study Report and Publications....................................................................................82 
11.4. 
Study and Study Center Closure .................................................................................83 
11.5. 
Records Retention and Study Files .............................................................................83 
11.6. 
Information Disclosure and Inventions ......................................................................85 
11.7. 
Joint Investigator/Sponsor Responsibilities ................................................................85 
11.7.1. 
Access to Information for Monitoring ........................................................................85 
11.7.2. 
Access to Information for Auditing or Inspections ....................................................86 
12. 
REFERENCES ...........................................................................................................87 
APPENDIX 1. SIGNATURE OF INVESTIGATOR .................................................................91 
APPENDIX 2. CLL RESPONSE DEFINITIONS ......................................................................92 
APPENDIX 3. THE LUGANO CLASSIFICATION FOR CT-BASED RESPONSE 
FOR SLL (CHESON ET AL 2014)............................................................................94 
APPENDIX 4. NEW YORK HEART ASSOCIATION CLASSIFICATION ...........................97 
APPENDIX 5. CYP3A INHIBITORS AND INDUCERS .........................................................98 
APPENDIX 6. ECOG PERFORMANCE STATUS...................................................................99 
APPENDIX 7. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-LEVELS 
HEALTH QUESTIONNAIRE .................................................................................100 
APPENDIX 8. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 .................................................................................102 
APPENDIX 9. GRADING SCALE FOR HEMATOLOGIC TOXICITY IN CLL 
STUDIES HEMATOLOGIC GRADING SCHEME ...............................................104 
APPENDIX 10. SCHEDULE OF ASSESSMENTS ................................................................105 
APPENDIX 11. SELECT ADVERSE EVENTS OF INTEREST: TOXICITY 
MANAGEMENT .....................................................................................................109 
 


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LIST OF TABLES  
Table 1: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection (Detected Positive 
by PCR) ......................................................................................................................44 
Table 2: 
Zanubrutinib Dose Reduction Levels .........................................................................52 
Table 3: 
Zanubrutinib Dose Reduction Steps for Nonhematologic Toxicity ...........................53 
Table 4: 
Dose Modification for Zanubrutinib when CoAdministered with 
Strong/Moderate CYP3A Inhibitors or Inducers ........................................................54 
Table 5: 
Example of Local Prescribing Guidance for Ibrutinib Dose Reduction Levels .........54 
Table 6: 
Example of Local Prescribing Guidance for Dose Modifications for Use of 
Ibrutinib with CYP3A Inhibitors ................................................................................56 
Table 7: 
Time Frames and Documentation for Reporting SAEs to the Sponsor or 
Designee .....................................................................................................................66 
Table 8: 
Monitoring Boundaries for the ORR Non-inferiority Testing ....................................71 
Table 9: 
Monitoring Boundaries for the ORR Superiority Testing ..........................................71 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................27 
 


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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BTK 
Bruton tyrosine kinase 
CBC  
complete blood count 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CRi 
complete response with incomplete bone marrow recovery 
CT 
computed tomography 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer quality of life 
cancer core questionnaire 
EQ-5D-5L 
European quality of life 5-dimensions 5-levels health questionnaire 
FDA 
Food and Drug Administration 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IGHV 
immunoglobulin variable region heavy chain 
IRB 
Institutional Review Board 


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Abbreviation 
Definition 
IRT 
Interactive Response Technology 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PR 
partial response 
PR-L 
partial response with lymphocytosis 
PRO 
patient-reported outcome 
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SLL 
small lymphocytic lymphoma 
BGB-3111 
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1. 
INTRODUCTION  
1.1. 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  
Chronic lymphocytic leukemia (CLL) is a malignant disorder of B lymphocytes.  It is the most 
common leukemia in the Western world with an incidence of 4.2 in every 100,000 persons per 
year.  The incidence increases to > 30 in 100,000 per year in people aged more than 80 years.  
The disease has a median age at diagnosis of 72 years (Eichhorst et al 2015). 
The World Health Organization classification considers CLL and small lymphocytic lymphoma 
(SLL) to be different clinical manifestations of the same disease (Swerdlow et al 2008); 
therefore, CLL and SLL are considered collectively.  CLL is a treatable but essentially incurable 
disease.  Diagnosis of CLL requires the presence of ≥ 5000 B lymphocytes/µL in the peripheral 
blood for at least 3 months with clonality of the circulating B lymphocytes confirmed by flow 
cytometry.  The leukemia cells are characteristically small, mature lymphocytes with a narrow 
border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially 
aggregated chromatin.  Presence of a cytopenia caused by a typical marrow infiltrate defines the 
diagnosis of CLL regardless of the number of peripheral blood B lymphocytes or lymph node 
involvement.  Diagnosis of SLL requires the presence of lymphadenopathy and absence of 
cytopenia caused by a clonal marrow infiltrate.  The number of B lymphocytes in the peripheral 
blood should also not exceed 5000/µL for SLL.  CLL cells co-express the T-cell antigen CD5 
and B-cell surface antigens CD19, CD20, and CD23.  The levels of surface immunoglobulin are 
characteristically low compared to those found on normal B cells, with each clone of leukemia 
cells restricted to expressing either kappa or lambda immunoglobulin light chains 
(Moreau et al 1997; Ginaldi et al 1998; Hallek 2017). 
Genomic landscaping of CLL has revealed that the disease may often be initiated by the loss or 
addition of large chromosomal elements, eg, deletion 13q (~ 55%), deletion 11q (~ 25%), or 
trisomy 12 (10% to 20%), followed by additional mutations that may render the leukemia more 
aggressive (Landau et al 2015).  Deletions of the short arm of chromosome 17 (del17p) are 
detected in 5% to 8% of chemotherapy-naïve patients and almost always include band 17p13 
where the tumor suppressor gene TP53 is located.  Patients with the del17p clone tend to show 
marked resistance against genotoxic chemotherapies that cannot be overcome by the addition of 
anti-CD20 antibodies (Hallek M et al 2010; Seiffert et al 2012).  In addition to these mutations, 
additional recurrently mutated genes and somatic copy number variations have also been 
identified including NOTCH1, MYD88, TP53, ATM, SF3B1, FBXW7, POT1, CHD2, RPS15, 
IKZF3, ZNF292, ZMYM3, ARID1A, and PTPN11 (Landau et al 2015; Quesada et al 2011; 
Puente et al 2011; Puente et al 2015). 
Survival of CLL cells is dependent on a permissive microenvironment composed of 
macrophages, T cells, or stromal follicular dendritic cells providing stimuli for activation of 
crucial survival and pro-proliferative signaling pathways in transformed cells 
(Tsukada et al 2002; Pedersen et al 2002; Burger et al 2009; Hallek 2017).  This 
microenvironment produces chemokines, cytokines, and angiogenic factors that can interact with 
the leukemia cells, providing support for their survival (Burger et al 2009; Chiorazzi et al 2005; 
Reinart et al 2013; Hallek 2017). 


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Staging of CLL is typically per either the modified Rai or Binet staging system.  Modified Rai 
defines low-risk disease as those with lymphocytosis with circulating leukemia cells and/or 
marrow involvement (lymphoid cells > 30%) (formerly Rai stage 0).  Patients with 
lymphocytosis, lymphadenopathy, splenomegaly, and/or hepatomegaly are categorized as 
intermediate-risk disease (formerly Rai stage I or II), whereas high-risk disease includes patients 
with disease-related anemia (hemoglobin [Hgb] < 11 g/dL) and/or thrombocytopenia (platelet 
count < 100 x 109/L) (formerly Rai stage III and formerly Rai stage IV, respectively) 
(Rai et al 1975).  The Binet staging system is based on the number of areas involved, ie, presence 
of enlarged lymph nodes, organomegaly, or whether there is anemia or thrombocytopenia.  Areas 
of involvement considered include head and neck (including Waldeyer ring), axillae, groins, 
spleen, and liver.  Binet defines stage A as Hgb ≥ 10 g/dL, platelet count ≥ 100 x 109/L, and up 
to 2 involved areas; stage B is Hgb ≥ 10 g/dL, platelet count ≥ 100 x 109/L, and organomegaly 
greater than that defined for stage A (3 or more areas of nodal or organ enlargement); stage C is 
Hgb < 10 g/dL and/or platelet count < 100 x 109/L (Binet et al 1981). 
Decision to initiate treatment for CLL/SLL is based upon the presence of progressive or 
active/symptomatic disease, eg, progressive marrow failure, massive or progressive 
splenomegaly and/or lymphadenopathy, worsening lymphocytosis with an increase of > 50% 
over a 2-month period, lymphocyte doubling time of < 6 months, autoimmune complications that 
respond poorly to corticosteroids or other standard therapies, and/or constitutional symptoms 
(Hallek M et al 2008). 
Front-line CLL treatment for those without del17p or TP53 mutations may include combination 
fludarabine, cyclophosphamide, and rituximab, or bendamustine and rituximab for the frail 
elderly patients, while for those with del17p or TP53 mutations, ibrutinib (Bruton tyrosine kinase 
[BTK] inhibitor) or idelalisib (phosphatidyl inositol 3-kinase [Pi3K] delta inhibitor) plus 
rituximab should be considered.  For patients with impaired physical condition such as those 
with abnormal creatinine clearance and/or a low cumulative illness rating scale score but without 
del17p or TP53 mutations, treatment with chlorambucil + an anti-CD20 antibody such as 
obinutuzumab, or single-agent ibrutinib, may be considered.  For those with impaired physical 
condition who have del17p or TP53 mutations, single-agent ibrutinib, alemtuzumab, high-dose 
rituximab, or ofatumumab would be the preferred treatment options (Bauer et al 2012; 
Goede et al 2015; Hillmen et al 2015; Hallek 2017; Robak et al 2010).   
Second-line treatment for refractory CLL, defined as disease relapse within 6 months after last 
treatment, or for disease that relapses within 3 years after first remission, may include ibrutinib, 
idelalisib plus rituximab, venetoclax (BH3-mimetic designed to block the function of the Bcl-2 
protein) alone or in combination with an anti-CD20 antibody; alemtuzumab; fludarabine, 
cyclophosphamide, and rituximab (after bendamustine and rituximab) and vice versa; or 
lenalidomide.  For the suitable patient, allogeneic stem cell transplantation may also be offered.  
For patients who progress after 3 years from initial remission, the same first-line therapy may be 
administered again. 
1.2. 
B-cell Receptor Signaling  
B-cell receptor signaling is an important component for the survival of CLL cells, with 
continuous or repetitive B-cell receptor signaling capable of enabling the growth of CLL cells 
(Petlickovski et al 2005; Stevenson et al 2011).  The B-cell receptor signaling in CLL cells is 


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supported by different tyrosine kinases including BTK, spleen tyrosine kinase, ZAP70, Src 
family kinases, and Pi3K.  
Blockade of the B-cell receptor signaling cascade by inhibition of either BTK 
(Honigberg et al 2010) or the delta isoform of Pi3K (Zelenetz et al 2017) has been shown to 
induce profound inhibition of proliferative signaling from CLL cell-host interactions, resulting in 
frequent and durable responses in patients with both previously untreated and relapsed/refractory 
(R/R) CLL.  While the use of Pi3K delta inhibitors is often limited by toxicities including 
hepatotoxicity, colitis, and infection complications, particularly when used in combination with 
other agents (Zydelig® Summary of Product Characteristics) and in previously untreated patients 
(Falchi et al 2016), the BTK inhibitor ibrutinib has a highly favorable tolerability profile when 
compared to conventional therapies.   
1.2.1. 
Ibrutinib  
Ibrutinib is a small-molecule inhibitor of BTK.  Nonclinical studies have demonstrated inhibition 
of malignant B-cell proliferation and survival by ibrutinib in vivo, as well as cell migration and 
substrate adhesion in vitro.  In patients with recurrent B-cell lymphoma, > 90% occupancy of the 
BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after 
ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).   
In a Phase 1b/2 study of patients with R/R CLL (n = 85) where 51 patients received ibrutinib at a 
daily dose of 420 mg and 34 patients received ibrutinib at a daily dose of 840 mg, the overall 
response rate (ORR) was identical at 71% for both groups of patients.  An additional 20% and 
15% of patients had partial response (PR) with lymphocytosis (PR-L) in the 2 groups, 
respectively.  The responses observed were independent of clinical and genomic risk factors 
including del17p.  At 26 months, the estimated progression-free survival (PFS) rate was 75%, 
and the overall survival (OS) rate was 83% (Byrd et al 2013).  In another Phase 1b/2 trial that 
evaluated the combination of ibrutinib with ofatumumab in patients with either R/R CLL/SLL, 
prolymphocytic leukemia, or Richter’s transformation who had failed at least 2 prior therapies, 
ORR for patients with CLL/SLL was 100%, with estimated 12-month PFS of 89% 
(Jaglowski et al 2015). 
In a Phase 3 study that compared ibrutinib to ofatumumab in patients with relapsed or refractory 
CLL (RESONATE), at median follow-up of 9.4 months, ibrutinib was found to significantly 
improve PFS compared to ofatumumab (ibrutinib: median duration not reached; ofatumumab: 
8.1 months; p < 0.001).  Ibrutinib also significantly improved OS, with an OS rate of 90% at 12 
months for ibrutinib versus 81% for ofatumumab (p = 0.005). 
Overall response rate, per independent central review, was 42.6% (PR: 42.6%) for ibrutinib 
versus 4% (PR: 4%) for ofatumumab; PR-L rate was 20% and 0% for the 2 treatment groups, 
respectively. 
Overall response rate, per investigator review, was 69.7% (complete response [CR]/complete 
response with incomplete bone marrow recovery [CRi]: 2%; PR: 68%) for ibrutinib versus 
21.4% (CR/CRi: 1%; PR: 21%) for ofatumumab; PR-L rate was 15% and 2% for the 2 treatment 
groups, respectively. 
In another Phase 3 study (HELIOS) that compared 6 courses of bendamustine and rituximab in 
combination with either ibrutinib or placebo (n = 578) in patients with R/R CLL, at a median 


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follow-up of 17 months, PFS was significantly improved in the ibrutinib group (not reached) 
versus placebo (13.3 months) (p < 0.0001) (Chanan-Khan et al 2016). 
Ibrutinib is well tolerated compared with chemotherapeutic treatments for CLL.  In the Phase 3 
RESONATE study, Grade 3 or higher adverse reactions reported in ≥ 10% of patients treated 
with ibrutinib were diarrhea (4%), nausea (2%), stomatitis (1%), pyrexia (2%), upper respiratory 
tract infection (1%), pneumonia (10%), sinusitis (1%), urinary tract infection (4%), rash (3%), 
musculoskeletal pain (2%), arthralgia (1%), headache (1%), neutrophils decreased (23%), and 
platelets decreased (5%).  For the Phase 3 study comparing ibrutinib to chlorambucil in patients 
with CLL (RESONATE2), Grade 3 or higher adverse reactions reported in ≥ 10% of patients 
treated with ibrutinib were diarrhea (4%), stomatitis (1%), musculoskeletal pain (4%), arthralgia 
(1%), rash (4%), skin infection (2%), pneumonia (8%), urinary tract infections (1%), peripheral 
edema (1%), hypertension (4%), and headache (1%).  Across clinical trials, Grade 3 or higher 
bleeding events occurred in up to 6% of patients treated with ibrutinib, with bleeding event of 
any grade including bruising and petechiae occurring in approximately 50% of patients.  Atrial 
fibrillation and atrial flutter occurred in 6% to 9% of patients treated with ibrutinib, particularly 
in patients with cardiac risk factors, hypertension, acute infection, and a prior history of atrial 
fibrillation.  Other malignancies (3% to 16%) including non-skin carcinomas (1% to 4%) have 
been observed in patients on ibrutinib.  Tumor lysis syndrome has infrequently been reported 
with ibrutinib therapy.  Based on findings in animals, ibrutinib can cause fetal harm when 
administered to a pregnant woman (Imbruvica® US Prescribing Information). 
Ibrutinib is currently approved by the United States Food and Drug Administration (FDA) for 
treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy, 
patients with CLL/SLL with or without 17p deletion, patients with Waldenström 
macroglobulinemia, patients with marginal zone lymphoma who have received at least 1 prior 
anti-CD20 based therapy, and patients with chronic graft versus host disease after failure of 1 or 
more lines of systemic therapy (Imbruvica® US Prescribing Information). 
1.2.2. 
Zanubrutinib  
Zanubrutinib (also known as BGB-3111) is a potent, specific, and irreversible BTK inhibitor 
with a favorable pharmacologic and pharmacokinetic (PK) profile.  Zanubrutinib is different 
from ibrutinib in the following ways: 
• Zanubrutinib is more selective in the relative inhibition of BTK versus off-target 
tyrosine kinases, including EGFR, FGR, FRK, HER2, HER4, ITK, JAK 3, LCK, and 
TEC, which may reduce toxicities possibly due to off-target inhibition such as 
diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue;  
• Zanubrutinib has improved oral bioavailability;  
• Zanubrutinib displays significantly less inhibitory effect on rituximab-induced 
antibody-dependent cell-mediated cytotoxicity, and so is unlikely to adversely impact 
the anti-tumor effects of rituximab. 
1.2.2.1. 
Nonclinical Data for Zanubrutinib  
Summaries of nonclinical studies are provided below.  For more detailed information, please 
refer to the zanubrutinib Investigator’s Brochure (BGB-3111 Investigator’s Brochure). 


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Zanubrutinib is a potent, specific, and irreversible BTK kinase inhibitor with a 50% maximum 
inhibitory concentration (IC50) of 0.3 nM.  Cellular assays confirm that zanubrutinib inhibits 
B-cell receptor aggregation-triggered BTK autophosphorylation, and blocks downstream 
phospholipase C gamma 2 signaling in mantle cell lymphoma cell lines.  Zanubrutinib had an 
IC50 of 1.8 nM in a homogeneous time-resolved fluorescence-based BTKpY223 assay.  It 
potently and selectively inhibited cellular growth of several mantle cell lymphoma cell lines 
(REC-1, Mino, and JeKo-1) and the activated B-cell-type diffuse large B-cell lymphoma cell line 
TMD-8, with IC50 values from 0.36 to 20 nM, while it was inactive in many other hematologic 
cancer cell lines.  
In vivo studies have demonstrated that zanubrutinib induces dose-dependent anti-tumor effects 
against REC-1 mantle cell lymphoma xenografts engrafted either subcutaneously or systemically 
in mice, which are significantly more effective than ibrutinib.  Zanubrutinib also demonstrated 
better anti-tumor activity than ibrutinib in a TMD-8 diffuse large B-cell lymphoma subcutaneous 
xenograft model.  In a PK/pharmacodynamics study, oral administration of zanubrutinib resulted 
in time-dependent occupancy of BTK in blood and in spleen in mice and was approximately 
3-fold more potent than ibrutinib in mouse pharmacodynamic assays.  
In a panel of 342 human kinases, 1 µM zanubrutinib inhibited only 12 other kinases by > 70%.  
Zanubrutinib was more selective than ibrutinib for inhibition of kinase activity of BTK, EGFR, 
FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC.  Cellular assays also confirmed that 
zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR 
(> 6-fold).  Inhibition of ITK has been reported to reduce rituximab-induced antibody-dependent 
cell-mediated cytotoxicity.  Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib 
in inhibiting rituximab-induced antibody-dependent cell-mediated cytotoxicity, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity 
than ibrutinib in both biochemical and cellular assays. 
The toxicity profiles of zanubrutinib have been well characterized in rats and dogs.  No specific 
safety concerns were identified in vital organs/systems including cardiovascular system, 
respiratory system, and central nervous systems.  No corrected QT interval (QTc) changes were 
noted in the conscious telemetry-implanted dogs over 24 hours after dosing up to 100 mg/kg, or 
in the repeat dose toxicity studies in dogs over 91 days at doses up to 100 mg/kg/day.  No 
mortality or severe toxicity was noted in 91-day repeat dose toxicity studies in both rats and dogs 
at doses up to 300 and 100 mg/kg, respectively.  Test article-related reversible histopathology 
changes were mainly noted in rats, including pancreas, spleen, prostate gland, cecum, colon, 
rectum, skin (lip and/or nose), and uterus.  None of the above findings were considered to be 
adverse in the 91-day repeated dosing studies.  No genotoxicity was noted in the genotoxicity 
core battery studies. 
1.2.2.2. 
Summary of Relevant Clinical Experience with Zanubrutinib  
Dose Selection for Zanubrutinib 
In the first-in-human, Phase 1 study, BGB-3111-AU-003, the PK of zanubrutinib was linear 
between 40 and 320 mg orally once daily (BGB-3111 Investigator’s Brochure).  The absorption 
of zanubrutinib is rapid with median time to maximum plasma concentration (Cmax) of 2 hours.  
The terminal elimination half-life is approximately 4 hours at 320 mg once daily.  Results from a 
food effect study showed that zanubrutinib exposure was not altered by a high-fat breakfast, and 


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mean area under the plasma concentration time curve (AUC) and Cmax were increased by 12% 
and 51%, respectively, with standard breakfast when compared to fasting.  The magnitude of 
increase in exposure with food was well within doubling of exposure associated with 320 mg 
administered once a day in the ongoing Phase 1 study and was not associated with any new 
safety findings; therefore, zanubrutinib can be administered with or without food. 
Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all patients in the 
BGB-3111-AU-003 study, while occupancy in lymph node tissue was assessed only at 160 mg 
twice a day and 320 mg once a day (Tam et al 2015).  At the 160 mg twice daily dose, full BTK 
occupancy was observed at trough, suggesting that sustained target occupancy could be achieved 
in disease-originating tissues, thus more efficiently inhibiting BTK on a continuous basis, further 
preventing breakthrough signaling despite cycles of new BTK synthesis.  Activity has been 
observed across various B-cell malignancies (including CLL, mantle cell lymphoma, 
Waldenström macroglobulinemia, and follicular lymphoma) at all tested dose levels; thus, a 
minimum effective dose cannot be established at this time.  Conversely, there is now extensive 
experience at the 160 mg twice daily and 320 mg once daily dose; both schedules show a high 
level of activity without compromise of the tolerability profile as compared to lower doses of 
zanubrutinib.  Therefore, the dose of 160 mg administered orally twice daily has been selected as 
the recommended Phase 3 dose based on sustained target occupancy, high rates of objective 
response in multiple types of B-cell malignancies, and a favorable safety and tolerability profile. 
Preliminary Efficacy and Safety Data for Zanubrutinib in CLL/SLL Patients 
As of 16 September 2018, 123 patients with CLL/SLL have been enrolled in the BGB-3111-AU-
003 study (first-in-human, Phase 1).  Zanubrutinib was well tolerated, with 23.6% of patients 
reporting no drug-related adverse events (AEs) > Grade 2 severity.  The most frequent AEs of 
any attribution were contusion (54 patients; 43.9%), upper respiratory tract infection (36.6%), 
diarrhea (26.8%), cough (25.2%), headache (20.3%), and fatigue (18.7%).  There were 49 
patients (39.8%) that experienced at least one SAE, the most frequent included pneumonia 
(5.7%), febrile neutropenia (1.6%), neutropenia (1.6%), urinary tract infection (1.6%), lower 
respiratory tract infection (1.6%), arthralgia (1.6%), and cellulitis (1.6%). Of these SAEs, 18 
(14.6%) were assessed as possibly related to zanubrutinib. For more detailed information on the 
clinical experience for zanubrutinib please refer to the Investigator’s Brochure (Zanubrutinib). 
Efficacy for CLL/SLL patients from the BGB-3111-AU-003 trial was last reported for a data cut 
of 31 March 2017 (Seymour et al 2017). For the 66 patients evaluable for efficacy, after a 
median follow-up of 10.5 months (range, 2.2 to 26.8 months), the ORR was 94% (62/66), with 
partial response (PR) rate of 82% (54/66), partial response with lymphocytosis rate of 9% (6/66), 
and stable disease (SD) rate of 5% (3/66).  The response rate to zanubrutinib therapy in 
previously untreated patients (n = 16) was 100% (16/16 with 1 complete response [CR], 13 with 
PR and 1 with partial response with lymphocytosis). 
Clinical Pharmacology 
The QT interval prolongation potential of zanubrutinib was evaluated in healthy subjects in a 
thorough QT study (BGB-3111-106).  Results from this study demonstrated that single oral 
doses of zanubrutinib at a therapeutic dose of 160 mg and a supratherapeutic dose of 480 mg did 
not have a clinically relevant effect on electrocardiogram (ECG) parameters, including QTc 


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intervals and other ECG intervals.  Because of the short half-life and no accumulation seen upon 
multiple-dosing, these results are also applicable for steady-state conditions. 
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicate that 
coadministration of zanubrutinib with the strong cytochrome P450 (CYP) 3A inducer rifampin 
(600 mg every day for 8 days) decreased exposure of zanubrutinib by 13.5-fold for AUC 
extrapolated to infinity (AUC0-∞), and 12.6-fold for Cmax, in healthy subjects.  Coadministration 
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. 
Additionally, a preliminary physiologically-based pharmacokinetic (PBPK) model was 
developed and was used to predict the effect of moderate CYP3A inhibitors and CYP3A 
inducers on the PK of zanubrutinib.  PBPK simulations suggest that coadministration of multiple 
doses of a moderate CYP3A inhibitor (eg, fluconazole, diltiazem and erythromycin) may 
increase the Cmax and AUC of zanubrutinib by approximately 2-fold.  PBPK simulations suggest 
that a moderate CYP3A inducer (eg, efavirenz) may decrease the Cmax and AUC of zanubrutinib 
by approximately 2 to 3-fold.  
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), and BCRP (rosuvastatin) using a cocktail approach.  The results 
show that zanubrutinib does not significantly affect drugs metabolized by CYP2C9 (warfarin) or 
transported by BCRP (statins).  Zanubrutinib has a weak induction effect on CYP3A and 
CYP2C19 enzymes.  AUC from time 0 to the last measurable timepoint (AUC0-t) and Cmax 
values were approximately 47% and 30% lower, respectively, when midazolam was 
coadministered with zanubrutinib.  AUC0-t and Cmax values were approximately 36% and 20% 
lower, respectively, when omeprazole was coadministered with zanubrutinib. Repeated dosing of 
zanubrutinib increased exposure of digoxin (P-gp substrate) with a mean increase of 11% for 
AUC0-t and 34% for Cmax. 
1.2.2.3. 
Benefit-Risk Assessment  
As of 16 September 2018, approximately 1200 patients have received zanubrutinib in completed 
and ongoing clinical trials evaluating zanubrutinib either as monotherapy or in combination with 
another agent.  Available data for zanubrutinib in patients with CLL/SLL support a positive 
benefit-risk profile for the use of zanubrutinib as an investigational agent for treatment of 
CLL/SLL. 


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2. 
STUDY OBJECTIVES  
Primary: 
• To compare the efficacy of zanubrutinib versus ibrutinib as measured by overall 
response rate determined by investigator assessment 
Secondary: 
• To compare the efficacy of zanubrutinib versus ibrutinib as measured by: 
− Progression-free survival determined by investigator assessment and independent 
central review 
− Overall response rate determined by independent central review 
− Duration of response as determined by independent central review  
− Duration of response as determined by investigator assessment 
− Time to treatment failure 
− Rate of partial response with lymphocytosis or higher determined by independent 
central review  
− Overall survival 
− Patient-reported outcomes 
• To compare the safety of zanubrutinib versus ibrutinib 
Exploratory: 
• To evaluate the correlation between clinical outcomes (eg, overall response rate, 
progression-free survival, duration of response, overall survival, rate of partial 
response) and the prognostic and predictive biomarkers, including minimal residual 
disease (MRD) 
• To evaluate the pharmacokinetics of zanubrutinib 


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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a Phase 3, randomized study of zanubrutinib versus ibrutinib in approximately 600 
patients with R/R CLL/SLL.  The primary efficacy endpoint is ORR determined by investigator 
assessment.  While the primary efficacy endpoint is per investigator assessment, ORR per 
independent central review will also be analyzed to support the primary analysis.  In the United 
States, ORR assessed by independent central review will be the basis for regulatory decisions.  
Disease response will be assessed per the “modified” 2008 International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) guidelines (Hallek M et al 2008) with modification for 
treatment-related lymphocytosis (Cheson et al 2012) for patients with CLL (Appendix 2), and 
per Lugano Classification for non-Hodgkin lymphoma (NHL) (Cheson et al 2014) for patients 
with SLL (Appendix 3).  Rate of PR-L or higher will be assessed as a secondary efficacy 
endpoint considering the finding that treatment with BTK inhibitors may lead to lymphocytosis 
due to redistribution of leukemia cells from lymphoid compartment to blood.  In these instances, 
treatment-related transient progressive lymphocytosis is not a sign of treatment failure or disease 
progression and has no bearing on treatment outcome (Woyach et al 2014).  
The study is broken into three periods for every patient: 
• Screening Period (Section 5.2) 
• Treatment Period (Section 5.11) 
• Post-Treatment Period 
− End of Treatment Visit (Section 5.12.1) 
− Long-Term Follow-up (Section 5.12.2)  
− Survival Follow-up (Section 5.12.3)  
Patients will be randomized in a 1:1 manner to one of the following treatment arms: 
• Arm A:  Zanubrutinib 160 mg orally twice daily 
• Arm B:  Ibrutinib 420 mg orally once daily 
Randomization will be stratified by age (< 65 years versus ≥ 65 years), geographic region (China 
versus non-China), refractory status (yes or no), and del17p/TP53 mutation status (present or 
absent). For the purposes of stratification, refractory disease is defined as either no objective 
response or disease progression within 6 months of the last CLL/SLL treatment, and relapsed 
disease is defined as patients whose disease relapses more than 6 months after the last CLL/SLL 
treatment and subsequently progressed.   
Treatment with zanubrutinib and ibrutinib will be open label.  Study treatment will continue until 
disease progression, or any of the events outlined in Section 6.7. The study duration is estimated 
to be approximately 51 months (see Section 3.5). 


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Study Assessments: 
The timing of all study assessments is described in Appendix 10. Assessments to be performed 
during the study include: 
• Pharmacokinetics (Section 5.4) 
• Disease-related constitutional symptoms (Section 5.6.1) 
• Physical examination of liver, spleen, and lymph nodes (Section 5.6.2) 
• Computed tomography (CT) scan of neck, chest, abdomen, and pelvis with contrast 
(see Section 5.6.3 for details) 
• Bone marrow examination at screening, for patients with baseline marrow 
involvement who meet clinical and laboratory criteria for CR or CRi, and at time of 
suspected cytopenic progression (see Section 5.6.4 for details) 
• Patient-reported outcomes (PROs) including the European quality of life 5-
dimensions 5-levels health questionnaire (EQ-5D-5L) and European Organisation for 
Research and Treatment of Cancer quality of life cancer core questionnaire (EORTC 
QLQ-C30). In select countries there is also an optional device-based evaluation of 
quality of life and activity that patients may consent to (see Section 5.7). 
• Laboratory studies including hematology, serum chemistry, serum immunoglobulins, 
coagulation, hepatitis B and C, pregnancy, and HIV (See Sections 5.8) 
• Biomarkers blood and bone marrow samples to investigate genetic alterations in the 
tumor cells such as del17p, del11q, 12q+, and immunoglobulin variable region heavy 
chain (IGHV) mutation analysis as well as to measure potential resistance 
mechanisms for zanubrutinib (see Section 5.9) 
Patients should remain on study treatment until disease progression is confirmed by independent 
central review (as described in Section 6.7).   
Assessments of safety will include AEs, SAEs, clinical laboratory tests, physical examinations, 
electrocardiogram (ECG), and vital signs (Section 5.5).  AEs will be graded for severity per 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v4.03 and the Grading Scale for Hematologic Toxicities in CLL Studies (see Section 8.1.1.1).  
An independent Data Monitoring Committee (DMC) will periodically monitor safety data (see 
Section 10.2). 
Efficacy (Section 5.6) will be assessed locally by the investigator as well as by independent 
central review (Section 10.3). Progression must be confirmed by independent central review 
(Section 6.7). 


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3.2. 
Study Schema  
Figure 1: 
Study Schema  
 
Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma. 
Randomization will be stratified by age (< 65 years versus ≥ 65 years), geographic region (China versus non-China), 
refractory status (yes or no), and del17p/TP53 mutation status (present versus absent). 
3.3. 
Blinding  
Treatment with zanubrutinib and treatment with ibrutinib will be open label; however, the 
assessment of ORR by independent central review (primary endpoint) will be blinded. 
3.4. 
Study Rationale  
B-cell receptor signaling regulates multiple cellular processes, including proliferation, 
differentiation, apoptosis, and cell migration, and is essential for normal B-cell development and 
survival (Advani et al 2013).  It also plays an important role in survival of CLL cells.  BTK has a 
relevant role in the signal transduction of B-cell receptor and can lead to downstream activation 
of cell survival pathways such as NF-B and MAP kinases via the Src family kinases.  Ibrutinib, 
an FDA-approved first-generation BTK inhibitor that blocks B-cell receptor signaling in human 
B cells via specific active site occupancy, has been shown to be efficacious and tolerated in the 
treatment of CLL/SLL.  
In the Phase 3 RESONATE study that compared ibrutinib to ofatumumab in patients with 
relapsed or refractory CLL/SLL, ORR (PR or higher) per independent central review was 42.6% 
(PR: 42.6%) for ibrutinib, whereas per investigator review, ORR was 69.7% (CR/CRi: 2%; PR: 
68%) for ibrutinib (Byrd et al 2014).   Across ibrutinib clinical trials, Grade 3 or higher bleeding 
events occurred in up to 6% of patients treated with ibrutinib, with bleeding event of any grade 
including bruising and petechiae occurring in approximately 50% of patients.  Atrial fibrillation 
and atrial flutter occurred in 6% to 9% of patients treated with ibrutinib (Imbruvica® U.S. 
Prescribing Information). 
As of 31 March 2017, preliminary efficacy data from the Phase 1 BGB-3111-AU-003 revealed a 
response rate per protocol definition (CR/CRi + PR + PR-L) of 92% for patients with R/R CLL, 


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with 2% CR (n = 1), 82% PR (n = 41), and 8% PR-L (n = 4).  Response rate for PR or higher 
was 84% in the R/R population. 
Treatment with zanubrutinib has been well tolerated across all studies thus far.  Compared to 
ibrutinib, zanubrutinib is more selective in the relative inhibition of BTK versus off-target 
tyrosine kinases, henceforth possibly leading to reduced toxicities due to off-target inhibition 
such as diarrhea, thrombocytopenia, bleed, atrial fibrillation, rash, and fatigue.  In study 
BGB-3111-AU-003, there was 1 patient among 69 evaluable patients who had experienced a 
Grade 3 or higher AE of petechiae/purpura/contusion.  In terms of Adverse Event of Interest, 
atrial fibrillation was reported in 1 patient (1%), an SAE of Grade 2 diarrhea in 1 patient, and an 
SAE of purpura (subcutaneous hemorrhage) in 1 patient; none of which led to treatment 
discontinuation.  No event of Richter’s transformation has occurred. 
Based on the preliminary data from BGB-3111-AU-003, the efficacy of zanubrutinib in the 
treatment of CLL/SLL (PR or higher: 84%) is hypothesized to at least be non-inferior to ibrutinib 
(PR or higher [RESONATE]: 69.7% per investigator review; 42.6% per independent central 
review).  Preliminary safety data from the BGB-3111-AU-003 study also revealed a tolerable 
and safe profile for zanubrutinib, with possibly a lower rate of Adverse Event of Interest such as 
atrial fibrillation and bleed when compared with ibrutinib.  In view of these findings, a Phase 3 
non-inferiority study comparing the efficacy of zanubrutinib and ibrutinib measured by ORR, the 
primary endpoint, will be conducted.  
3.5. 
Duration of Study  
The total duration of this study is expected to be approximately 51 months based on assuming an 
expected enrollment duration of 24 months, and an estimated follow up of 27 months after the 
last patient is enrolled. 
3.5.1. 
Study Drug Access at Study Closure  
Patients, who in the opinion of the investigator, continue to benefit from study treatment with 
either zanubrutinib or ibrutinib may continue treatment with zanubrutinib after study closure by 
enrolling in the Zanubrutinib Long-Term Extension Study.  This study is a rollover study for 
patients who wish to continue receiving zanubrutinib, which will continue to be supplied until 
the patient progresses. 


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4. 
ELIGIBILITY CRITERIA  
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet ALL of the following criteria: 
1. Age 18 years or older 
2. Confirmed diagnosis of CLL or SLL that meets the IWCLL criteria (Hallek et al 2008) 
3. CLL/SLL requiring treatment as defined by at least 1 of the following criteria: 
a. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia 
b. Massive (≥ 6 cm below left costal margin), progressive, or symptomatic 
splenomegaly 
c. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic 
lymphadenopathy 
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or 
lymphocyte-doubling time of < 6 months.  Lymphocyte-doubling time may be 
obtained by linear regression extrapolation of absolute lymphocyte counts obtained at 
intervals of 2 weeks over an observation period of 2 to 3 months.  In patients with 
initial blood lymphocyte counts of < 30 x 109/L (30,000/L), lymphocyte-doubling 
time should not be used as a single parameter to define treatment indication.  In 
addition, factors contributing to lymphocytosis or lymphadenopathy other than 
CLL/SLL (eg, infection) should be excluded. 
e. Constitutional symptoms, defined as any 1 or more of the following disease-related 
symptoms or signs: 
i. Unintentional weight loss of ≥ 10% within the previous 6 months  
ii. Significant fatigue  
iii. Fevers > 100.5ºF or 38ºC for ≥ 2 weeks without other evidence of infection. 
iv. Night sweats for > 1 month without evidence of infection 
4. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL.  A line of 
therapy is defined as completing at least 2 cycles of treatment of standard regimen 
according to current NCCN or ESMO guidelines, or of an investigational regimen on a 
clinical trial.  
5. Measurable disease by CT/magnetic resonance imaging (MRI).  Measurable disease is 
defined as ≥ 1 lymph node > 1.5 cm in longest diameter and measurable in 2 
perpendicular diameters or an extranodal lesion must measure > 10 mm in longest 
perpendicular diameter (LPD).  
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
7. Life expectancy ≥ 6 months 


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8. Adequate bone marrow function as defined by: 
a. Absolute neutrophil count (ANC) ≥ 1000/mm3 (growth factor use is allowed), except 
for patients with bone marrow involvement in which case ANC must be ≥ 750/mm3 
• the screening hematology values confirming patient meets the ANC 
requirement must be dated at least 14 days following the most recent 
administration of peg-filgrastim and at least 7 days following the most recent 
administration of other myeloid growth factors (eg, G-CSF, GM-CSF) 
b. Platelet ≥ 75,000/mm3 (may be post-transfusion), except for patients with bone 
marrow involvement by CLL in which case the platelet count must be ≥ 30,000/mm3 
c. Hemoglobin ≥ 7.5 g/dL (may be post-transfusion) 
9. Patient must have adequate organ function defined as: 
a. Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or 
the Modification of Diet in Renal Disease [MDRD] equation, or as measured by 
nuclear medicine scan or 24-hour urine collection) 
b. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper 
limit of normal unless due to CLL/SLL 
c. Serum total bilirubin < 3.0 × upper limit of normal (unless documented Gilbert’s 
syndrome) 
10. Female patients of childbearing potential must practice highly effective methods 
(Section 5.2.1) of contraception initiated prior to first dose of study drug, for the duration 
of the study, and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib   
11. Male patients are eligible if vasectomized or if they agree to the use of barrier 
contraception with other highly effective methods described in Section 5.2.1 during the 
study treatment period and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib 
12. Ability to provide written informed consent and can understand and comply with the 
requirements of the study. 
4.2. 
Exclusion Criteria  
Each patient eligible to participate in this study must NOT meet any of the following exclusion 
criteria: 
1. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s 
transformation (biopsy based on clinical suspicion may be needed to rule out 
transformation) 
2. Clinically significant cardiovascular disease including the following: 
a. Myocardial infarction within 6 months before screening 
b. Unstable angina within 3 months before screening 
c. New York Heart Association class III or IV congestive heart failure (Appendix 4) 
d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, 
ventricular fibrillation, Torsades de Pointes) 
e. QTcF > 480 milliseconds based on Fridericia’s formula 


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f. History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place 
g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure > 170 mmHg and diastolic 
blood pressure > 105 mmHg at screening 
3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous 
cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or 
breast 
4. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand 
disease, or history of spontaneous bleeding requiring blood transfusion or other medical 
intervention 
5. History of stroke or intracranial hemorrhage within 180 days before first dose of study 
drug  
6. Severe or debilitating pulmonary disease 
7. Unable to swallow study drug, or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, bariatric 
surgery procedures, symptomatic inflammatory bowel disease, or partial or complete 
bowel obstruction 
8. Active fungal, bacterial, and/or viral infection requiring systemic therapy 
9. Known central nervous system involvement by leukemia or lymphoma 
10. Underlying medical conditions that, in the investigator’s opinion, will render the 
administration of study drug hazardous or obscure the interpretation of toxicity or AEs 
11. Known infection with HIV or serologic status reflecting active viral hepatitis B or C 
infection as follows: 
a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb).  Patients with presence of HBcAb, but absence of HBsAg, are eligible if 
hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to 
undergo monitoring for HBV reactivation 
b. Presence of hepatitis C virus (HCV) antibody.  Patients with presence of HCV 
antibody are eligible if HCV RNA is undetectable  
12. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C 
13. Major surgery within 4 weeks of the first dose of study drug 
14. Prior treatment with a BTK inhibitor 
15. Last dose of prior therapy for CLL/SLL ≤ 14 days before randomization, with the 
following additional exclusion requirements:  
a. Treatment with monoclonal antibody-based therapy within 28 days of first dose of 
study drug 
b. Treatment with chimeric antigen receptor T-cell therapy within 180 days of first dose 
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c. Treatment with Chinese herbal medicine with anticancer intent within 28 days of first 
dose of study drug 
d. Chemotherapy or radiation treatment within 21 days of first dose of study drug or 
hematopoietic stem cell transplantation within 90 days of first dose of study drug 
16. Ongoing need for corticosteroid use during the trial. NOTE: systemic corticosteroids 
must be fully tapered off/stopped at least 5 days before the first dose of study drug 
17. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1 (except for 
alopecia, ANC, and platelet count; for ANC and platelet count, see inclusion criterion 8) 
18. Pregnant or lactating women 
19. Vaccination with a live vaccine within 35 days prior to the first dose of study drug 
20. Ongoing alcohol or drug addiction 
21. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug 
22. Patient requires treatment with warfarin or other vitamin K antagonists  
23. Requires ongoing treatment with a strong CYP3A inhibitor or inducer 
24. Concurrent treatment for CLL/SLL outside of this clinical trial (includes the screening 
period) 
25. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, 
idiopathic thrombocytopenia purpura) requiring treatment. 


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5. 
ENROLLMENT AND STUDY PROCEDURES  
Study enrollment and procedures are summarized in the following subsections.  The timing of all 
study procedures is provided in the Schedule of Assessments (Appendix 10).  
5.1. 
Study Visit Schedule  
Scheduled study visits are outlined in the Schedule of Assessments (Appendix 10). The study 
visit schedule is based around 28-day cycles, with visits expected to occur in D1 of a given 
cycle. The length of a cycle should remain 28-days regardless of any drug holds occurring during 
that cycle. Acceptable windows around these visits are indicated in Appendix 10:  a visit window 
of ± 6 days (ie, 6 days before or after the given day) can be assumed for any cases not otherwise 
specified in the Schedule of Assessments (Appendix 10).  Study drug supply (Section 6.1.3) and 
dispensation (Section 6.1.4) must be taken into account when scheduling study visits.  
Procedures for a given visit may be split across the window to allow for drug resupply and 
completion of study procedures.  
5.2. 
Screening  
Before screening procedures are conducted, the patient must sign an informed consent form 
(ICF). Study site personnel must explain to potential study participants all aspects of the study, 
including all scheduled visits and activities. A copy of the ICF will be given to the patient to 
read, and the patient must have adequate time to understand the content and ask questions. 
Study site personnel must obtain signed informed consent before any study-specific procedures 
are conducted unless the procedures are part of routine standard of care, and must document the 
informed consent process in the patient’s clinical record.  Consent must be obtained using the 
most current version of the form approved by the Independent Ethics Committee (IEC).  
A patient may sign the informed consent form without starting the screening window; the 
screening window will start with the first protocol-required screening procedure.  
All screening procedures must be performed within the screening window (35 days), unless 
noted otherwise; assessments not completed within this interval must be repeated.  Repeating 
screening procedures or tests are allowed once if the patient did not previously meet the 
inclusion and exclusion criteria or if needed to have a documented result within the 
protocol-specified screening window. 
For patients who provide informed consent and subsequently do not meet eligibility criteria or 
withdraw consent before randomization, study site personnel should document the screen failure 
in the patient’s source documents.  The documentation should include demographics and medical 
history, the reason for screen failure, the eligibility criteria reviewed, procedures performed, etc. 
Patients who provide informed consent and meet all eligibility criteria should be randomized to 
the trial (Section 5.2.6). 


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5.2.1. 
Females of Childbearing Potential and Contraception  
A woman is considered of childbearing potential, ie, fertile, following menarche and until 
becoming postmenopausal unless permanently sterile.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Contraception methods 
include the following: 
• Combined (estrogen- and progestogen- containing) hormonal contraception 
associated with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
• An intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success) 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day prior to first 
dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose 
of zanubrutinib or ibrutinib.  Total sexual abstinence should only be used as a 
contraceptive method if it is in line with the patients’ usual and preferred lifestyle.  
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to investigational medicinal 
product, and withdrawal are not acceptable methods of contraception.   
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and, if used, this method must be 
used in combination with another acceptable method listed above. 
If patient is using hormonal contraceptives such as birth control pills or devices, a barrier method 
of contraception (eg, condoms) must also be used. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  However, in the absence of 12 months of amenorrhea, a single 
follicle-stimulating hormone measurement is insufficient. 
5.2.2. 
Patient Numbering  
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant.  
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Once a patient number has been assigned to a patient, it cannot be re-assigned to any other 
patient.  
5.2.3. 
Demographics  
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
ethnicity data are collected in accordance with International Council for Harmonisation (ICH) 
guidance (ICH E5 1998, ICH E17 2017) adopted by the European Medicines Agency and US 
FDA, to understand whether race/ethnicity could influence the PK, safety, and/or efficacy of the 
study drug. For example, population PK analysis is a well-established, quantitative method that 
can quantify and explain the variability in drug concentrations among patients. Such variability 
can be attributed to intrinsic factors (eg, body weight, age, gender, race/ethnicity), or to extrinsic 
factors (eg, concomitant medications), and can lead to clinically relevant changes in drug 
concentrations that require a change in the dose or dosing regimen. Results from race/ethnicity 
and other demographic analyses will be incorporated into drug product labeling to provide 
guidance on safety and efficacy variations (if any) linked to certain populations (eg, race or 
ethnic group) as well as any potential dose adjustment needed for those populations. Therefore, 
collecting race/ethnicity data in the study is essential to understand whether race/ethnicity could 
influence the PK, safety, and/or efficacy. 
5.2.4. 
Medical and Cancer History  
Review all medical and cancer history after obtaining informed consent, including presence or 
absence of disease-related constitutional symptoms.  Clinically significant medical history (ie, 
previous diagnoses, diseases, or surgeries) that does not pertain to the study indication, started 
before signing the informed consent, but considered relevant to the patient’s study eligibility will 
be collected and captured in the electronic case report form (eCRF).  “Clinically significant” is 
defined as any event, diagnosis, or laboratory value requiring treatment or follow-up or the 
presence of signs or symptoms that require medical intervention.  Concurrent medical signs and 
symptoms must be documented to establish baseline severities. 
Other background information to be collected includes history of disease (including the date of 
initial diagnosis and current disease status), staging, sites of disease, and presence or absence of 
disease-related constitutional symptoms.  Prior medications/significant non-drug therapies and 
demographic data (gender, year of birth [or age], and race/ethnicity) will also be collected. 
Record non-serious AEs during the screening period as medical history.  
5.2.5. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient.  All screening procedure 
results and relevant medical history must be available before eligibility can be determined.  All 
inclusion criteria must be met, and none of the exclusion criteria may apply.  No eligibility 
waiver will be granted. 
After a patient is screened and the investigator determines the patient is eligible for 
randomization, study site personnel will complete an Eligibility Authorization Packet and the 
medical monitor or designee will provide final approval for enrollment in writing.  Study site 


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personnel should ensure that a medical monitor-approved Eligibility Authorization Packet is in 
the patient’s file before proceeding with study procedures.  
After a patient is randomized, refer to concomitant therapies (Section 7) and study drug 
discontinuation (Section 6.7) for guidance on a patient’s eligibility for treatment.  
5.2.6. 
Enrollment/Randomization  
Study treatment should commence within 5 days after randomization, although small extensions 
to this due to drug supply logistics are permissible with Sponsor approval. Interactive Response 
Technology (IRT) will be used to randomize patients to treatment arm and to assign study drug 
as applicable (see Section 6.1.3).  
5.3. 
Study Drug Dispensation  
At visits where study drug dispensation occurs, study center personnel should ensure adequate 
drug supply for administration at home throughout the treatment phase as detailed in the 
pharmacy manual. Drug may be dispensed as frequently as once every 28-day cycle, but may be 
modified to less frequently depending on supply considerations throughout the trial (consult the 
most recent pharmacy manual). 
Study patients should be instructed to bring all drug bottles to their study visits, and drug 
accountability should be performed at each visit (see Section 6.1.4 and Section 5.6.1 for further 
detail). 
Additional drug dispensation visits may occur to ensure a patient has sufficient supply to 
maintain drug administration compliance as per protocol. The investigator is to instruct the 
patient to take the study drug exactly as prescribed and at approximately the same time each day 
of dosing.  Patients will be requested to bring their unused medication, and all empty bottles, to 
the center at each visit in order for the study staff to perform drug accountability.  All dosages 
prescribed and dispensed to the patient and all dose changes including reason for dose changes 
during the study must be recorded on the appropriate eCRF. 
For dispensation of study drug provided by the sponsor, please ensure that the bottle number(s) 
listed in IRT matches what is being given to the patient. 
For drug that is locally procured, please ensure that the lot number dispensed is being recorded 
on the accountability log. 
5.4. 
Pharmacokinetics  
Blood will be collected to characterize the PK of zanubrutinib. 
Sparse PK samples will be collected from all patients assigned to Arm A (zanubrutinib) only at 
the timepoints as described in Appendix 10.  PK samples will only be collected from sites that 
are able to adequately follow the sampling, handling and processing procedures outlined in the 
laboratory manual. 
The time of study drug administration and actual PK collection time on Cycle 1 Day 1 must be 
recorded on the eCRF.  The actual time each sample is collected will be captured to the nearest 
minute in the eCRF and recorded in the database. 


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Blood samples (2 mL) for PK analysis will be collected into EDTA collection tubes.  Details 
concerning handling of the PK plasma samples, including labeling and shipping instructions, will 
be provided in the laboratory manual for this study.   
Samples will be shipped to the designated bioanalytical lab for quantification of plasma 
zanubrutinib concentrations using a validated method. 
5.5. 
Safety Assessments  
5.5.1. 
Cardiac Function  
An assessment of left ventricular ejection fraction will be performed and documented at 
Screening and as medically indicated.  Note:  An echocardiogram, multigated acquisition, and 
gated heart pool scan are all acceptable. 
5.5.2. 
Physical Examination and Vital Signs  
Physical examination, vital signs (sitting blood pressure, heart rate, and body temperature), 
weight, and review for arrhythmia signs/symptoms (eg, shortness of breath, dizziness, or 
fainting) will be performed at each study visit during study treatment and at the End of 
Treatment Visit.  Height (cm) is determined at Screening only.  Assessment of vital signs and a 
focused physical examination on Cycle 1 Day 1 may be skipped if performed within the last 7 
days. 
A complete physical examination includes an assessment of systems per standard of care at the 
study site and as clinically indicated by symptoms.  
5.5.3. 
ECOG Performance Status  
ECOG performance status (Appendix 6) will be assessed at the Screening visit, each visit during 
study treatment, and at the End of Treatment Visit.   
5.5.4. 
Electrocardiogram  
A 12-lead ECG will be performed locally in triplicate at screening for all subjects.  During study 
treatment, ECGs will be performed as specified per the Schedule of Assessments (Appendix 10).  
Subjects should be in the semi-recumbent or supine position. 
5.5.5. 
Concomitant Medications Review  
Record any new medications, changes in ongoing medications or procedures, and medications 
discontinued within the screening window (see Section 5.2), and on study thereafter. 
5.5.6. 
Adverse Events Review  
Record AEs that occurred during Screening on the medical history case report form and in the 
patient’s source document. 
Collect non-serious AE information from the time of first dose of study drug through End of 
Treatment Visit.  Information on all SAEs (regardless of relatedness) will be collected from the 
time of signing of informed consent through screen failure or End of Treatment.  The AE 
reporting period is defined in Section 8.4.1. 


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All treatment-related AEs and SAEs will be followed until resolution or stabilization.  The 
accepted regulatory definition for an AE is provided in Section 8.1, and the definition of an SAE 
is provided in Section 8.2.1.  Important additional requirements for reporting SAEs are explained 
in Section 8.  
In addition, arrhythmia signs/symptoms will be reviewed at every visit.  This will involve the 
investigators asking subjects for signs and symptoms of ventricular dysfunction (eg, shortness of 
breath, dizziness, or fainting) as part of the routine AE monitoring for each visit. 
5.6. 
Efficacy Assessments  
Overall response to study treatment will be assessed at the timepoints outlined in Appendix 10. 
Overall response will be determined as follows: 
• CLL: IWCLL criteria (Hallek M et al 2008) with addition of treatment-related 
lymphocytosis (Cheson et al 2012) for patients with CLL (Appendix 2) 
• SLL: the Lugano Classification for NHL (Cheson et al 2014) for patients with SLL 
using CT-based response criteria (Appendix 3) 
The primary endpoint of this trial is ORR. Assessments relevant to response assessment will be 
submitted to the central review vendor (Section 10.3). Investigators will also assess overall 
response locally: refer to Appendix 2 and Appendix 3 for the individual assessments used to 
determine response and the guidelines on how to integrate them into a single overall response 
assessment for a given timepoint.  Confirmed, unequivocal progression may require 
discontinuation of study treatment (see Section 6.7).  
Assessments relevant to determining a patient’s overall response to study drug at a given time 
point are detailed below. Parameters relevant to response assessment may also include laboratory 
assessments as detailed in Section 5.8. 
An additional early response assessment visit to confirm overall response may be performed in 
addition regularly scheduled visits as indicated in Appendix 10. 
5.6.1. 
Disease-Related Constitutional Symptoms  
Disease-related constitutional symptoms based on  IWCLL criteria (Hallek M et al 2008) 
(unexplained fever of ≥ 38oC; unexplained, recurrent drenching night sweats; or unexplained loss 
of > 10% body weight within the previous 6 months) will be evaluated as specified per the 
Schedule of Assessments (Appendix 10). 
5.6.2. 
Physical Examination of Liver, Spleen, and Lymph Nodes  
Record presence and extent of hepatomegaly, splenomegaly, and/or lymphadenopathy as 
specified per the Schedule of Assessments (Appendix 10).  PD assessed by physical examination 
must be confirmed by a CT scan. 
5.6.3. 
Computed Tomography  
All patients must have baseline CT scan with contrast of neck, chest, abdomen, and pelvis and 
any other disease sites as specified in Appendix 10. 


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All efforts will be made to ensure that the imaging equipment, contrast agent, and person 
(investigator or radiologist) performing the evaluation are kept constant throughout a patient’s 
course on study.   
An MRI may be used in place of CT only for patients who have a contraindication to CT scans.  
If used, MRI should be performed of neck, abdomen, pelvis, and any other disease sites. In 
addition to the MRI, a non-contrast CT of the chest should be performed. In Germany, an MRI 
may be used in place of CT for all patients but CT with contrast is still preferred. 
CT or MRI will be performed as specified per the Schedule of Assessments (Appendix 10), 
independent of possible study drug hold. 
All malignant lesions identified by imaging at baseline and meeting the following requirements 
will be recorded in the eCRF: lymph node > 1.5 cm in at least one dimension, or non-nodal 
lesion measuring at least 10 mm in at least 1 dimension. Up to 6 of the lesions with bi-
dimensional measurements will be identified as ‘target’ lesions.  From the remaining measurable 
lesions, up to 6 Non-Index lesions may be selected and followed qualitatively throughout the 
course of the study.  The remaining lesions, whether measurable or non-measurable, will be 
recorded as ‘non-target’ lesions.  For target lesions, measurements will be recorded in the eCRF 
at each imaging timepoint in 2 perpendicular dimensions: longest diameter (LDi) and short 
diameter (SDi).  LDi is the longest diameter, and SDi is the longest diameter perpendicular to 
LDi. Multiple non-target lesions co-located in the same anatomical region may be classified 
under a single non-target annotation. Examples of non-target lesions include:  
• Any measurable nodal disease beyond the maximum number of six (6) target lesions 
• Extranodal disease beyond the maximum number of six (6) target lesions 
• Assessable disease 
• All bone lesions, irrespective of the modality used to assess them 
• Cutaneous lesions 
• Gastrointestinal disease 
• Spleen, liver, kidneys 
• Irradiated lesions 
• Groups of lesions that are small and numerous 
• Pleural/pericardial effusions and/or ascites 
At each imaging timepoint, lesions (nodal and nonnodal) recorded at baseline should have their 
actual measurements recorded, even when very small (eg, 2 mm).  However, sometimes lesions 
become so faint on a scan that the radiologist may not feel comfortable assigning an exact 
measurement and may report them as being “too small to measure” (TSTM).  When this occurs, 
it should be indicated as “too small to measure” in the electronic data capture system (EDC). If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. 
All CT scans and MRIs obtained during the study will be collected and reviewed by a central 
imaging vendor identified for this trial.  De-identified copies of all scans and radiology reports 


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(including those from Screening) must be provided to the sponsor or designee (eg, central 
imaging vendor). 
5.6.4. 
Bone Marrow Examination  
The schedule of required bone marrow examinations is given in Appendix 10. Details on these 
examinations and when they are required are given below: 
Bone Marrow Biopsy 
• In lieu of performing a bone marrow procedure, a site can submit any of the following 
from a previously performed diagnostic bone marrow biopsy if it is obtained within 
90 days before randomization: 
− an archival block 
− 15 unstained slides 
• At the time of potential CR or CRi. 
− Patients with baseline marrow involvement who meet clinical and laboratory 
criteria for CR or CRi, and need bone marrow examination to confirm CR or CRi. 
This should be collected within 40 days from the CT/MRI meeting the criteria of 
CR or CRi.  All the other clinical data should be within ± 14 days from the 
CT/MRI (ie, complete blood count [CBC] with differential and physical 
examination. 
▪ Patients who are otherwise complete responders but show bone marrow 
involvement preventing CR/CRi classification should recheck bone marrow 
at least once every 12 months until CR or CRi is confirmed as long as the 
patient is still showing evidence of being CR or CRi outside of bone marrow 
results. Recheck may be done earlier than 12 months as clinically indicated 
• At time of suspected progression due to cytopenias. 
Bone Marrow Aspirate 
• At Screening, for patients with SLL, for biomarker purposes (see Section 5.9). This 
must be a fresh sample within the screening window. 
• At time of potential CR or CRi to confirm response (see guidance for bone marrow 
biopsy for timing) and for assessment of MRD. For assessment of MRD 
(see Section 5.9). 
• At time of suspected progression due to cytopenias. 
All bone marrow samples will be collected and reviewed by a pathologist from the central 
pathology laboratory. 
5.6.5. 
Survival Status  
Survival follow-up assessments may be conducted on an ad hoc basis for data analysis to 
monitor survival status for all patients in the study. The information may be confirmed via a 


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phone call, medical records, or other methods. Refer to the Schedule of Assessments 
(Appendix 10). 
5.7. 
Patient-Reported Outcomes  
Patients should complete the PROs per the Schedule of Assessments (Appendix 10) before study 
drug is administered and prior to performing any other procedures. 
5.7.1. 
EQ-5D-5L  
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(The EuroQol Group 1990; Herdman et al 2011).  Patients will self-rate their current state of 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 
possible responses that record the level of severity (no problems, slight problems, moderate 
problems, severe problems, or extreme problems) within each dimension.  The questionnaire also 
includes a visual analog scale to self-rate general health state on a scale from “the worst health 
you can imagine” to “the best health you can imagine.”  A sample questionnaire is provided in 
Appendix 7 as an example only. 
5.7.2. 
EORTC QLQ-C30  
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients.  It is a copyrighted instrument, which has been translated and validated in over 100 
languages and is used in more than 3000 studies worldwide.  The EORTC QLQ-C30 includes 30 
separate questions (items) resulting in 5 functional scales (Physical Functioning, Role 
Functioning, Emotional Functioning, Cognitive Functioning, and Social Functioning), 1 Global 
Health Status scale, 3 symptom scales (Fatigue, Nausea and Vomiting, and Pain), and 6 single 
items (Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, and Financial Difficulties) 
(Fayers et al 2001).  The recall period is 1 week (the past week).  The EORTC QLQ-C30 has 
been widely used among cancer patients in general and specifically in NHL patients.  It is a 
reliable and valid measure of PRO in cancer patients and takes about 11 minutes to administer.  
A sample questionnaire is provided in Appendix 8 as an example only. 
5.7.3. 
Self-administered Activity and Quality of Life Evaluation (Optional)  
A self-administered, device-based quality of life questionnaire and activity tracker may be 
optionally consented to, per patient, in select countries. All evaluations will be self-administered 
via an application designed for select electronic mobile devices. Patients must be able to use their 
own applicable device (ie, a smartphone) and must have a compatible device in order to consent. 
Device requirements and application operation instructions will be specified in the optional 
consent form.  
The evaluations consist of two categories of data collection: 
• Elicited activity evaluations 
− Walk test: the patient will be asked to walk as far as they can for six minutes and 
data about distance and time will be collected. 


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− Questionnaire: the patient will be asked to answer the questions outlined in 
Appendix 12. 
• Passive activity tracking 
− Activity data will be collected by the patient’s device in the background, 
including data such as steps taken and time active. 
Data from this optional evaluation will be stored separately from EDC. Since the questionnaire 
and activity tracking is self-administered and optional, site staff will not be held responsible for 
compliance. Feedback about patient compliance may be provided to sites in order for them to 
communicate with the patient about compliance. 
Administration and Schedule  
The site staff will invite the patient to participate during screening, after which the questionnaire 
and activity tasks will be self-administered and patients will enter data directly into the 
application on their mobile device without requiring site staff involvement. Patients will activate 
and conduct the first elicited evaluations any time during the Screening Period (preferred), or, at 
the latest, on Cycle 1 Day 1 before study drug administration. The evaluations will occur as 
follows: 
Actively elicited evaluations 
• Weekly for the first 12 weeks 
• Monthly for up to 2 years. 
Passive activity tracking 
• Collected continuously in the background after first use with no further action from 
the patient required 
Patients should attempt to complete the questionnaire and elicited activity tasks at roughly the 
same time and day each week or month, but may adjust their timing within a given time period 
as needed. Patients will be prompted by the application to remind them to conduct their weekly 
or monthly evaluation.  
5.8. 
Laboratory Assessments  
Laboratory assessments required during the trial are detailed below.  
Laboratory assessments will be performed at the timepoints specified in the Schedule of 
Assessments (Appendix 10) and may also be performed as medically necessary.  On Cycle 1 Day 
1 (day of first dose of study drug), laboratory assessments should be done before the first study 
drug administration. If local laboratories are being used, screening laboratory assessments 
performed within 72 hours of the first study drug administration do not need to be repeated in 
Cycle 1. 
Study Central Laboratories versus Local Laboratories 
If not otherwise specified below, laboratory assessments may be done at the study central 
laboratory or at the site’s local laboratory. The method used at baseline for a given patient should 
be used throughout the rest of the trial. For a specific visit, if there is an issue with that method 


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the other method may be substituted (ie, if a patient was using central laboratories since baseline 
but on the most recent visit the sample is lost, the site can enter local laboratories into the EDC 
for that visit).   
If the study central laboratory is used, a detailed description of the procedures for sample 
collection, handling, storage, and shipment of the laboratory samples and all materials such as 
test tubes and labels is provided in the laboratory manual. 
If the study central laboratory is used, local laboratories may still be used for patient safety and 
monitoring. In these cases, a specific local laboratory only needs to be entered in the EDC if it is 
relevant to study actions or data (ie, if local labs are triggering a dose interruption, modification, 
or resulting in a reported adverse event). If the central lab adequately reflects study actions and 
data, then there is no requirement to enter local labs into the EDC. 
Some blood samples will also be taken for biomarkers and submitted to the study central 
laboratory: please follow the guidance in Section 5.9. 
5.8.1. 
Hematology  
CBC with differential includes hemoglobin, hematocrit, platelet count, red blood cell count, and 
white blood cell count with differential (neutrophil, lymphocyte, monocyte, eosinophil, and 
basophil). 
5.8.2. 
Serum Chemistry  
Serum chemistry includes sodium, potassium, chloride, bicarbonate (carbon dioxide, or if neither 
is available carbon dioxide combining power), glucose, blood urea nitrogen (or serum urea), 
creatinine, calcium, phosphate (or phosphorus), magnesium, total bilirubin, total protein, 
albumin, ALT, AST, lactate dehydrogenase, and alkaline phosphatase.   
The following 2 chemistry tests will only be done at Screening and will be performed locally: 
direct antiglobulin test and β-2 microglobulin. 
5.8.3. 
Serum Immunoglobulins  
Quantitative serum immunoglobulins (IgG, IgM, and IgA) will be measured.  
5.8.4. 
Coagulation  
The coagulation profile includes prothrombin time, which will also be reported as international 
normalized ratio, and activated partial thromboplastin time.  The coagulation profile will be 
performed at Screening only and as clinically indicated. 
5.8.5. 
Hepatitis B and C testing  
Hepatitis B/C serologic markers and/or viral load will be tested at screening via study central 
laboratory.  
The hepatitis B testing includes HBsAg, HBcAb, and HBsAb, as well as HBV DNA by PCR if 
the patient is negative for HBsAg, but HBcAb positive (regardless of HBsAb status).  The 
hepatitis C testing includes HCV antibody as well as HCV RNA by PCR if the patient is HCV 


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antibody positive.  Patients with positive HBsAg and/or detectable level of HBV DNA or 
detectable level of HCV RNA are not eligible.  
Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo HBV 
DNA monitoring by PCR at least once on every cycle.  These patients should be considered for 
prophylactic antiviral treatment in consultation with a local HBV expert.  If a patient is being 
treated prophylactically with antivirals, HBV DNA monitoring by PCR must be done at least 
every 90 days (every third cycle).  HBV DNA at screening or for monitoring may be done 
locally if local testing sensitivity is adequate and after discussion with the medical monitor. 
If, during monthly monitoring of HBV DNA by PCR, the value is between 20 and < 100 IU/mL, 
then the HBV DNA by PCR should be rechecked within 2 weeks.  If the value is 100 IU/mL or 
greater, or at rechecked a detectable copy number, then study drug should be stopped and 
antiviral therapy initiated or continued.  Resumption of study drug in patients whose HBV 
reactivation resolves should be discussed with, and approved by, the medical monitor and 
physicians with expertise in managing hepatitis B.  
Patients positive for HCV antibody, but negative for HCV RNA, must undergo HCV RNA 
monitoring per cycle/every 4 weeks.  HCV RNA at screening or for monitoring may be done 
locally if local testing sensitivity is adequate and after discussion with the medical monitor.  
Patients with HCV RNA of 15 IU/mL or greater should stop study drug and antiviral therapy 
should be initiated.  Resumption of study drug in patients whose HCV reactivation resolves 
should be discussed with, and approved by, the medical monitor and physicians with expertise in 
managing hepatitis C.  
The medical monitor should be informed of any suspected hepatitis B or hepatitis C reactivation.  
Table 1 describes how the results for HBV and HCV testing at screening relate to study 
eligibility  
Table 1: 
Active Hepatitis B (HBV) or Hepatitis C (HCV) Infection (Detected Positive 
by PCR)  
Screening 
assessment 
Meets inclusion criteria 
To be excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA “Not detected” 
Perform monitoring of HBV DNA during 
every cycle 
HBsAg (-) and HBcAb (+) 
HBV DNA detected 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not detected” 
Perform monitoring of HCV RNA during 
every cycle 
Antibody (+) 
HCV RNA detected 
Abbreviations: HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; 
HCV, hepatitis C virus. 


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5.8.6. 
Pregnancy Test  
A serum pregnancy test will be performed at Screening within 7 days of randomization and End 
of Treatment in women of childbearing potential.  Any female patient who is pregnant will not 
be eligible for the study.  Laboratory-based highly sensitive pregnancy tests (urine or serum) will 
be performed on Day 1 of every cycle and for at least 90 days after the last dose of study drug.  If 
a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  A patient 
who has a positive pregnancy test result at any time after the study drug administration will be 
immediately withdrawn from participation in the study.  
5.8.7. 
HIV Testing  
Subjects with HIV infection are excluded from the study. HIV testing will be performed during 
Screening unless previous HIV test results from ≤ 4 weeks prior to Screening are available. 
5.9. 
Biomarkers  
Samples for biomarkers will be collected as indicated in Appendix 10. Details on these samples 
and when they are required are given below. 
5.9.1. 
Del17p and Cytogenetics  
CLL/SLL is characterized by various mutations shown to be linked to favorable prognosis 
(del13q and hypermutation of IGHV) or poor prognosis (del17p, del11q, unmutated IGHV, 
mutations in TP53, ATM, and Notch1).  
Screening blood samples will be used for the assessment of prognostic biomarkers including the 
assessment of chromosomal abnormalities (del17p, del11q, and the marker D13S319 on 
chromosome 13q, and to determine trisomy 12) by fluorescence in situ hybridization (FISH) 
using a specialized central laboratory. 
Screening bone marrow samples will also be collected for patients with SLL (Section 5.6.4), for 
central del17p FISH testing. 
5.9.2. 
Flow Cytometry for MRD  
Blood and bone marrow samples (see Section 5.6.4) will be collected for the assessment of MRD 
by flow and molecular techniques as indicated in Appendix 10.   
5.9.3. 
TP53 Mutation and Other Molecular Analysis  
Blood samples will also be collected for the assessment of the mutation status of relevant genes 
by molecular techniques including, but not limited to, TP53, IGHV, Notch, etc, as indicated in 
Appendix 10. Samples taken at progression leading to permanent study drug discontinuation will 
be used for the assessment of relevant BTK pathway genes for specific mutations that have been 
identified as markers of resistance, including, but not limited to, mutations of the BTK and 
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5.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and 
may include vital signs/focused physical examination; ECOG performance status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments.  The date and reason for the unscheduled visit 
must be recorded in the source documentation.   
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
5.11. 
Treatment Period  
The treatment period starts with the first day of assigned study treatment and ends 30 days 
following date of permanent study drug discontinuation (ie, 30 days after the final administered 
dose of zanubrutinib or ibrutinib)  
Patients may discontinue study drug treatment for any one of the reasons presented in 
Section 6.7. Patients that end treatment should move on to the End of Treatment Visit. 
Patients may voluntarily withdraw consent for treatment at any time.   
5.12. 
Post-Treatment Period  
5.12.1. 
End of Treatment  
All patients who permanently discontinue study drug will have an End of Treatment Visit 
approximately 30 days after the last dose of study drug to collect AEs, including AEs that may 
have occurred or been ongoing after the patient discontinued study treatment.  The investigator 
or his/her designee will also continue to collect information on new anticancer therapy given 
after the last dose of study drug.  A laboratory assessment is only required if the patient had an 
ongoing laboratory abnormality at the previous visit that the investigator considered to be related 
to study drug.  If the patient is unable to return to the clinic and no laboratory assessment is 
necessary, the investigator or his/her designee will contact the patient or guardian to collect this 
information.  Refer to the Schedule of Assessments (Appendix 10) for the assessments to be 
performed at the End of Treatment Visit.  This visit should signify the patient’s transition to 
Long-term Follow-up (if they have yet to progress) or Survival Follow-up (if they have already 
progressed). 
5.12.2. 
Long-term Follow-up  
All patients who discontinue study drug treatment and have yet to have documented and 
confirmed progression by independent central review will remain in the study and subsequently 
commence Long-term Follow-up, which includes monitoring survival status, subsequent 
therapies for CLL/SLL, and overall response assessments (including radiographic imaging) to 
monitor for disease progression. Refer to the Schedule of Assessments (Appendix 10) for the 
assessments to be performed at the Long-term Follow-up Visits. 


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If the patient refuses to return for these visits or is unable to do so, every effort should be made 
to contact him/her or the patient’s guardian by telephone to determine the patient’s disease status 
and survival.  
Patients who have documented and confirmed progression by independent central review during 
Long-term Follow-up should move to Survival Follow-up. 
5.12.3. 
Survival Follow-up  
Patients who have discontinued study treatment and have documented and confirmed 
progression by independent central review should enter Survival Follow-up, which consists of 
monitoring for survival status and subsequent therapies for CLL/SLL. There are no mandatory 
study visits during Survival Follow-up: information may be confirmed via a phone call, medical 
records, or other methods. Patients should continue in Survival Follow-up every 24 weeks ± 14 
days until the end of the study. 
5.13. 
End of Study  
Reasons for complete withdrawal from the study (including treatment and all follow-up visits) 
will occur under the following circumstances: 
• Patient withdrew consent 
• Death  
• Study termination by sponsor 
The patient may elect to withdraw from the study for reasons other than those listed above - any 
other reasons need to be documented and explained in the eCRF.  Patients may voluntarily 
withdraw consent from the study at any time.  
5.14. 
Lost to Follow-up  
Every reasonable effort should be made to contact any patient lost to follow-up during the study 
to complete study-related assessments, record outstanding data, and retrieve study drug.   
Following unsuccessful telephone contact, an effort to contact the patient by mail using a method 
that provides proof of receipt should be attempted.  Alternate contacts are permissible if the 
patient is not reachable (eg, primary care providers, referring physician, relatives).  Such efforts 
should be documented in the patient’s source documents.   
If all efforts to establish contact fail, the patient will be considered lost to follow-up.   
5.15. 
Future Research (Optional)  
Patients may optionally consent to use leftover or unused samples collected during this study for 
additional, future research purposes. No additional samples will be taken for future research 
purposes.  
Future research may include evaluation of additional potential biomarkers of response and 
resistance to zanubrutinib, which may be used to inform trials in other hematological indications. 
Mutations in other known pathways in B-cell proliferation or survival (such as but not limited to 


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CD79b, NFkb; Bcl-2 family members and ATM) could also be evaluated as part of an NGS-
based evaluation. Such potential drivers could be used to guide the treatments following further 
corroborative studies. Samples may also be used to evaluate novel technologies which will 
support patient treatment in the future. No cell lines will be generated with patient derived 
samples including DNA or RNA.  
All samples will be de-identified and coded as described in the ICF. In the event of publication, 
de-identified data will be submitted to public databases as needed, to meet the publication 
(journal) requirements. Access to de-identified and coded samples is limited to BeiGene and/or 
BeiGene affiliate.  
All future research is optional.  Patients may withdraw consent at any time and request that 
samples solely used for future research be destroyed. For patients that do not withdraw consent, 
samples will be stored up to 10 years and destroyed after this period.   


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6. 
STUDY TREATMENT  
6.1. 
Study Treatment Preparation and Dispensation  
6.1.1. 
Packaging and Labeling  
Zanubrutinib capsules will be provided in a child-resistant high-density polyethylene bottle with 
an induction seal and bottle label.  Commercial supplies of ibrutinib will either be provided by 
the sponsor or directly purchased via local procurement by the site.   
Refer to the pharmacy manual for specifics on packaging and label content. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
6.1.2. 
Handling and Storage  
The Interactive Response Technology (IRT) system will be used for drug supply management. 
Sponsor-supplied study drug(s) will be dispatched to a study center only after receipt of the 
required documents in accordance with applicable regulatory requirements and the sponsor’s 
procedures.  The investigator or pharmacist/designated personnel is responsible for maintaining 
the drug supply inventory and acknowledging receipt of all study drug shipments.  All study 
drugs must be stored in a secure area, with access limited to the investigator and authorized study 
center personnel, and kept under physical conditions that are consistent with study drug-specific 
requirements.  The study drugs must be kept at the temperature condition as specified on the 
labels.  
Zanubrutinib bottles must be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).  
The storage conditions for ibrutinib are found on the local drug label.  Retain in original package 
until dispensing.  
6.1.3. 
Study Drug Supply  
Zanubrutinib capsules will be provided by the sponsor.  
Ibrutinib will be provided via local procurement by the site. In limited circumstances, they may 
be provided by the sponsor. 
6.1.4. 
Study Drug Dispensation Procedures  
Study drugs must be dispensed or administered according to procedures described herein.  Only 
patients enrolled in the study may receive study drug(s), in accordance with all applicable 
regulatory requirements.  Only authorized study center personnel may supply or administer study 
drug(s).   
Study drug will be dispensed by the study center personnel to patients to ensure adequate drug 
supply for administration at home throughout the treatment phase. Visits for dispensation should 
occur no less frequently then at every scheduled study visit (see Appendix 10) on this trial.  
The investigator is to instruct the patient to take the study drug exactly as prescribed and at 
approximately the same time on each day of dosing.  Patients will be requested to bring their 
unused medication, and all empty bottles, to the center at each visit.  All dosages prescribed and 


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dispensed to the patient and all dose changes, including reason for dose changes, during the 
study must be recorded on the appropriate eCRF. 
For dispensation of study drug provided by the sponsor, please ensure that the bottle number(s) 
listed in IRT matches with what is being given to the patient. 
For drug that is locally procured, please ensure that the lot number dispensed is being recorded 
on the accountability log. 
6.1.5. 
Compliance and Accountability  
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or guardian.  
The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed and used by each patient.  This information must be captured in the source document 
at each patient visit.  The investigator is responsible for study drug accountability, reconciliation, 
and record maintenance.  In accordance with all applicable regulatory requirements, the 
investigator or designated study center personnel must maintain study drug accountability 
records throughout the course of the study.  This person will document the amount of study drug 
received from the sponsor, the amount supplied, and/or the amount administered to and returned 
by patients, if applicable. 
6.1.6. 
Disposal and Destruction  
After completion of the study, and following final drug inventory reconciliation by the monitor, 
the study site will destroy or return all unused study drug supplies.  The inventoried supplies can 
be destroyed on site or at the depot according to institutional policies after receiving written 
sponsor (or designee) approval.  
6.2. 
Dosage and Administration  
6.2.1. 
Zanubrutinib  
Zanubrutinib 160 mg will be taken twice a day with or without food.  Patients will take 
zanubrutinib with water at approximately the same time every day, with a minimum of 8 hours 
between consecutive doses.  Zanubrutinib capsules should not be opened, broken, or chewed at 
any time.  In case of dose reduction (See Section 6.5.1), the number of capsules taken at each 
administration will be reduced. 
Patients randomized to Arm A (zanubrutinib) should be instructed that if a dose of the study drug 
is not taken at the scheduled time, they should skip the study drug if the time to next dose is 8 
hours or less and return to normal dosing with next dose.  If a patient vomits after taking the 
zanubrutinib capsules, that dose should not be repeated. 
On the days of PK blood sampling, study drug administration for patients assigned to Arm A 
(zanubrutinib) will occur at the center after the pre-dose blood sampling has occurred under the 
supervision of the investigator or his/her designee.  The investigator or his/her designee must 
instruct the patient not to self-administer the study drug prior to the office visit on those days.   


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6.2.2. 
Ibrutinib  
Patients randomized to Arm B will receive ibrutinib.  Ibrutinib should be administered per local 
prescribing guidelines (ie, Prescribing Information or Summary of Product Characteristics) and 
those guidelines should be followed throughout the study for these patients. The text below 
summarizes common current prescribing guidance, but local prescribing guidelines should 
always take precedence where applicable. 
Ibrutinib will be administered at a dose of 420 mg orally once daily.  Patients will take ibrutinib 
with water at approximately the same time every day. Ibrutinib, in any dosage form, should not 
be opened, broken, or chewed at any time.  If a dose of ibrutinib is not taken at the scheduled 
time, it can be taken as soon as possible on the same day with return to the normal schedule the 
following day.  Extra doses of ibrutinib should not be taken to make up for the missed dose.  If a 
patient vomits after taking ibrutinib, that dose should not be repeated. 
6.3. 
Overdose  
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any AE or SAE criterion must be 
reported in the appropriate time frame and documented as clinical sequelae to an overdose.  
There is no specific antidote for zanubrutinib or ibrutinib.  In an event of an overdose, patients 
should be closely monitored and given appropriate supportive treatment. 
6.4. 
Precautions  
For information on warnings and precautions for zanubrutinib, refer to the Zanubrutinib 
Investigator’s Brochure.  Additional information on the following precautions is detailed in this 
protocol: 
• Surgery and procedures (see Section 6.4.1) 
• Dose modifications for zanubrutinib when coadministered with CYP3A inhibitors 
and inducers (see Section 6.5.1.3) 
• Tumor lysis syndrome (see Section 7.1.1) 
• Infection prophylaxis (see Section 7.1.1) 
For information on warnings and precautions for ibrutinib, refer to the most recent local 
prescribing information. 
6.4.1. 
Surgery and Procedures  
Susceptibility to bleeding has been observed with BTK inhibitors.   
Study treatment with zanubrutinib should be held for 3 to 7 days before and after surgery, 
depending upon the type of surgery and the risk of bleeding.  
Study treatment with ibrutinib should follow local prescribing information. Current prescribing 
guidelines state that ibrutinib should be held for 3 to 7 days pre and post-surgery, depending 
upon the type of surgery and the risk of bleeding. 


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6.5. 
Dose Interruption and Modification  
The guidelines below should be followed for dose interruption or modification of zanubrutinib or 
ibrutinib in the event of toxicities. The dose reduction guidance refers to an individual toxicity 
event (ie, successive thrombocytopenia events) and is not cumulative amongst different events of 
the same class (ie, a thrombocytopenia event followed by a neutropenia event). 
Assessment of the presence and severity of adverse events which may a trigger dose interruption 
and/or modification should follow the guidance in Section 8.1. 
Management of toxicities via methods not involving the interruption and modification of study 
drug is discussed in Section 6.6. 
If study drug is interrupted for > 28 days, written approval must be obtained from the medical 
monitor before study drug can be restarted (see Section 6.7). 
For surgery and procedure guidance see Section 6.4.1. 
6.5.1. 
Zanubrutinib  
The guidelines below should be followed for dose interruption or modification of zanubrutinib 
for hematologic (Section 6.5.1.1) and non-hematologic (Section 6.5.1.2) toxicities.  
Table 2: 
Zanubrutinib Dose Reduction Levels  
Toxicity occurrence 
Dose level 
Zanubrutinib dose (Arm A) 
First 
0 = starting dose 
Restart at 160 mg twice daily 
Second 
-1 dose level 
Restart at 80 mg twice daily 
Third 
-2 dose level 
Restart at 80 mg once daily 
Fourth 
Discontinue zanubrutinib 
Discontinue zanubrutinib 
Zanubrutinib may be restarted upon resolution of toxicity or as otherwise specified per event. If, 
in the investigator’s opinion, it is in the patient’s best interest to restart treatment after > 28 days, 
then written approval must be obtained from the medical monitor (Section 6.7). 
6.5.1.1. 
Zanubrutinib Dose Reduction for Hematologic Toxicity  
Dosing will be held for individual patients under any of the following conditions, based on 
investigator assessment (using Hallek M et al 2008) of study drug relatedness: 
• Grade 4 neutropenia (that is persistent for at least 10 consecutive days)  
• Grade 4 thrombocytopenia (that is persistent for at least 10 consecutive days) 
• Grade 3 thrombocytopenia associated with significant bleeding 
• ≥ Grade 3 febrile neutropenia 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery 
of the toxicity to ≤ Grade 1 or baseline. 
Patients with ≥ Grade 3 thrombocytopenia associated with significant bleeding requiring medical 
intervention should be discussed with the medical monitor. 


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Asymptomatic treatment-related lymphocytosis should not be considered an AE.  Patients with 
treatment-related lymphocytosis should remain on study treatment and continue with all 
study-related procedures. 
6.5.1.2. 
Zanubrutinib Dose Reduction for Non-hematologic Toxicity  
Guidelines for non-hematologic toxicities are given in Table 3. For dose reductions, follow the 
guidance described in Table 2. 
Table 3: 
Zanubrutinib Dose Reduction Steps for Nonhematologic Toxicity  
Toxicity 
Action for Zanubrutinib 
Re-start Dose 
≥ Grade 3 bleeding not 
considered related to study 
drug 
Hold until recovery to less than or equal to 
Grade 1 
Re-start at either the 
original dose or dose level 
(-1), at the discretion of 
the treating investigator 
≥ Grade 3 bleeding 
considered related to study 
drug 
Hold until underlying condition has fully 
resolved.  
If underlying condition cannot be treated to 
full resolution, permanently discontinue 
zanubrutinib. 
Re-start at dose level (-1) 
Any grade intracranial 
hemorrhage 
Permanently discontinue zanubrutinib. 
Not Applicable 
Atrial fibrillation (AF) that 
is symptomatic and/or 
incompletely controlled 
Hold until AF is clinically controlled 
Re-start at either the 
original dose or dose level 
(-1), at the discretion of 
the treating investigator 
Other ≥ grade 3 toxicity 
considered related to study 
drug, including 
inadequately controlled 
hypertension (HTN) and/or 
liver or renal laboratory 
value abnormalities 
Hold until recovery to less than or equal to 
baseline (BL) if BL is greater than grade 1; 
hold until less than or equal to Grade 1 if BL 
is less than or equal to Grade 1. 
Re-start at either the 
original dose level or dose 
level (-1), at the discretion 
of the treating investigator 
For subjects experiencing atrial fibrillation that is symptomatic and/or incompletely controlled: 
after the atrial fibrillation is adequately controlled, the study drug may be restarted at either the 
original dose or dose level -1, per discretion of the treating investigator.  Zanubrutinib should be 
permanently discontinued for any intracranial hemorrhage. 
For information on study drug holds based on the results of hepatitis B or hepatitis C testing, 
see Section 5.8.5. 
6.5.1.3. 
Zanubrutinib Dose Modifications When taking CYP Inhibitors and Inducers  
If strong/moderate CYP3A inhibitors and inducers are used during the trial (see Section 7.2.1) 
follow the dose modifications in Table 4. For use of prophylactic anti-infectives (ie, 


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voriconazole) during screening, it is recommended that patients stop the treatment at least 5 days 
before first dose of study treatment. 
Table 4: 
Dose Modification for Zanubrutinib when CoAdministered with 
Strong/Moderate CYP3A Inhibitors or Inducers   
CYP3A 
Coadministered Drug 
Recommended use 
Inhibition  
Strong CYP3A inhibitor (eg, 
ketoconazole, conivaptan, clarithromycin, 
indinavir, itraconazole, lopinavir, 
ritonavir, telaprevir, posaconazole, 
voriconazole)  
80 mg once daily  
Moderate CYP3A inhibitor (eg, 
erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil, 
aprepitant, imatinib, grapefruit products)  
80 mg twice daily  
Induction  
Strong CYP3A inducer (eg, 
carbamazepine, phenytoin, rifampin, 
St. John’s wort)  
Interrupt study drug; Consider alternative 
agents with less induction potential.  If 
unavoidable, monitor for potential lack of 
efficacy. 
Moderate CYP3A inducer (eg, bosentan, 
efavirenz, etravirine, modafinil, nafcillin)  
No dose modification necessary, use with 
caution. 
A more comprehensive list of Strong/Moderate CYP3A Inhibitors and Inducers is found in Appendix 5 
6.5.2. 
Ibrutinib  
For dose modification of Ibrutinib, local prescribing guidelines appropriate for your country (ie, 
Prescribing Information or Summary of Product Characteristics) should be followed throughout 
the study. The information below uses one example of local prescribing guidelines, but local 
prescribing guidelines applicable to your country should always take precedence. 
Table 5 below is an example of local prescribing information that describes the dose reduction 
levels for ibrutinib. Please follow your local prescribing info as applicable. 
Table 5: 
Example of Local Prescribing Guidance for Ibrutinib Dose Reduction Levels  
Toxicity occurrence 
Dose level 
Ibrutinib (Arm B) 
First 
0 = starting dose 
Restart at 420 mg once daily 
Second 
-1 dose level 
Restart at 280 mg once daily 
Third 
-2 dose level 
Restart at 140 mg once daily 
Fourth 
Discontinue ibrutinib 
Discontinue ibrutinib 
If, in the investigator’s opinion, it is in the patient’s best interest to restart treatment after 
> 28 days, then written approval must be obtained from the medical monitor (see Section 6.5). 
Specific events may require dose reduction to specific doses outside the general dose reduction 
guidance in Table 5 (refer to Sections 6.5.2.2 and 6.5.2.3). 


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6.5.2.1. 
Ibrutinib Dose Reduction for Hematologic Toxicity  
Local prescribing guidelines should be followed for dose reductions related to hematologic 
toxicity. An example of common local prescribing guidelines is given here, but follow the local 
prescribing guidelines applicable to your country. 
Dosing will be held for individual patients under any of the following conditions, based on 
investigator assessment of study drug relatedness: 
• ≥ Grade 3 neutropenia with infection or fever 
• Grade 4 hematologic toxicities.   
Once the symptoms of the toxicity have resolved to Grade 1 or baseline, ibrutinib therapy may 
be re-initiated at the starting dose.  If the toxicity recurs, reduce dose by 1 dose level (280 mg 
orally once daily).  A second dose reduction to dose level -2 (140 mg orally once daily) may be 
considered as needed.  If these toxicities persist or recur following 2 dose reductions, discontinue 
ibrutinib. 
6.5.2.2. 
Ibrutinib Dose Reduction for Non-Hematologic Toxicity  
Local prescribing guidelines should be followed for dose reductions related to non-hematologic 
toxicity. An example of common local prescribing guidelines is given here, but follow the local 
prescribing guidelines applicable to your country. 
Ibrutinib should be interrupted for ≥ Grade 3 non-hematologic toxicities. 
For patients with mild hepatic impairment, please follow local prescribing guidelines.  
6.5.2.3. 
Ibrutinib Dose Modifications When Taking CYP Inhibitors and Inducers  
Local prescribing guidelines should be followed for dose modifications related to CYP inhibitors 
and inducers. An example of common local prescribing guidelines is given here, but follow the 
local prescribing guidelines applicable to your country. 


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Table 6: 
Example of Local Prescribing Guidance for Dose Modifications for Use of 
Ibrutinib with CYP3A Inhibitors  
Patient Population 
Coadministered Drug 
Recommended Ibrutinib Dose 
B-Cell Malignancies 
• 
Moderate CYP3A inhibitor 
• 
Voriconazole 200 mg twice daily 
• 
Posaconazole suspension 100 mg 
once daily, 100 mg twice daily, or 
200 mg twice daily 
140 mg once daily 
Interrupt dose as recommended 
(see Dosage and Administration 
Section 6.2) 
• 
Posaconazole suspension 200 mg 
three times daily or 400 mg twice 
daily 
• 
Posaconazole IV injection 300 mg 
once daily 
• 
Posaconazole delayed-release tablets 
300 mg once daily 
70 mg once daily 
Interrupt dose as recommended 
(see Dosage and Administration 
Section 6.2) 
• 
Other Strong CYP3A inhibitors 
Avoid concomitant use. 
If these inhibitors will be used 
short-term (such as anti-
infectives for 7 days or less), 
interrupt ibrutinib 
Abbreviations: IV, Intravenous 
6.6. 
Toxicity Management Recommendations  
Additional recommendations are provided in Appendix 11 for the diagnosis and management of 
adverse events of interest (toxicity management). These recommendations are intended as 
guidance. Appendix 11 should be used in conjunction with expert clinical judgement (eg, by 
experts specializing in cardiology for management of atrial fibrillation), and individual 
institutional guidelines or policies. 
6.7. 
Discontinuation from Study Treatment  
Patients should discontinue study treatment for the following:  
• Withdrawal from the study (see Section 5.13).  
• Pregnancy 
• The investigator or sponsor determines it is in the best interest of the patient 
• Intercurrent illness that compromises the patient’s ability to participate in the study 
• Unequivocal disease progression  
− Patients should remain on study treatment until disease progression is confirmed 
by independent central review. 


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− Note that patients with disease progression may continue study drug treatment 
with zanubrutinib if they are benefiting from study treatment in the judgment of 
the investigators, with approval from the medical monitor. 
• Need for prohibited medication 
• Start of alternative anticancer therapy to treat the condition initially being evaluated 
in this study, or start of therapy for secondary malignancy that would interfere with 
assessment of zanubrutinib safety and efficacy 
• Study drug interruption > 28 days (unless agreed by the investigator and the medical 
monitor) 
• Significant, persistent, or recurrent AEs as described in Section 6.5 
The investigator/patient may elect to discontinue study treatment for reasons other than those 
listed above, but are not required to do so.  Withdrawal of consent to the study is not required to 
discontinue study treatment. 


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7. 
CONCOMITANT THERAPY  
7.1. 
Concomitant Therapy  
All concomitant medications and herbal supplements taken during the study will be recorded in 
the eCRF with indication, dose information, and dates of administration.   
Patients with high tumor burden should be monitored closely, and prophylactic measures, 
including allopurinol or rasburicase, may be instituted per institutional standards for tumor lysis 
syndrome. 
7.1.1. 
Permitted Medications  
The following treatments are allowed: 
• Blood product transfusion and growth factor support per standard of care and 
institutional guidelines 
• Corticosteroids for non-CLL/SLL indications with the following restrictions: 
Patients should not receive treatment with systemic corticosteroids other than 
intermittently to control or prevent infusion reactions, or for short durations (< 2 
weeks) to treat non-CLL/SLL-related conditions (eg, to treat a flare of chronic 
obstructive pulmonary disease).  Chronic systemic corticosteroid use is not permitted, 
except for adrenal replacement. 
• Therapy to reduce symptoms per standard of care and institutional guidelines 
Tumor lysis syndrome has been infrequently reported with zanubrutinib and ibrutinib treatment. 
Patients with high tumor burden should be monitored closely, and prophylactic measures, 
including allopurinol or rasburicase, may be instituted per institutional standards. 
Patients with hematologic malignancies, particularly those having received prior 
lymphodepleting chemotherapy or having prolonged corticosteroid exposure, are pre-disposed to 
opportunistic infections as a result of disease and treatment-related factors. In patients with a 
high risk for opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP), 
prophylaxis should be considered as per institutional standards. Otherwise for other infection 
prophylaxis should be as per institutional standards. 
7.1.2. 
Prohibited Medications  
Patients should not receive other anticancer therapy (including but not restricted to 
chemotherapy, immunotherapy, corticosteroids for treatment of CLL, experimental therapy, 
radiotherapy, and herbal medications) during screening or while on treatment in this study.  
Other anticancer therapies should not be administered until disease progression (as per clinical 
practice standards at the study center), un-manageable toxicity, or no further clinical benefit 
occurs, which requires permanent discontinuation of the study drug. 


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7.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
7.2.1. 
CYP-Inhibiting/Inducing Drugs  
7.2.1.1. 
Zanubrutinib  
Zanubrutinib is primarily metabolized by CYP3A (Section 1.2.2.2).  Administration of 
zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers (refer to Appendix 5 
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. If at all possible, patients are 
encouraged not to use strong/moderate CYP3A inhibitors and inducers and consider using 
alternative agents. If these agents will be used, follow the dose modification table in 
Table 4.  The medical monitor should be consulted in these situations. Please refer to Appendix 5 
and http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list. 
A clinical drug-drug interaction study indicated that zanubrutinib is a mild inducer of CYP3A4 
and CYP2C19 (Section 1.2.2.2). 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.  
Because ethinylestradiol (a key ingredient in a variety of combined oral contraceptives) is partly 
metabolized by CYP3A4, patients using hormonal contraceptives (eg, birth control pills or 
devices) must use a barrier method of contraception (eg, condoms) as well (see Section 4.1). 
Repeated dosing of zanubrutinib increased exposure of digoxin (P-gp substrate) with a mean 
increase of 11% for AUC0-t and 34% for Cmax (Section 1.2.2.2).  The coadministration of oral 
P-gp substrates with a narrow therapeutic index (eg, digoxin) should be used with caution as 
zanubrutinib may increase their concentrations. 
7.2.1.2. 
Ibrutinib  
Local prescribing guidelines should be followed for guidance on drug interactions and 
contraindications when using ibrutinib. An example of common local prescribing guidelines for 
use of ibrutinib with CYP3A Inhibitors is given in Table 6, Section 6.5.2.3, but follow the local 
prescribing guidelines applicable to your country. 
Coadministration of strong or moderate CYP3A4 inhibitors (see Appendix 5 and Table 6, 
Section 6.5.2.3) with ibrutinib may lead to increased ibrutinib exposure and, consequently, a 
higher risk for toxicity.  On the contrary, coadministration of CYP3A4 inducers may lead to 
decreased ibrutinib exposure and, consequently, a risk for lack of efficacy.  Therefore, 
concomitant use of ibrutinib with strong or moderate CYP3A4 inhibitors/inducers should be 
avoided.  
Do not take ibrutinib with grapefruit or Seville oranges (bitter oranges) - this includes eating 
them, drinking the juice, or taking a supplement that might contain them.  This is because it can 
increase the amount of ibrutinib in the blood. Refer to Appendix 5 for examples of strong and 
moderate CYP3A inhibitors and CYP3A inducers.  
Agents that may have their plasma concentrations altered by ibrutinib 


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Ibrutinib is a P-gp and breast cancer resistance protein (BCRP) inhibitor in vitro. As no clinical 
data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal 
P-gp and BCRP after a therapeutic dose. To minimize the potential for an interaction in the GI 
tract, oral narrow therapeutic range, P-gp or BCRP substrates such as digoxin or methotrexate 
should be taken at least 6 hours before or after ibrutinib. Ibrutinib may also inhibit BCRP in the 
liver and increase the exposure of medicinal products that undergo BCRP-mediated hepatic 
efflux, such as rosuvastatin. 
Based on in vitro data, ibrutinib is a weak reversible inhibitor towards CYP3A4 at the intestinal 
level and may therefore increase the exposure to CYP3A4 substrates sensitive to gut CYP3A 
metabolism. No clinical data are available on this interaction. Caution should be exercised if 
coadministering ibrutinib with CYP3A4 substrates administered orally with narrow therapeutic 
range (such as dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus and tacrolimus). 
Based on in vitro data, ibrutinib is a weak CYP2B6 inducer and may have the potential to affect 
the expression of other enzymes and transporters regulated via the constitutive androstane 
receptor (CAR), eg, CYP2C9, CYP2C19, UGT1A1 and MRP2. The clinical relevance is not 
known, but the exposure to substrates of CYP2B6 (such as efavirenz and bupropion) and of 
co-regulated enzymes may be reduced upon coadministration with ibrutinib.  


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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol. 
8.1. 
Adverse Events  
8.1.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of an AE include: 
• Worsening of a chronic or intermittent pre-existing condition including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• New condition detected or diagnosed after study drug administration even though it 
may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) related to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In these instances, all patient identifiers will be blinded on 
the copies of the medical records prior to submission to the sponsor. 
8.1.1.1. 
Assessment of Severity  
The investigator will assess the severity for each AE and SAE reported during the study.  When 
applicable, AEs and SAEs should be assessed and graded based upon the NCI-CTCAE v4.03. 
Patients with CLL may have low blood counts at initiation of therapy so assessment of AE 
severity for hematologic toxicity should be based on the Grading Scale for Hematologic Toxicity 
in CLL Studies (Appendix 9). 
Toxicities that are not specified in the NCI-CTCAE will follow general NCI-CTCAE guidance 
as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living  


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• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
NOTE: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions.  Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.2. 
8.1.1.2. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE.  The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the AE or SAE to the study drug will be considered 
and investigated.  The investigator will also consult the Investigator’s Brochure and/or 
Prescribing Information, for marketed products, in the determination of his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to the sponsor.  However, it is very important that the investigator 
always makes an assessment of causality for every SAE prior to transmission of the SAE report 
to the sponsor since the causality assessment is one of the criteria used when determining 
regulatory reporting requirements.  The investigator may change his/her opinion of causality 
considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.”  An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation).  A number of factors should be considered in making this assessment, 
including: 
• Temporal relationship of the AE to the administration of study treatment/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
• Biological plausibility 
• An AE should be considered “related” to study drug if any of the following are met, 
otherwise the event should be assessed as not related: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 


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− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
8.1.1.3. 
Follow-up of Adverse Events and Serious Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent.  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 patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
New or updated information will be recorded on the originally completed SAE report/eCRF, 
with all changes signed and dated by the investigator.  The updated SAE report/eCRF should be 
re-sent to the sponsor within the time frames outlined in Section 8.6.1. 
8.1.2. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, chemistry, CBC, coagulation) or other abnormal assessments 
(ECG, radiographical studies, and vital signs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs.  This includes clinically significant abnormal 
laboratory findings or other abnormal assessments that are present at baseline and significantly 
worsen during the study.  However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are present at the start of the study and do not worsen will not be 
reported as AEs or SAEs.  The definition of clinically significant is left to the judgment of the 
investigator; in general, these are events that result in clinical signs or symptoms, require active 
medical intervention, or lead to dose interruption or discontinuation. Laboratory events 
indicating liver or renal dysfunction should be considered clinically significant. 
For hematologic toxicities, refer to the Grading Scale for Hematologic Toxicity in CLL Studies 
(Appendix 9). 
Asymptomatic treatment-related lymphocytosis should not be considered an AE. 


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For information on procedures for the monitoring and prevention of hepatitis B and hepatitis C, 
see Section 5.8.5. 
8.1.3. 
Lack of Efficacy  
“Lack of efficacy” will not be reported as an AE.  The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including 
clarifications).  
8.2. 
Serious Adverse Events  
8.2.1. 
Definitions  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
NOTE:  the term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE; it does not refer to an AE, 
which hypothetically might have caused death, if it was more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.   
• Results in disability/incapacity 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions, but do not constitute a substantial 
disruption. 
• Results in a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical judgment 
(eg, may jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 


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8.3. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information) and meets the 
definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the current protocol and/or Investigator’s Brochure.  
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.4.1. 
Adverse Event Reporting Period  
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported.   
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drugs. 
Beyond 30 days after the last dose of study drug the investigator should report any SAEs that are 
believed to be related to prior study drug treatment.  SAEs that are not considered related to 
study treatment do not need to be reported and are not subject to the reporting requirements 
outlined in Section 8.6, but these SAEs should still be recorded in the EDC (see Section 11.2.6) 
per the guidelines outlined in Sections 8.1.1 and 8.2. 
8.4.2. 
Eliciting Adverse Events  
The investigator or designee will ask about AEs by asking the following standard questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.5. 
Specific Instructions for Recording Adverse Events and Serious 
Adverse Events  
8.5.1. 
Disease Progression  
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term.  Instead, 
the symptoms, signs or clinical sequelae that result from disease progression should be reported 
as the AE term(s).  Adverse events secondary to disease progression should be clearly indicated 
as such.  For instance, a patient presents with pleural effusion resulting from disease progression 
of metastasis to lungs.  The AE term should be reported as “pleural effusion” instead of disease 
progression.  If a patient experiences a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression”.     
If there is any uncertainty regarding whether an AE is due to disease progression, it should be 
reported as an AE. 


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8.5.2. 
Death  
Death is an outcome and not usually considered an event.  If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death,” 
“death of unknown cause,” or “death unexplained.” 
8.6. 
Prompt Reporting of Serious Adverse Events  
8.6.1. 
Time Frames for Submitting Serious Adverse Events  
SAEs will be reported promptly (within 24 hours of first knowledge of the SAE) to the sponsor 
or designee as described once the investigator determines that the AE meets the protocol 
definition of an SAE. 
Table 7: 
Time Frames and Documentation for Reporting SAEs to the Sponsor or 
Designee  
 
Time frame for 
making initial 
report 
Documentation 
method 
Time frame 
for making 
follow-up 
report 
Documentation 
method 
Reporting 
method 
All SAEs 
Within 24 hours 
of first 
knowledge of the 
SAE 
SAE report 
As 
expeditiously 
as possible 
SAE report 
Email or fax 
SAE form 
Abbreviation: SAE, serious adverse event. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the sponsor within 24 hours.  The SAE report will always be completed as 
thoroughly as possible with all available details of the SAE and forwarded to the sponsor within 
the designated time frames.  If the investigator does not have all information regarding an SAE, 
he/she will not wait to receive additional information before notifying the sponsor 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 8.1.1.2. 
The sponsor will provide a list of study contacts for SAE receipt. 
8.6.2. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.1  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 toward 
the safety of other patients are met. 


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The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/IEC. 
Expedited investigator safety reports are prepared according to the sponsor’s policy and are 
forwarded to investigators as necessary.  The purpose of the report is to fulfill specific regulatory 
and Good Clinical Practice (GCP) requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the responsible person according to local 
requirements is required to promptly notify his/her IRB or IEC.  The investigator should place 
copies of Safety Reports from the sponsor in the Investigator Site File. 
8.7. 
Pregnancy Reporting  
If a female patient or the partner of a male patient becomes pregnant while receiving study 
treatment or within 90 days of the last dose of study drug, a pregnancy report form should be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up.  
Information on the status of the mother and child will be forwarded to the sponsor.  Generally, 
follow-up will be no longer than 8 weeks following the estimated delivery date.  Any premature 
termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should always be reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
8.8. 
Post-Study Adverse Event  
A post-study AE or SAE is defined as any AE that occurs after the AE/SAE reporting period, 
defined in Section 8.4.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients.  However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will 
notify the sponsor. 
8.9. 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference documents: 
• BGB-3111 Investigator’s Brochure  
• Ibrutinib Prescribing Information 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
All statistical analyses will be performed by the sponsor or designee.  Data will be listed and 
summarized according to sponsor -agreed reporting standards.  
Details of the statistical analyses will be included in a separate Statistical Analysis Plan. 
9.1. 
Study Endpoints  
9.1.1. 
Primary Endpoint  
The primary endpoint is ORR (PR or higher, defined as CR/CRi + PR + nodular PR) determined 
by investigator assessment using the “modified” 2008 IWCLL guidelines (Hallek M et al 2008) 
with modification for treatment-related lymphocytosis (Cheson et al 2012) for patients with CLL 
(Appendix 2) and per Lugano Classification for non-Hodgkin lymphoma (NHL) 
(Cheson et al 2014) for patients with SLL (Appendix 3). While the primary efficacy endpoint is 
per investigator assessment, ORR per independent central review will also be analyzed to 
support the primary analysis.  In the United States, ORR assessed by independent central review 
will be the basis for regulatory decisions. 
9.1.2. 
Secondary Endpoints  
Key Secondary Endpoint: 
The key secondary endpoint is PFS, defined as the time from randomization to the date of first 
documentation of disease progression or death, whichever occurs first, determined by the 
investigator.   While the key secondary efficacy endpoint is per investigator assessment, PFS per 
independent central review will also be analyzed to support the key secondary endpoint analysis.  
In the United States, PFS assessed by independent central review will be used to support 
regulatory decisions. 
Other Secondary Endpoints: 
• Duration of response, defined as the time from the date that response criteria are first 
met to the date that disease progression is objectively documented or death, 
whichever occurs first, determined by independent central review  
• Duration of response by investigator assessment  
• Time to treatment failure, defined as time from randomization to discontinuation of 
study drug due to any reason  
• Rate of PR-L or higher, defined as the proportion of patients who achieve a CR/CRi + 
PR + nodular PR + PR-L determined by independent central review 
• Overall survival, defined as the time from randomization to the date of death due to 
any cause 
• PROs measured by the EQ-5D-5L and EORTC QLQ-C30 questionnaires 
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, 
and vital signs 


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9.1.3. 
Exploratory Endpoints  
• Correlation between clinical outcomes (eg, ORR, PFS, DOR, OS) and the prognostic 
and predictive biomarkers 
• MRD  
• PK parameters 
• Self-administered Activity and Quality of Life questionnaire 
9.2. 
Statistical Analysis  
9.2.1. 
Randomization Methods  
Patients will be randomized using the Interactive Response Technology system for this study by 
permuted block stratified randomization.  
The stratified randomization using age (< 65 years versus ≥ 65 years), geographic region (China 
versus non-China), refractory status (yes or no), and del17p/TP53 mutation status (present versus 
absent) as stratification factors will be produced, reviewed, and approved by an independent 
statistician.  
9.2.2. 
Analysis Sets   
The Intent-to-Treat Analysis Set includes all randomized patients.  The Intent-to-Treat Analysis 
Set will be the primary analysis set for efficacy analyses.  
The Safety Analysis Set includes all patients who received any dose of study drug.  Patients will 
be included in the treatment group corresponding to the actual treatment received.  The Safety 
Analysis Set will be used for all safety analyses. 
The Per-protocol Analysis Set includes patients who received any dose of study drug and had no 
major protocol deviations.  Criteria for exclusion from the Per-protocol Analysis Set will be 
determined and documented before the database lock for the primary analysis.  For the primary 
analysis of non-inferiority testing in ORR, the Per-protocol Analysis Set will be used as the 
secondary population. 
The PK Analysis Set includes all zanubrutinib treated- patients who have at least 1 post-dose 
drug concentration.    
9.2.3. 
Subject Disposition  
The number of patients screened, randomized, randomized but not treated, treated, discontinued 
from study drug, and discontinued from study will be summarized.  The primary reason for study 
drug discontinuation and study discontinuation will be summarized according to the categories 
recorded in the eCRF. 
9.2.4. 
Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized in the Intent-to-Treat 
Analysis Set using descriptive statistics.  Continuous variables include age, weight, vital signs, 
and time since initial CLL/SLL diagnosis; categorical variables include sex, age group, race, 


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disease stage, ECOG-performance status, geographic region, and genetic status including del17p, 
del11q, 12q+, and IGHV mutation analysis. 
9.2.5. 
Prior and Concomitant Therapy  
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes.  Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical code indicating therapeutic classification.  Prior and 
concomitant medications will be summarized and listed by drug and drug class in the Clinical 
Study Report for this protocol.  Prior medications will be defined as medications that started 
before the first dose of study drug, whether continuing at or stopped at the first dose of study 
drug.  Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) started 
on or after the date of the first dose of study drug up to 30 days after the patient’s last dose. 
9.2.6. 
Efficacy Analysis  
9.2.6.1. 
Primary Efficacy Endpoint Analyses  
The primary hypothesis testing for the primary endpoint of ORR by investigator assessment (for 
the United States, by independent central review) will be to demonstrate the non-inferiority of 
zanubrutinib to ibrutinib.  The null and alternative hypotheses for the non-inferiority test are as 
follows: 
• H0NI: Response Ratio (zanubrutinib/ibrutinib) ≤ 0.8558 
• HaNI: Response Ratio (zanubrutinib/ibrutinib) > 0.8558 
One interim analysis will occur approximately 12 months after 415 patients (69% information 
fraction) have been randomized.  The final analysis will occur approximately 12 months after 
600 patients have been randomized.  
A Cochran-Mantel-Haenszel test for response ratio adjusting for the 4 randomization 
stratification factors (age [< 65 years versus ≥ 65 years], geographic region (China versus non-
China), refractory status [yes or no], and del17p/TP53 status [present versus absent]) will be 
performed for the hypothesis testing.  The p-value from the test will be compared against the 
monitoring boundaries for the non-inferiority testing (Table 8) and used for the primary 
inference.  The treatment effect in ORR and its 95% Wald confidence interval (CI) will be 
estimated, and the Clopper-Pearson 95% CIs will be calculated for ORR for each treatment 
group. 
If the non-inferiority is demonstrated either at the interim or the final analysis, further testing for 
the superiority of zanubrutinib to ibrutinib will be performed (Brannath et al 2003).  The null and 
alternative hypotheses for the superiority test are as follows: 
• H0 SUP: Response Ratio (zanubrutinib/ibrutinib) ≤ 1 
• Ha SUP: Response Ratio (zanubrutinib/ibrutinib) > 1 
The monitoring boundaries for the non-inferiority and superiority tests are based on the O’Brien-
Fleming boundary approximated by the Lan-DeMets spending function and are listed in Table 8 
and Table 9.  The monitoring boundaries will be adjusted based on the actual information 


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fraction (number of subjects for ORR) observed up to the data cutoff.  Deviation from the 
scheduled interim analysis will not affect the overall type I error (Lan and DeMets 1983). 
Table 8: 
Monitoring Boundaries for the ORR Non-inferiority Testing  
 
Number of 
patients evaluable 
Information 
fraction 
Nominal p-value 
boundary (primary 
inference) 
Response ratio 
boundary 
Interim 
415 
69% 
0.007 
1.003 
Final 
600 
100% 
0.023 
0.956 
Abbreviation: ORR, overall response rate.  
Table 9: 
Monitoring Boundaries for the ORR Superiority Testing  
 
Number of patients 
evaluable 
Information 
fraction 
Nominal p-value 
boundary (primary 
inference) 
Response ratio 
boundary 
Interim 
415 
69% 
0.007 
1.167 
Final 
600 
100% 
0.023 
1.11 
Abbreviation: ORR, overall response rate. 
Justification of the Non-inferiority Margin 
A non-inferiority margin of 0.8558 in response ratio was derived using the 95% to 95% fixed 
margin approach (FDA Guidance for Industry Non-Inferiority 2016).  In the RESONATE trial 
(Byrd et al 2014), the ibrutinib effect over ofatumumab represented by the ratio of response rate 
(PR or higher) was 10.43 with a 95% CI of (5.2, 21.0) based on the independent review 
committee assessment.  In the RESONATE2 trial (Burger et al 2015), the ibrutinib effect over 
chlorambucil represented by the ratio of response rate (PR or higher) was 2.33 with a 95% CI of 
(1.83, 2.97) based on the independent review committee assessment.  In a fixed-effect meta-
analysis of the 2 studies using inverse variance weighting, the ibrutinib effect in response rate 
ratio is estimated as 2.7392 with a 95% CI of (2.1781, 3.4450).  Thus, M1 is 2.1781, the lower 
bound of the 95% CI.  Since the effect sizes of ibrutinib are overactive controls in both studies 
(ofatumumab and chlorambucil, respectively), rather than placebos, the choice of M1 is very 
conservative and results in a narrow margin.  Requiring 80% of M1 to be retained (on the log 
scale) in zanubrutinib to demonstrate non-inferiority generates a non-inferiority margin of 0.8558 
(for the response ratio), which is within the clinically acceptable limit. 
9.2.6.2. 
Secondary Efficacy Endpoint Analyses  
If the primary objective of demonstrating the non-inferiority of zanubrutinib to ibrutinib in ORR 
is met, the treatment effect of the key secondary efficacy endpoint of PFS by investigator 
assessment (for the United States, by independent central review) will be tested for 
non-inferiority under hierarchical testing to control the study-wise type I error.  
If non-inferiority is demonstrated for the key secondary efficacy endpoint of PFS, further testing 
of superiority will be performed for the endpoint (Brannath et al 2003). 


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Treatment arm comparison for the other secondary efficacy endpoints will be descriptive, and no 
hypothesis testing will be performed. 
Key Secondary Efficacy Endpoints 
Progression-free Survival 
The non-inferiority of zanubrutinib to ibrutinib for PFS will be tested under the non-inferiority 
margin of 1.3319 (for the hazard ration [HR] of zanubrutinib/ibrutinib) using a stratified log-rank 
test based on the 4 randomization stratification factors: age (< 65 years versus ≥ 65 years), 
geographic region (China versus non-China), refractory status (yes or no), and del17p/TP53 
mutation status (present versus absent).  The null and alternative hypotheses to test the non-
inferiority are as below: 
• H0NI: HR (zanubrutinib/ibrutinib) ≥ 1.3319 
• HaNI: HR (zanubrutinib/ibrutinib) < 1.3319 
There will be a single analysis of PFS for the purpose of inference when approximately 205 PFS 
events have occurred; however, a one-sided significance level of 0.00001 will be applied to the 
analysis of PFS at the time when ORR is analyzed to compensate for the potential type I error 
increase from the descriptive analysis. Two hundred five (205) PFS events are expected to 
accrue 45 months after study start (as described in Section 9.4).  If the p-value from the stratified 
log-rank test for non-inferiority is significant, the non-inferiority of zanubrutinib to ibrutinib in 
terms of PFS will be demonstrated.  Further testing of superiority in terms of PFS will be 
performed in this case. 
The non-inferiority margin of 1.3319 was derived using the 95%-95% fixed margin method 
based on a meta-analysis of the RESONATE and RESONATE 2 studies.  In the RESONATE2 
study, the estimated PFS HR for ibrutinib versus chlorambucil is 0.16 with a 95% CI of (0.09, 
0.28).  In the updated RESONATE results (Brown et al 2014), the estimated PFS HR for 
ibrutinib versus ofatumumab is 0.106 with a 95% CI of (0.073, 0.153).  In a fixed-effect meta-
analysis, the pooled HR is estimated as 0.120 with a 95% CI of (0.088, 0.163).  Therefore, the 
control arm effect (M1) is -0.163 in HR and 1.814 in log HR.  Requiring 84.2% of M1 to be 
retained in zanubrutinib, a non-inferiority margin of 1.3319 for the HR (zanubrutinib/ibrutinib) is 
generated.   
The HR for PFS and its 95% CI will be estimated from a stratified Cox regression model.  
The distribution of PFS including median and other quartiles, and PFS rate at selected 
timepoints, will be estimated using the Kaplan-Meier method for each arm.   
PFS will be calculated as the time from the date of the randomization to the date of the first 
documentation of disease progression or death due to any cause, regardless of the use of 
subsequent anticancer therapy prior to the documented PD or death.  PFS for the patients without 
a documented PD or death will be censored at the last disease assessment. 
Other Secondary Efficacy Endpoints 
Duration of Response 
The distribution of DOR by independent central review including median and other quartiles, 
will be estimated using the Kaplan-Meier method for each treatment group.  There will be no 


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treatment arm comparison for DOR.  The same analysis will be performed for DOR by 
investigator assessment.  The same censoring rule used in the PFS analysis will be used for the 
analysis of DOR. 
Time to Treatment Failure 
The HR for time to treatment failure and its 95% CI will be estimated from a stratified Cox 
regression using the 4 randomization stratification factors (age [< 65 years versus ≥ 65 years], 
geographic region (China versus non-China), refractory status [yes or no], and del17p/TP53 
status [present versus absent]).  The Kaplan-Meier method will be used to estimate the 
distribution of time to treatment failure for each treatment group. 
Time to treatment failure will be calculated as the time from the date of randomization to the 
date of discontinuation of study treatment due to any cause.  Time to treatment failure will be 
censored at the data cutoff for the patients who did not discontinue study treatment. 
Rate of PR-L or Higher by Independent Central Review 
Rate of response ratio for PR-L or higher by independent central review and its 95% Wald CI 
will be estimated using the Cochran-Mantel-Haenszel method.  Clopper-Pearson 95% CI for the 
rate of response will be calculated for each treatment group. 
Overall Survival 
OS will be analyzed using the same methods employed for PFS by investigator assessment.  
Patient-Reported Outcomes   
The EORTC QLQ-C30 questionnaire will be summarized for each assessment timepoint for each 
treatment group.  The percentage of patients with a clinically meaningful change from baseline 
in “global health status/QOL” and functional domains will be summarized as “improved,” 
“stable,” or “worsened” and compared between 2 treatment groups.  The data may also be 
analyzed using repeated measure mixed model to account for missing data under the Missing at 
Random assumption. 
Changes in the EQ-5D-5L will be summarized for each treatment group.  
9.2.6.3. 
Exploratory Efficacy Analyses  
Cox and/or logistic regression models, as well as descriptive comparisons, may be used to 
explore the association between the prognostic, predictive biomarkers, as well as MRD and the 
clinical outcomes. 
Changes in the self-administered activity and quality of life questionnaire may be summarized 
for each treatment group. 
9.2.6.4. 
Sensitivity Analyses  
For PFS, alternative censoring rules such as censoring for new anticancer therapy will be used as 
sensitivity analyses.  Details of sensitivity analyses will be described in the SAP. 


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9.2.7. 
Pharmacokinetics Analyses  
A population PK analysis may be performed to include plasma concentrations of zanubrutinib 
from this trial in an existing model.  PK parameters such as apparent systemic clearance and 
AUC may be derived from the population PK analysis if supported by data. 
An exposure-response (efficacy or safety endpoints) analysis may be performed if supported by 
data.  The results from the population PK and exposure-response analyses may be reported 
separately from the Clinical Study Report. 
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v4.03.  
Laboratory values (CBC, serum chemistry, and coagulation), vital signs, physical exams, and 
ECG findings will also be used in the safety assessment.  Descriptive statistics will be used to 
analyze all safety data by the actual treatment group. 
9.3.1. 
Extent of Exposure  
The extent of exposure to the study drug will be summarized descriptively as the number of 
cycles received (number and percentage of patients), duration of exposure (days), cumulative 
total dose received per patient (mg), dose intensity (mg/day), and relative dose intensity (%). 
The number (and percentage) of patients with dose reductions, dose interruption, and drug 
discontinuation will be summarized with the respective reasons.  The cycles in which dose 
reduction/interruption occurred will be summarized using descriptive statistics.  Frequency of 
dose modifications will be summarized by category.  
Patient data listings will be provided for all dosing records. 
9.3.2. 
Adverse Events  
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified 
into standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to MedDRA (Version 20.0 or higher) lower level term closest to 
the verbatim term.  The linked MedDRA preferred term and primary system organ class will also 
be captured in the database. 
A treatment-emergent AE is defined as an AE that has an onset date on or after the first dose of 
study drug up to 30 days following the study drug discontinuation or the start of a new anticancer 
therapy, whichever comes first.  After this period, only treatment-related SAEs are to be reported 
(per Section 8.4.1).  Only the AEs that are treatment-emergent will be included in the summary 
tables.  All AEs, treatment-emergent or otherwise, will be presented in patient data listings.  
The incidence of treatment-emergent AEs will be reported as the number (and percentage) of 
patients with treatment-emergent AEs by system organ class and preferred term.  A patient will 
be counted only once by the highest severity grade according to CTCAE v4.03 within a system 
organ class and preferred term, even if the patient experienced more than 1 treatment-emergent 
AEs within a specific system organ class and preferred term.  The number (percentage) of 
patients with treatment-emergent AEs will also be summarized by the relationship to the study 
drug.  Treatment-related AEs include those events considered by the investigator to be related to 


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the study drug or with a missing assessment of the causal relationship.  SAEs, deaths, 
treatment-emergent AEs ≥ Grade 3, study drug-related treatment-emergent AEs, and 
treatment-emergent AEs that led to treatment discontinuation, dose reduction, or dose 
interruption will be summarized. 
Incidence and time to diarrhea (≥ Grade 3), severe bleeding (defined as ≥ Grade 3 bleeding of 
any site or central nervous system bleeding of any grade), and atrial fibrillation (both new onset 
and exacerbation of existing atrial fibrillation) will also be summarized.  
9.3.3. 
Laboratory Analyses  
Selected CBC components and serum chemistry values will be evaluated for each laboratory 
parameter by treatment group.  Abnormal laboratory values will be flagged and identified as 
those outside of (above or below) the normal range.  Reference (normal) ranges for laboratory 
parameters will be included in the Clinical Study Report.  Descriptive summary statistics (eg, n, 
mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables) for the laboratory parameters and their changes from baseline will be 
calculated.  Laboratory values will be summarized by visit and by the worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE (v4.03) will be summarized by CTCAE 
grade.  In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions (eg, calcium, glucose, magnesium, phosphorus, 
potassium, sodium) will be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for the vital sign parameters (systolic and diastolic blood pressure, heart 
rate, temperature, and weight) and the changes from baseline will be presented by visit and 
treatment group for all visits.  Vital signs will be listed by patient and visit. 
9.3.5. 
Electrocardiogram  
ECG assessments will be performed as described in Section 5.5.4 and in Appendix 10.  
Descriptive statistics for absolute and change from baseline ECG parameters will be presented.  
9.4. 
Sample Size Consideration  
The sample size calculation is based on the primary efficacy analysis for the primary endpoint of 
ORR.  Assuming a response ratio (zanubrutinib arm/ibrutinib arm) of 1.03 (72%/70%), 
600 patients will provide more than 90% power to demonstrate the non-inferiority of 
zanubrutinib to ibrutinib at the non-inferiority margin of 0.8558 (response ratio) and 1-sided 
alpha level of 0.025 when there is 1 interim analysis at 69% information fraction.  The response 
rate for ibrutinib is approximated from published clinical data (Byrd et al 2019).   
Assuming an HR (zanubrutinib arm/ibrutinib arm) of 0.9, 205 events are required to achieve 
80% power at a 1-sided alpha of 0.025 to demonstrate the non-inferiority of zanubrutinib to 
ibrutinib at the non-inferiority margin of 1.3319 (HR) in PFS  
If the 600 patients are randomized in a 1:1 ratio to the 2 arms over a 24-month period including a 
9-month ramp-up period before reaching the peak enrollment of 33 patients/month with a 
0.0017/month hazard rate for drop-out, 205 events are expected to be accumulated in 45 months 


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from study start.  A median PFS of 47 months for ibrutinib and an exponential distribution for 
PFS are also assumed. 
9.5. 
Interim Analysis  
There will be 1 interim analysis for the non-inferiority (and the superiority if the non-inferiority 
is met) testing of ORR.  The interim analysis will be performed approximately 12 months after 
the randomization of 415 patients.  The monitoring boundaries for the interim and the final 
analyses for the non-inferiority and superiority tests are based on the O’Brien-Fleming boundary 
approximated by the Lan-DeMets spending function and are depicted in Table 8 and Table 9 
(Section 9.2.6.1).  
If the boundary is met for the interim non-inferiority analysis and the DMC recommends 
stopping the study, the sponsor may stop the study and file the results to the regulatory agencies 
for approval. 
9.6. 
Final Analysis  
If the primary objective of the ORR non-inferiority is met, the study will continue to follow up 
for PFS until 205 events are observed, which is estimated to be approximately 45 months from 
study start.   


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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Steering Committee  
This study will be overseen by a Steering Committee consisting of experts in CLL/SLL and 
members of the sponsor’s staff.  The Steering Committee plays a central role in the design of the 
study, oversees the conduct of the study, and is to agree on a plan for communication of the 
results. 
10.2. 
Data Monitoring Committee  
An independent DMC consisting of experts in CLL/SLL, clinical trial safety monitoring, and 
statistics will evaluate safety data on a periodic basis and perform the efficacy interim analysis 
for this study.  Approximately every 6 months, the DMC will review all available safety data and 
also perform the interim efficacy analysis.  A separate charter will outline the details for the 
composition and responsibility of the DMC. 
10.3. 
Independent Central Review  
The sponsor will contract with an independent central review facility to provide an independent 
and blinded review of imaging and clinical data necessary to assess tumor response in this study.  
This will be conducted by qualified, board-certified radiologists and hematologists assigned to 
this study.  An independent central review charter will describe the independent review and 
define the processes, roles, and responsibilities of the sponsor, the sites, the independent central 
review facility, and the reviewers. 
10.4. 
Provision of Study Results and Information to Investigators  
When the Clinical Study Report is completed, the sponsor will provide the major findings of the 
study to the investigator.  
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s). 
The sponsor will not routinely inform the investigator or patient of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results would be undetermined at such an early stage of research. 


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11. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS  
11.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
an appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2. 
Investigator Responsibilities  
11.2.1. 
Good Clinical Practice  
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” ICH guidelines and that the basic principles of “Good Clinical 
Practice,” as outlined in 21 Code of Federal Regulations 312, Subpart D, “Responsibilities of 
sponsors and Investigators,” 21 Code of Federal Regulations, Part 50, and 21 Code of Federal 
Regulations, Part 56, are adhered to. 
11.2.2. 
Ethical Conduct of the Study and Ethics Approval  
This study will be conducted by the investigator and the study center in accordance with GCP 
and all applicable regulatory requirements, including, where applicable, the current version of 
the Declaration of Helsinki. 
The sponsor’s sample ICF will be provided to each investigator who shall adapt it, subject to 
sponsor’s approval, for use at his/her site.  The investigator (or sponsor, where applicable) is 
responsible for ensuring that: 1) this protocol, 2) the study center’s ICF, and 3) any other 
information or forms that will be presented to potential patients (eg, advertisements, Health 
Insurance Portability and Accountability Act of 1996 authorization, or information that supports 
or supplements the informed consent) are reviewed and approved by the appropriate IEC/IRB.  
The IEC/IRB must be constituted in accordance with all applicable regulatory requirements.  The 
sponsor will provide the investigator with relevant document(s)/data that are needed for IEC/IRB 
review and approval of the study.  Before the study drug(s) can be shipped to the study center, 
the sponsor or its authorized representative must receive copies of the IEC/IRB approval, the 
approved ICF, and any other information that the IEC/IRB has approved for presentation to 
potential patients. 
11.2.2.1. Protocol Amendments  
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene.  All protocol modifications must be submitted by the investigator (or 
sponsor, where applicable) to competent authorities according to local requirements and to the 
IRB/IEC together with, if applicable, a revised model ICF in accordance with local requirements.  
Written documentation from competent authorities (according to local requirements) and from 
the IRB/IEC and required site approval must be obtained - before changes can be implemented. 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF, 
confirming willingness to remain in the trial. 


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If the protocol, the ICF, or any other information that the IEC/IRB has approved for presentation 
to potential patients is amended during the study, the investigator (or sponsor, where applicable) 
is responsible for ensuring the IEC/IRB reviews and approves, where applicable, these amended 
documents.  The investigator must follow all applicable regulatory requirements pertaining to the 
use of an amended ICF including obtaining IEC/IRB approval of the amended form before new 
patients can consent to take part in the study using this version of the form.  Copies of the 
IEC/IRB approval of the amended ICF/other information and the approved amended ICF/other 
information must be forwarded to the sponsor promptly. 
11.2.3. 
Informed Consent  
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures.  The 
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 must be obtained before the patient can participate in the study.  The contents 
and process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
In the event that the ICF or other form signed by the patient is amended during their participation 
in the study, patients must be re-consented to the most current version of the ICFs or form.  For 
any updated or revised ICFs or forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was reobtained using 
the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
master study file and must be available for verification by study monitors at any time. 
11.2.4. 
Investigator Reporting Requirements  
As indicated in Section 8.6.2, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs to the IEC/IRB, in accordance with all applicable regulations.  Furthermore, the 
investigator may be required to provide periodic safety updates on the conduct of the study at 
his/her study center and notification of study closure to the IEC/IRB.  Such periodic safety 
updates and notifications are the responsibility of the investigator and not of the sponsor. 
11.2.5. 
Confidentiality  
The investigator and sponsor will maintain confidentiality and privacy standards by following 
applicable data privacy laws covering the collection, storage, transmission, and processing of 
patients’ personal and medical information.   
Patient medical information obtained during this study is confidential and may be disclosed only 
to third parties as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law.  


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In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting obligations 
under applicable data privacy laws.   
Information on maintaining patient confidentiality in accordance with individual local and 
national patient privacy regulations must be provided to each patient as part of the ICF process, 
either as part of the ICF or as a separate signed document (for example, in the United States, a 
site-specific Health Insurance Portability and Accountability Act of 1996 consent may be used).   
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  The investigator shall code the medical 
information obtained during the study with a unique patient identification number assigned to 
each patient enrolled in the study.  This approach ensures that patients’ names are not included in 
any data set transmitted to any sponsor location.  Only patient initials (where allowed), date of 
independent central review, and an identification code (ie, not names) should be recorded on any 
form or biological sample submitted to the sponsor, IRB, or laboratory.  The investigator must 
keep a screening log showing codes, names, and addresses for all patients screened and for all 
patients enrolled in the trial. 
The investigator agrees that all information received from BeiGene, including but not limited to 
the Investigator’s Brochure, this protocol, eCRFs, the investigational drug, and any other study 
information, remain the sole and exclusive property of BeiGene during the conduct of the study 
and thereafter.  This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from BeiGene.  The investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study site to any third party or otherwise 
into the public domain. 
If the written contract for the conduct of the study includes confidentiality provisions regarding 
BeiGene’s confidential information inconsistent with this section, that contract’s provisions shall 
apply to the extent they are inconsistent with this section. 
11.2.6. 
Data Collection  
Data required by the protocol will be entered into an EDC system.  
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee as identified on Statement of 
Investigator Form must sign the completed casebooks to attest to its accuracy, authenticity, and 
completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities.  
11.2.7. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at BeiGene at the end of the study.  


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Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the course of the study, a study monitor (clinical research associate) will make site visits 
to review protocol compliance, compare eCRFs against individual patient’s medical records, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation.  The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained.  Checking the eCRFs 
for completeness, clarity, and cross-checking with source documents is required to monitor the 
progress of the study.  Direct access to source data is also required for inspections and audits and 
will be carried out giving due consideration to data protection and medical confidentiality. 
AEs will be coded using the MedDRA Version 20.0 or higher.  Concomitant medications will be 
coded using the World Health Organization Drug Dictionary.  Concomitant diseases/medical 
history will be coded using the MedDRA Version 20.0 or higher. 
11.2.8. 
Data Integrity and In-house Blinding  
Due to the open-label design of the study, access to the patient-level clinical data in the EDC 
system will only be assigned to predefined study personnel.  Functions/persons with access to the 
EDC system shall be prohibited from using the EDC system to generate unnecessary 
listings/summaries that may introduce unwanted bias, or sharing such outputs from the EDC 
system with other functions/persons who do not have access to the EDC.  In addition, the central 
imaging vendor will perform the central imaging review without knowledge of treatment arm 
assignment.  Although the trial is open label, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. 
11.2.9. 
Drug Accountability at Site  
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 where applicable (quantity and condition), patient-drug dispensation records, and 
returned or destroyed study product.  Dispensing records will document quantities received from 
BeiGene and/or commercially sourced, 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, sites should have an appropriate standard operating procedure for study drug 
disposal/destruction.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures and applicable law, including that regarding 
disposal of hazardous waste.  If the site cannot meet BeiGene’s requirements for disposal, 
arrangements will be made between the site and BeiGene or its representative for destruction or 
return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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11.2.10. 
Inspections, Audits, and Monitoring Visits  
The investigator must ensure the facilities used for this trial and all the source documents for this 
trial should be made available to appropriately qualified personnel from BeiGene or its 
representatives, to IRBs/IECs, or to regulatory authority or health authority inspectors. 
11.2.11. 
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. 
The investigator is to document and explain any deviations from the approved protocol.  The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and, if applicable, to the IRB/IEC, in accordance with established 
IRB/IEC policies and procedures. 
11.2.12. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient, accurate financial information 
in accordance with regulations to allow the sponsor to submit complete disclosure or certification 
to the absence of certain financial interest of clinical investigators and/or disclose those financial 
interests, as required by the appropriate health authorities.  This is intended to ensure financial 
interests and arrangements of clinical investigators with BeiGene that could affect reliability of 
data submitted to health authorities are identified and disclosed by the sponsor.  Investigators are 
responsible for providing information about their financial interests before participation in the 
study, and to update this information if any relevant changes occur during the study and for 1 
year after completion of the study (ie, last patient, last visit). 
11.3. 
Study Report and Publications  
A Clinical Study Report will be prepared and provided to the regulatory agency(ies).  BeiGene 
will ensure that the report meets the standards set out in the International Conference on 
Harmonisation Guideline for Structure and Content of Clinical Study Reports (International 
Conference on Harmonisation E3).  Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the trial.  The data generated in this clinical trial are the exclusive 
property of the sponsor and are confidential.  As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor.  Thereafter, any secondary publications will reference the original 
publication(s).  Authorship will be determined by mutual agreement, and all authors must meet 
the criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors, 2013). 


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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 in advance 
of the publication/presentation.   
11.4. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolve and close all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Return of treatment codes to the sponsor 
• Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend or prematurely discontinue this study either 
at a single study center or at all study centers at any time for reasons including, but not limited 
to, safety or ethical issues or severe noncompliance 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. 
11.5. 
Records Retention and Study Files  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 


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be classified into at least the following 2 categories: (1) investigator’s study file and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECG, electroencephalogram, X-ray, pathology and special 
assessment reports, consultant letters, screening and enrollment log, etc.  
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 of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples remaining after this study may be retained in storage by the sponsor for the 
shorter of: a period of up to 10 years or as allowed by the IRB/IEC.  A longer storage period may 
apply in the event that subjects consent to BeiGene retaining remaining samples for future 
research (Section 5.15). 


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11.6. 
Information Disclosure and Inventions  
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights, whether or not patentable, which are conceived or reduced to practice by the 
study center personnel during the course of or as a result of the study are the sole property of the 
sponsor, and are hereby assigned to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) will be kept by the investigator 
and other study center personnel.  This information and data will not be used by the investigator 
or other study center personnel for any purpose other than conducting the study.   
These restrictions do not apply to: 
• Information which becomes publicly available through no fault of the investigator or 
study center personnel 
• Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information which is necessary to disclose in order to provide appropriate medical 
care to a patient 
• Study results which may be published as described in Section 11.3. 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
11.7. 
Joint Investigator/Sponsor Responsibilities  
11.7.1. 
Access to Information for Monitoring  
In accordance with International Conference on Harmonisation GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected or queries raised in the course of these monitoring visits are resolved. 


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11.7.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study.   If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to cooperate with representatives of a regulatory agency 
and BeiGene and to provide them access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 


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12. 
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Lymphocytic Leukemia. Blood. 2015;126:1733.  
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, 
phase 3 trial. Lancet. 2010;376(9747):1164-74.  
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukaemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute - Working Group 1996 guidelines. Blood. 
2008;111(12):5446-56.  
Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and 
treatment. Am J Hematol. 2017;92(9):946-65.  
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Quality of Life Research. 2011;20(10):1727-36.  
Hillmen P, Robak T, Janssens A, et al.  Chlorambucil plus ofatumumab versus chlorambucil 
alone in previously untreated patients with chronic lymphocytic leukemia (COMPLEMENT 1): a 
randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873-83.  
Honigberg LA, Smith AM, Sirisawad M, et al.  The Bruton tyrosine kinase inhibitor PCI-32765 
blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell 
malignancy. Proc Natl Acad Sci USA. 2010;107(29):13075-80.  
Imbruvica® US Prescribing Information. Pharmacyclics LLC; 2018.  
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Updated 
August 2013. Available at: http://www.icmje.org  
Jaglowski SM, Jones JA, Nagar V, et al.  Safety and activity of BTK inhibitor ibrutinib 
combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 
2015;126(7):842-50.  


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Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-63.  
Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in 
progression and relapse.  Nature. 2015;526(7574):525-30.  
Moreau EJ, Matutes E, A’hern RP, et al.  Improvement of the chronic lymphocytic leukemia 
scoring system with the monoclonal antibody SN8 (CD79a).  Am J Clin Pathol. 
1997;108(4):378-82.  
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.  
Pedersen IM, Kitada S, Leoni LM, et al.  Protection of CLL B cells by a follicular dendritic cell 
line is dependent on induction of Mcl-1.  Blood. 2002;100(5):1795-1801.  
Petlickovski A, Laurenti L, Li X, et al. Sustained signaling through the B-cell receptor induces 
Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells.  Blood. 
2005;105(12):4820-27.  
Puente XS, Bea S, Valdes-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic 
leukaemia.  Nature. 2015;526(7574):519-24.  
Puente XS, Pinyol M, Quesada V, et al.  Whole-genome sequencing identifies recurrent 
mutations in chronic lymphocytic leukaemia.  Nature. 2011;475(7354):101-5.  
Quesada V, Conde L, Villamor N, et al.  Exome sequencing identifies recurrent mutations of the 
splicing factor SF3B1 gene in chronic lymphocytic leukemia.  Nat Genet. 2011;44(1):47-52.  
Rai KR, Sawitsky A, Cronkite EP, et al.  Clinical staging of chronic lymphocytic leukemia.  
Blood. 1975;46(2):219-34.  
Reinart N, Nguyen PH, Boucas J, et al. Delayed development of chronic lymphocytic leukemia 
in the absence of macrophage migration inhibitory factor. Blood. 2013;121(5):812-21.  
Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and 
cyclophosphamide prolongs progression-free survival compared with fludarabine and 
cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 
2010;28(10):1756-65.  
Seiffert M, Dietrich S, Jethwa A, et al. Exploiting biological diversity and genomic aberrations in 
chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(6):1023-31.  
Seymour JF, Opat S, Cull G, et al. High overall response rate with the BTK inhibitor BGB-3111 
in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: an update on 
safety and activity (Data presented at the 14th International Conference on Malignant 
Lymphoma presentation, Abstract #237). Hematol Oncol. 2017;35(S2):234-5.  
Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic 
leukemia. Blood. 2011;118(16):4313-20.  
Swerdlow S, Campo E, Harris NL, et al. WHO classification of tumors of Hematopoetic and 
Lymphoid Tissues. IARC, Lyon. 2008.  
Tam C, Grigg AP, Opat S, et al. The BTK Inhibitor, Bgb-3111, Is Safe, Tolerable, and Highly 


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Active in Patients with Relapsed/ Refractory B-Cell Malignancies: Initial Report of a Phase 1 
First-in-Human Trial. Blood. 2015;126:832.  
Tsukada N, Burger JA, Zvaifler NJ, et al.  Distinctive features of “nurselike” cells that 
differentiate in the context of chronic lymphocytic leukemia. Blood. 2002;99(3):1030-37.  
Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is 
associated with distinct molecular characteristics and does not indicate a suboptimal response to 
therapy. Blood. 2014;123(12):1810-7.  
Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib or placebo in combination with 
bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic 
leukaemia: interim results from a phase 3, randomized, double-blind, placebo-controlled trial. 
Lancet Oncol. 2017;18(3):297-311.  
Zydelig® - Summary of Product Characteristics: 15 December 2016.  


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APPENDIX 1. SIGNATURE OF INVESTIGATOR  
PROTOCOL TITLE: 
A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared 
with Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small 
Lymphocytic Lymphoma 
PROTOCOL NO: BGB-3111-305; Amendment 4.0 
This protocol is a confidential communication of BeiGene, Ltd. and its subsidiaries.  I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd. or one of its subsidiaries. 
Instructions to the Investigator:  Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol.  PRINT your name, title, and the name of 
the center in which the study will be conducted. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
 
_______________________________   Date:  _____________ 
Printed Name:  
 
 
 
 
_______________________________ 
Investigator Title:  
 
 
 
_______________________________ 
Name/Address of Center:  
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 


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APPENDIX 2. CLL RESPONSE DEFINITIONS  
(From “Modified” IWCLL guidelines Hallek et al 2008 and Cheson et al 2012) 
Parameter 
Complete Responsec 
Partial Responsee 
Partial Response with 
Lymphocytosisg 
Progressive Diseaseh 
Group A 
Lymphadenopathya 
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 
 
Marrowb 
Normocellular, < 30% 
lymphocytes, no B-lymphoid 
nodules. Hypocellular marrow 
defines CRid 
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodulesf 
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 
Neutrophilsb 
> 1500/μL 
> 1,500/μL or > 50% 
improvement over baseline 
> 1,500/μL or > 50% 
improvement over baseline 
 
Abbreviations: CLL, chronic lymphocytic leukemia; CRi, CR with incomplete bone marrow recovery; CT, computed tomography; PD, progressive disease; 
PR, partial response. 
Group A criteria define the tumor load, Group B criteria define the function of the hematopoietic system (or marrow). 
a. 
Sum of the products of multiple lymph nodes (as evaluated by CT scans, or by physical examination). 
b. These parameters are irrelevant for some response categories. 
c. 
Complete response: all the criteria have to be met, and patients have to lack disease-related constitutional symptoms. 
d. Complete response with incomplete marrow recovery: all the criteria met for complete response except for hypocellular bone marrow. 


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e. 
Partial response: at least 2 of the criteria of group A plus 1 of the criteria of Group B must be met.  If only one Group A parameter is abnormal at 
baseline, then one Group A parameter is sufficient.  Bone marrow results are not required as a Group A parameter to determine PR unless that is the 
only Group A parameter abnormal at baseline. 
f. 
Nodular partial response: all the criteria met for complete response except for the presence of lymphoid nodules in the bone marrow 
g. Partial response with lymphocytosis: blood lymphocytes decreased < 50% or increased from baseline + otherwise meeting criteria for PR 
h. Progressive disease: at least 1 of the above progressive disease criteria must be met. 
• Stable disease: is absence of progressive disease and failure to achieve at least a PR-L 
Note:  BTK inhibition may cause lymphocytosis due to a redistribution of leukemia cells from the lymphoid tissues to the blood.  In such cases, increased blood 
lymphocytosis may not be a sign of treatment failure or progressive disease.  The opposite may occur during periods of temporary holds of BTK inhibitors (due 
to adverse events or other reasons), and leukemia cells may redistribute from the blood to lymphoid tissue; this also may not be a sign of treatment failure or 
progressive disease. Isolated increase in lymph nodes and/or splenomegaly during periods of study drug hold may occur leading to PD. Sites should do their best 
to obtain CT scans and perform response assessments using the time allotted in assessment windows to avoid this situation. Patient may continue study treatment 
post first assessed PD if it is perceived that the patient will benefit from continued treatment. After the second assessment of PD, the patient must discontinue 
from study treatment. In rare instances, after discussion with the Medical Monitor, the patient may remain on study treatment even after the second assessment of 
PD. 


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APPENDIX 3. THE LUGANO CLASSIFICATION FOR CT-BASED 
RESPONSE FOR SLL (CHESON ET AL 2014)  
Response and Site 
CT-Based Response 
Complete 
 
     Lymph nodes and 
     extralymphatic sites 
Complete radiologic response (all of the following): 
• 
Target nodes/nodal masses must regress to ≤ 1.5 cm in longest 
transverse diameter of a lesion 
• 
No extralymphatic sites of disease 
     Non-measured  
     lesion 
Absent 
     Organ enlargement 
Regress to normal 
     New lesions 
None 
     Bone marrow 
Normal by morphology, if indeterminate, IHC negative 
Partial 
      
 
     Lymph nodes and 
     extralymphatic sites 
 
Partial remission (all of the following): 
• ≥ 50% decrease in sum of the product of the perpendicular 
diameters for multiple lesions of up to 6 target measurable 
nodes and extranodal sites and no criteria for PD are met 
• 
When a lesion is too small to measure on CT, assign 5 mm x 5 
mm as the default value 
• 
When no longer visible, 0 x 0 mm 
• 
For a node > 5 mm x 5 mm, but smaller than normal, use 
actual measurement for calculation 
     Non-measured 
     lesions 
Absent/normal, regressed, but no increase 
     Organ enlargement 
Spleen must have regressed by > 50% in length beyond normal 
     New lesions 
None 
     Bone marrow 
Not applicable 
No response or stable 
disease 
      
 
     Target nodes/nodal  
     masses, extra-nodal 
     lesions 
 
Stable disease 
< 50% decrease from baseline in sum of the product of the perpendicular 
diameters for multiple lesions of up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive disease are met 
 
     Non-measured 
     lesions 
No increase consistent with progression 
 
     Organ enlargement 
No increase consistent with progression 
     New lesions 
None 


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Response and Site 
CT-Based Response 
     Bone marrow 
Not applicable 
Progressive disease* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progressive disease requires at least 1 of the following cross product of the 
longest transverse diameter of a lesion and perpendicular diameter 
progression: 
 
An individual node/lesion must be abnormal with: 
• 
longest transverse diameter of a lesion > 1.5 cm and 
• 
Increase by ≥ 50% from cross product of the longest transverse 
diameter of a lesion and perpendicular diameter nadir and 
• 
An increase in longest transverse diameter of a lesion or 
shortest axis perpendicular to the longest transverse diameter 
of a lesion from nadir 
• 
0.5 cm for lesions ≤ 2 cm 
• 
1.0 cm for lesions > 2 cm 
• 
In the setting of splenomegaly**, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (eg a 15-cm spleen must increase to > 16 cm).  If no 
prior splenomegaly, must increase by at least 2 cm from 
baseline 
• 
New or recurrent splenomegaly 
     Individual target  
     nodes/nodal masses 
 
 
     Non-measured 
     lesions 
 
New or clear progression of pre-existing non-measured lesions 
     New lesions 
Regrowth of previously resolved lesions 
• A new node > 1.5 cm in any axis 
• 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be attributable 
to lymphoma 
• 
Assessable disease of any size unequivocally attributable to 
lymphoma 
     Bone marrow 
New or recurrent involvement 
Source:  Cheson et al 2014. 
Abbreviations: CT, computed tomography; IHC, immunohistochemistry; PD, progressive disease. 
Modification from Lugano Classification for NHL (Cheson et al 2014): 
*Note:  Temporary withholding of study drug (eg, for drug-related toxicity, surgery, or intercurrent illness) for as 
little as 7 days can cause a transient worsening of disease and/or of constitutional symptoms.  In such circumstances, 


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and if medically appropriate, patients may resume therapy and relevant clinical, laboratory, and/or radiologic 
assessments should be performed to document whether tumor control can be maintained or whether actual disease 
progression has occurred.   
Isolated increase in lymph nodes and/or splenomegaly during periods of study drug hold may occur leading to PD. 
Sites should do their best to obtain CT scans and perform response assessments using the time allotted in assessment 
windows to avoid this situation. Patients may continue study treatment post-first assessed PD if it is perceived that 
the patient will benefit from continued treatment. After the second assessment of PD, the patient must discontinue 
from study treatment. In rare instances, after discussion with the Medical Monitor, the patient may remain on study 
treatment even after the second assessment of PD. 
**Splenomegaly defined as vertical spleen length > 13 cm.   


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APPENDIX 4. NEW YORK HEART ASSOCIATION CLASSIFICATION  
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, 
eg no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, eg walking short distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 


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APPENDIX 5. CYP3A INHIBITORS AND INDUCERS  
Strong CYP3A Inhibitors 
Antibiotics:  clarithromycin, troleandomycin 
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals:  boceprevir, telaprevir 
Food products:  grapefruit juice (a) 
Other:  cobicistat, conivaptan, elvitegravir,  nefazodone, diltiazem, idelalisib 
Protease inhibitors:  nelfinavir, ritonavir or ritonavir(b) in combination with 
danoprevir/elvitegravir/indinavir/lopinavir/paitprevir and (obitasvir and/or 
dasabuvir)/saquinavir/tipranavir 
 
Moderate CYP3A Inhibitors 
Antibiotics:  ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
Calcium channel blockers:  verapamil 
Tyrosine kinase inhibitors (anticancer):  imatinib, crizotinib 
Others: aprepitant, cimetidine, cyclosporine, dronedarone, tofisopam, fluvoxamine  
 
Strong CYP3A Inducers 
Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
 
Moderate CYP3A Inducers  
Bosentan, efavirenz, etravirine, modafinil 
Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers  (9/26/2016). 
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A. 
Note: The list of drugs in this table is not exhaustive.  Please refer to the prescribing information of concomitant 
medication to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
a. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg,  high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg,, low dose, single strength). 
b. Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. 
Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of 
combination regimens on CYP3A activities. 


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APPENDIX 6. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg light house work/office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
 


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APPENDIX 7. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-
LEVELS HEALTH QUESTIONNAIRE  
 


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APPENDIX 8. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30  
 


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APPENDIX 9. GRADING SCALE FOR HEMATOLOGIC TOXICITY IN 
CLL STUDIES HEMATOLOGIC GRADING SCHEME  
Grade1 
Decrease in platelets2 or Hgb3 (nadir) 
from pretreatment value 
Absolute neutrophil count/μL4 (nadir) 
0 
No change to 10% 
≥ 2,000 
1 
11%-24% 
≥ 1,500 and < 2,000 
2 
25%-49% 
≥ 1,000 and < 1,500 
3 
50%-74% 
≥ 500 and < 1,000 
4 
≥ 75% 
< 500 
Source: Hallek et al 2008. 
Abbreviation: ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia 
Hgb: hemoglobin; WBC, white blood cell;  
1 Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be reported as Grade 5. 
2 Platelet counts must be below normal levels for Grades 1 to 4.  If, at any level of decrease, the platelet count 
is < 20 × 109/L (20,000/μL), this will be considered Grade 4 toxicity, unless a severe or life-threatening decrease 
in the initial platelet count (eg < 20 × 109/L [20,000/μL]) was present pretreatment, in which case the patient is not 
evaluable for toxicity referable to platelet counts. 
3 Hemoglobin (Hgb) levels must be below normal levels for Grades 1 to 4. Baseline and subsequent Hgb 
determinations must be performed before any given transfusions. The use of erythropoietin is irrelevant for the 
grading of toxicity, but should be documented. 
4 If the ANC reaches < 1 × 109/L (1,000/μL), it should be judged to be Grade 3 toxicity. Other decreases in the 
WBC, or in circulating neutrophils, are not to be considered because a decrease in the WBC is a desired 
therapeutic endpoint. A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of 
toxicity. If the ANC was < 1 × 109/L (1,000/μL) before therapy, the patient is not evaluable for toxicity referable 
to the ANC. The use of growth factors such as granulocyte colony-stimulating factor (G-CSF) is not relevant to the 
grading of toxicity, but should be documented. 
 


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APPENDIX 10. SCHEDULE OF ASSESSMENTS  
 
Screening 
Enrollment/ 
Randomizationa 
Treatment Periodee (1 cycle = 28 days) 
Continue Until End of Treatment (Section 6.7) 
Post-Treatment Follow-Upee 
Cycle 
– 
 
1 
2 to 3 
4 
5 to 6 
Every 3 
Cycles 
beginning 
Cycle 7 (C7, 
10, etc.)  
End of 
Treatmentb 
Long-term 
Follow-upc 
Survival 
Follow-
upd 
Cycle Day 
-35 to  
randomization 
-5 to -1 prior to 
C1D1 
1e 
1 
1 
1 
1 
30 days 
after EOT 
Every 24 
weeks 
Every 24 
weeks 
Window (Days) 
– 
 
- 
± 2 
± 2 
± 2 
± 6f 
+ 7 days 
± 14 days 
± 14 days 
Informed consent, screen numberg 
X 
 
 
 
 
 
 
 
 
 
Medical & cancer history 
X 
 
 
 
 
 
 
 
 
 
Eligibility authorization packeth 
X 
 
 
 
 
 
 
 
 
 
Randomization/Treatment arm 
assignmenti 
X 
 
 
 
 
 
 
 
 
 
Zanubrutinib & ibrutinib 
dispensing/accountabilityj 
 
 
X 
X 
X 
X 
Xj 
 
 
 
Sparse PK samplingk 
 
 
X 
C3 only 
X 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Cardiac function 
X 
 
 
 
 
 
 
 
 
 
Vital signs (temperature, BP, heart 
rate) 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examinationl 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECG (local read)m 
X 
 
X 
X 
X 
 
X 
 
 
 
Concomitant medications review 
X 
 
X 
X 
X 
X 
X 
X 
 
 
AE reviewn 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
 
Survival status of patient 
 
 
 
 
 
 
 
 
 
X 


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Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
Overall response assessment 
 
 
 
 
X 
 
Xo 
X 
X 
 
Disease-related constitutional 
symptoms 
X 
 
 
 
X 
 
X 
X 
X 
 
Physical exam of liver, spleen & 
lymph nodes 
X 
 
 
 
X 
 
X 
X 
X 
 
CT with contrastp 
X 
 
 
 
X 
 
Xo 
Xq 
X 
 
Bone marrow examinationr 
X 
 
As neededr 
As needed 
X 
 
PRO Questionnairess 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
X 
 
X 
 
X 
X 
X 
 
EORTC QLQ-C30 
 
 
X 
 
X 
 
X 
X 
X 
 
Self-administered Activity and 
Quality of Life Evaluation 
(Optional)t 
For select patients, see Section 5.7.3 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematologyu, chemistryv 
Xw 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum immunoglobulins 
X 
 
 
 
X 
 
C7 then every 
6 cycles  
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B & C testingx 
X 
 
 
 
 
 
 
 
 
 
 
HIV testing y 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable)z 
X 
 
X 
X 
X 
X 
Every cycle 
X 
 
 
Biomarker Assessments 
 
 
 
 
 
 
 
 
 
 
del17p by FISHaa 
X 
 
 
 
 
 
 
 
 
 
Molecular analysesbb 
X 
Xbb 
Xbb 
 
 
HBV DNA screening by PCRcc 
 
 
Every cycle 
 
 
Flow Cytometrydd 
X 
X 
 
 
 
 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BP, blood 
pressure; BTK, Bruton tyrosine kinase; C#, Cycle #; CR, complete response; CRi, complete response with incomplete bone marrow recovery; CT, computed 
tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; HBcAb, hepatitis B core antibody; HBsAb, 
hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IEC, Independent Ethics Committee; IGHV, 
immunoglobulin variable region heavy chain; INR, international normalized ratio; MRI, magnetic resonance imaging; MRD, minimal residual disease; PD, 
progressive disease; PK, pharmacokinetics; PRO, patient-reported outcome; SAE, serious adverse event. 
a. Time between randomization and Day 1 should be no more than 5 days. See Section 5.2.6. 


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b. Approximately 30 days (+ 7 days) after permanent treatment discontinuation or before initiation of a new anticancer therapy, whichever comes first. See 
Section 5.12.1. 
c. Visits repeat every 24 weeks (± 14 days) after end of treatment. Assessments during this phase are conducted primarily to assess disease progression. See 
Section 5.12.2. 
d. Survival Follow-up phase will be every 24 weeks (± 14 days) until the end of the study for patients who have ended treatment and progressed.  A study visit is 
not mandatory during Survival-Follow-up: see Section 5.12.3. 
e. All Day 1 assessments should occur pre-dose unless otherwise specified. 
f. Cycle 7 has a ± 2 day window 
g. Informed consent and assignment of screen number must occur before any study specific procedures, and may be obtained before the screening window 
begins.  Consent must be obtained on the current version of the form approved by the IEC. See Section 5.2. 
h. After a patient is screened and the investigator determines the patient is eligible for randomization, study site personnel will complete an Eligibility 
Authorization Packet and the medical monitor or designee will provide final approval for enrollment in writing.  Study site personnel should ensure that a 
medical monitor-approved Eligibility Packet is in the patient’s file before proceeding with Day 1 study procedures. See Section 5.2.5. 
i. Patients will be randomized 1:1 to one of two arms - Arm A: zanubrutinib or Arm B: ibrutinib. See Section 3.1 and Section 9.2.1. 
j. Zanubrutinib will be administered 160 mg orally twice daily with or without food (See Section 6.2.1).  Ibrutinib will be administered 420 mg orally once daily 
(See Section 6.2.2). Study drug (both zanubrutinib and ibrutinib) may be supplied and dispensed as frequently as every cycle and accountability should be 
done at that time (See Section 6.1.4). Please refer to the pharmacy manual for further information and the most recent guidance on study drug supply 
frequency during the trial. 
k. Sparse PK samples will be collected from all patients assigned to Arm A (zanubrutinib) on Cycle 1 Day 1 pre-dose (within 30 min prior to the morning dose), 
2 hours post-dose (± 30 minutes), and before subject discharge (4-6 hours post-dose); and pre-dose (within 30 min prior to the morning dose) on Cycle 3 Day 
1 and Cycle 4 Day 1 (See Section 5.4). 
l. Assess systems per standard of care at the study site and as clinically indicated by symptoms.  Includes weight (height at Screening only).  Assessment of vital 
signs and a focused physical examination on Cycle 1 Day 1 may be skipped if performed within the last 7 days. See Section 5.5.2. 
m. Perform a 12-lead ECG in triplicate at screening for all subjects.  For subjects assigned to the zanubrutinib arm, one 12-lead ECG will be performed at, pre-
dose (within 30 min prior to dose) and 2 hours (± 30 min) post-dose on Day 1 of Cycles 1 and 2, and one 12-lead ECG performed on Day 1 of Cycles 3 and 4 
and Day 1 of every 3 cycles thereafter (at Cycle 7, Cycle 10, etc) until EOT.  The ECG can be performed at either pre-dose or post-dose.  For subjects 
assigned to the ibrutinib arm, a 12-lead ECG in triplicate will be performed at Day 1 of Cycles 1, 2, 3, and 4 and Day 1 of every 3 cycles thereafter (Cycle 7, 
Cycle 10, etc) until EOT.  The ECG can be performed at either pre-dose or post-dose. See Section 5.5.4. 
n. After informed consent has been signed but prior to the administration of the study drug, only SAEs should be reported.  If patients screen fail, reporting of 
SAEs will end at the time of screen failure.  After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be reported until 30 
days after the last dose of study drug. After this period, the investigator should report any SAEs that are believed to be related to prior study drug treatment.  
In addition, arrhythmia signs/symptoms will be reviewed at every visit.  This will involve the investigators asking subjects for signs and symptoms of 
ventricular dysfunction (eg, shortness of breath, dizziness or fainting), as part of the routine AE monitoring for each visit. See Section 8.4.1. 
o. Efficacy will be assessed every 6 cycles following C25 (C31, C37, C43, etc.) until progression.  Patients that end treatment but do not progress will continue 
to conduct efficacy assessments as part of Long-term Follow-up (See Section 5.12.2). 
p. CT with contrast of neck, chest, abdomen, and pelvis to be performed at Screening, Cycle 4 Day 1, then every 3 cycles until Cycle 25, followed by every 6 
cycles thereafter, until disease progression, withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first.  Copies of all scans will be 
sent for independent central review for response assessment.  MRI may be used in place of CT; for details on imaging requirements see Section 5.6.3.  All 
imaging should use the specified visit window or a ± 7-day window, whichever is longer. Imaging is to be performed as scheduled, independent of study drug 
hold. 


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q. Imaging does not need to be repeated if performed within 45 days before the End of Treatment Visit. 
r. Bone marrow biopsy and aspirate are required during 1) the screening period. Fifteen unstained slides or archival block of a previously performed diagnostic 
bone marrow biopsy are acceptable if within 90 days of randomization. Aspirate only required for patients with SLL; 2) if clinical and laboratory results 
demonstrate a potential CR or CRi. This should be done within 40 days from the CT/MRI meeting the criteria of CR/CRi. If this is done and patients show 
bone marrow involvement preventing CR/CRi classification it should recheck bone marrow at least once every 12 months until CR or CRi is confirmed as 
long as the patient is still showing evidence of CR or CRi outside of bone marrow results.  Recheck may be done earlier than 12 months as clinically 
indicated. 3) At time of suspected progression due to cytopenias.  See Section 5.6.4 for details. 
s. Patients should complete the EQ-5D-5L and EORTC QLQ-C30 questionnaires before the first dose of study drug, and before performing any other 
procedures.   See Section 5.7. 
t. Self-Administered Activity and Quality of Life Evaluation may be optionally consented to in select countries. Assessments will be conducted weekly for the 
first 12 weeks and monthly up to 2 years (See Section 5.7.3). 
u. Complete blood count and differential will be evaluated by a central or local laboratory. Complete blood count includes hemoglobin, hematocrit, platelet 
count, red blood cell count, white blood cell count with differential (neutrophil, lymphocyte, monocyte, eosinophil, and basophil). See Section 5.8.1. 
v. Serum chemistry will be evaluated by a central or local laboratory.  Serum chemistry includes sodium, potassium, chloride, bicarbonate (carbon dioxide, or if 
neither is available carbon dioxide combining power), glucose, blood urea nitrogen (or serum urea), creatinine, calcium, phosphate (or phosphorus), 
magnesium, total bilirubin, total protein, albumin, ALT, AST, lactate dehydrogenase, and alkaline phosphatase. See Section 5.8.2. 
w. The following 2 chemistry tests will only be done at Screening: direct antiglobulin test and β-2 microglobulin. See Section 5.8.2. 
x. Hepatitis B serology includes HBsAg, HBcAb, HBsAb.  Patients who are HBcAb positive, HBsAg negative, and HBV DNA negative will undergo viral load 
measurement (HBV DNA by PCR) as outlined in Section 5.8.5.  Hepatitis C serology includes HCV antibody.  Patients who are HCV antibody positive, but 
negative for HCV RNA, will undergo viral load testing (HCV RNA by PCR) every cycle.  Viral hepatitis B and C testing will be performed in a central 
laboratory, but may be performed locally if local testing sensitivity is adequate and after discussion with the medical monitor. See Section 5.8.5. 
y. HIV test will be performed locally. HIV testing will be performed during Screening unless previous HIV test results from ≤ 4 weeks prior to Screening are 
available. See Section 5.8.7. 
z. For all women of childbearing potential (including those who have had a tubal ligation), a serum pregnancy test will be performed at screening within 7 days 
of randomization and at end of treatment.  Laboratory-based highly sensitive pregnancy tests (urine or serum) will be performed on Day 1 of every cycle and 
for at least 90 days after the last dose of study drug.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. See Section 5.8.6. 
aa. Blood samples (heparin) will be collected at the time of screening to assess prognostic factors such as del17p by FISH in a central laboratory (see the 
Laboratory Manual for details) 
bb. Blood samples (EDTA) are required at the time of Screening, and at the time of CR or CRi, and disease progression for the assessment of mutations by 
molecular methods in a central laboratory (see the Laboratory Manual for details). See Section 5.9. 
cc. Patients who are HBsAg negative, HBcAb positive, and HBV DNA negative must undergo at least once on every cycle HBV DNA monitoring by PCR.  
These patients should be considered for prophylactic antiviral treatment in consultation with a local HBV expert.  If a patient is being treated prophylactically 
with antivirals, HBV DNA monitoring by PCR must be done at least every 90 days (every third cycle). See Section 5.8.5. 
dd. Blood samples (EDTA) are required at the time of Screening, and at the time of CR or CRi, for the assessment of MRD by flow cytometry in a specialized 
central laboratory (see the Laboratory Manual for details). See Section 5.9. 
ee. Survival status assessment may be conducted on ad hoc basis for a data cut within 30 days prior to the data cutoff date. Survival information may be 
confirmed via a phone call, medical records, or other methods. See Section 5.6.5. 


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APPENDIX 11. SELECT ADVERSE EVENTS OF INTEREST: TOXICITY 
MANAGEMENT  
The recommendations below for the diagnosis and management of adverse events of interest are 
intended as a guidance. This Appendix should be used in conjunction with expert clinical 
judgement (eg, by experts specializing in cardiology for management of atrial fibrillation), and 
individual institutional guidelines or policies. Local prescribing guidance for ibrutinib applicable 
to your country should always take precedence for your country as applicable. 
Toxicity 
Grade (per CTCAE 
4.03 or Hallek et al, 
2008) 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Atrial Fibrillation 
1 
Asymptomatic, 
intervention not 
indicated 
For all grades, recommend 
consultation with cardiologist for 
co-management of patients on 
study and to help determine the 
overall risk of embolic stroke 
versus bleeding. The usage of the 
CHA2DS2-VASc risk assessment 
tool can be helpful. When selecting 
medical therapy for these patients, 
consider avoiding strong CYP3A4 
inducers and inhibitors 
(Section 7.2.1).  
If the patient requires 
anticoagulation, recommend 
minimizing other medications 
associated with increased bleeding 
risk; however, decisions needed to 
be balanced by the need for such 
medications in consultation with 
other specialists. Warfarin is 
highly discouraged given known 
bleeding risk. 
Recommend 
continuation of study 
treatment especially if 
CHA2DS2-VASc score 
is 0 or 1 and no 
anticoagulation is 
indicated. 
2 
Non-urgent medical 
intervention indicated 
3 
Symptomatic and 
incompletely controlled 
medically 
For atrial 
fibrillation/flutter 
≥ Grade 3, follow the 
dose reductions 
described in 
Section 6.5.1 for 
zanubrutinib and 
Section 6.5.2 for 
ibrutinib. For subjects 
experiencing atrial 
fibrillation that is 
symptomatic and/or 
incompletely 
controlled: After the 
atrial fibrillation is 
adequately controlled, 
the study drug may be 
restarted at either the 
original dose or dose 
level -1, per discretion 
of the treating 
investigator. 
Patients who have 
intracranial hemorrhage 
in the context of atrial 
fibrillation should 
permanently 
discontinue treatment. 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
If patients are unstable, urgent 
referral to a cardiologist and 
evaluation for cardioversion and/or 
therapeutic anticoagulation is 
recommended.  


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Toxicity 
Grade (per CTCAE 
4.03 or Hallek et al, 
2008) 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Anemiaa 
(per Hallek et al 
2008) 
1 
11%-24% decrease from 
pretreatment value 
Follow institutional guidelines if 
any intervention is needed. 
Recommend 
continuation of study 
treatment. If severe 
bleeding is also 
identified, study drug 
should then be held, 
until bleeding has 
resolved. 
2 
25%-49% decrease from 
pretreatment value 
3 
50%-74% decrease from 
pretreatment value 
Consider workup for possible 
sources of bleeding. 
Consider possibility of 
autoimmune hemolytic anemia. 
Follow institutional guidelines 
regarding transfusion of red blood 
cells. 
If anemia persists or recurs, 
consider more extensive workup, 
including possible bone marrow 
examination. 
4 
≥75% decrease in 
pretreatment value 
For ibrutinib, hold 
study treatment; resume 
when 
resolved/improved to 
≤ Grade 1. Follow the 
dose reductions 
described in 
Section 6.5.2.  
For zanubrutinib, if 
anemia is considered 
unrelated to study drug, 
continue study 
treatment, unless severe 
bleeding is also 
identified. Otherwise, 
follow the dose 
reductions described in 
Section 6.5.1. 
Neutropenia 
1 
1500-2000/mm3; 1.5–2.0 
x 10^9/L 
If neutropenia is associated with 
fever or suspected infection, 
consider hospitalization and 
treatment with antibiotics per local 
standard of care. 
Recommend 
continuation of study 
treatment. 
2 
1000–1500 mm3; 1.5–2.0 
x 10^9/L 
3 
500-1000/mm3; 0.5-1.0 
x 10^9/L 
If neutropenia is associated with 
fever or suspected infection, 
consider hospitalization and 
treatment with antibiotics or 
granulocyte stimulating cytokines 
such as G-CSF per local standard 
of care.  
Persistent or recurrent neutropenia 
should lead to further workup, 
including possible bone marrow 
examination. 
For ibrutinib, hold 
study treatment if 
neutropenia is 
associated with fever or 
suspected infection. 
Resume when 
resolved/improved to 
≤ grade 1. Follow the 
dose reductions 
described in 
Section 6.5.2. 
For zanubrutinib, 
dosing will be held for 
individual patients 
4 
<500/mm3; <0.5 x 
10^9/L 


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Toxicity 
Grade (per CTCAE 
4.03 or Hallek et al, 
2008) 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
under any of the 
following conditions, 
based on investigator 
assessment of study 
drug relatedness: 
Grade 4 neutropenia 
(lasting > 10 days)  
≥ Grade 3 febrile 
neutropenia 
 
Follow the dose 
reductions described in 
Section 6.5.1. 
Thrombocytopenia 
1 
11%-24% decrease from 
pretreatment value 
Intervention per institutional 
guidelines. Monitor closely for 
bleeding events. 
Recommend 
continuation of study 
treatment. If severe 
bleeding is also 
identified, study drug 
should then be held 
until bleeding has 
resolved. 
2 
25%-49% decrease from 
pretreatment value 
3 
50%-74% decrease from 
pretreatment value 
Continue ibrutinib 
unless severe bleeding 
is also identified.  
Otherwise, follow dose 
reductions described in 
Section 6.5.2. 
Hold zanubrutinib if 
any grade 3 
thrombocytopenia 
associated with 
significant bleed 
requiring medical 
intervention. Discuss 
with medical monitor. 
Otherwise, follow the 
dose reductions 
described in 
Section 6.5.1. 
4 
≥75% decrease in 
pretreatment value OR 
any platelet count 
<20,000/mm3; 20.0 x 
10^9/L. 
Consider transfusion for platelet 
count <10,000/mm3; <10.0 x 
10^9/L. 
Consider further workup for 
immune thrombocytopenia and 
disease progression, including if 
needed bone marrow examination. 
For ibrutinib, drug 
should be held until 
resolved to baseline or 
to grade 1. Follow the 
dose reductions 
described in Table 5. 
For zanubrutinib, hold 
study treatment if 
Grade 4 
thrombocytopenia lasts 


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Toxicity 
Grade (per CTCAE 
4.03 or Hallek et al, 
2008) 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Consider holding any other anti-
platelet therapy or anticoagulation 
as clinically indicated. 
for more than 10 days 
and is assessed to be 
related to drug. Follow 
the dose reductions 
described in 
Section 6.5.1. 
Bleeding 
≥ Grade 3 bleeding not 
considered related to 
study drug 
Intervention per institutional 
guidelines. 
Consider holding any other anti-
platelet therapy or anticoagulation 
as clinically indicated. 
If bleeding is considered related to 
study drug and bleeding requires 
hospitalization, platelet transfusion 
may be of benefit if given at least 
3-4 hr after last dose of drug, 
except for patients with CNS 
bleeding [Shatzel JJ et al, J Thomb 
Hemostat 2017]. 
Hold until recovery to 
≤ Grade 1. 
Restart at either the 
original dose or dose 
level (-1), at the 
discretion of the 
treating investigator.  
≥ Grade 3 bleeding 
considered related to 
study drug 
Hold until underlying 
condition has fully 
resolved. 
If underlying condition 
cannot be treated to full 
resolution, permanently 
discontinue 
zanubrutinib.  
If the underlying 
condition can be fully 
treated (eg, gastric ulcer 
resulting in 
gastrointestinal bleed) 
and the risk of a re-
bleed is deemed 
acceptable by the 
medical monitor, 
treatment may restart at 
dose level (-1). 
Zanubrutinib should be 
permanently 
discontinued for any 
intracranial 
hemorrhage. 
Other ≥ Grade 3 
toxicity considered 
related to study 
drug, including 
inadequately 
controlled 
hypertension 
(HTN) and/or liver 
or renal laboratory 
value 
abnormalities  
≥ 3 
 
Follow dose reductions 
described in 
Section 6.5.1 for 
zanubrutinib and 
Section 6.5.2 for 
ibrutinib. 


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APPENDIX 12. 
ACTIVITY AND QUALITY OF LIFE SELF-ADMINISTERED 
QUESTIONNAIRE  
 
Please answer the following questions based on your symptoms during the past week: 
1. Diarrhea 
What was the severity of your diarrhea at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 
2. Fatigue 
What is the severity of your fatigue, tiredness, or lack of energy at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 


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3. Pain in a Joint or Joints or muscle cramping 
What is the severity of your pain in a joint or joints at its worst: 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
4. Shortness of Breath 
What is the severity of your shortness of breath at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 
5. Bruising or Bleeding 
What was the severity of your bruising or bleeding at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 
6. Rash 
What was the severity of your skin rash at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 


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7. Nausea 
What was the severity of your nausea at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 
8. Palpitations (Fast or Irregular Heart Beat) 
What was the severity of your palpitations at its worst? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Very Severe 
 
9. Doses of Study Drug 
Over the past week, how often did you miss doses of study drug? 
• 
Never 
• 
1-2 doses 
• 
3-5 doses 
• 
5-8 doses 
• 
9 doses or more 
 
10. Contacted Doctor 
Over the past week, have you contacted your doctor (by phone or in person) regarding problems 
related to your chronic lymphocytic leukemia? 
• 
Yes 
• 
No 
 


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11. Activity: Over the past week 
On the scale 1 to 5, with 1 being low and 5 being high, have you been able to perform you preplanned 
daily activities? 
           1 (low) 
            2 
            3 
              4 
           5 (high) 
 
 
 
 
 
 
12. General Well Being 
This month compared to the prior month 
• 
I feel worse than last month 
• 
I feel the same as last month 
• 
I feel better than last month 
 
13. Mobile device tracking 
How much of the time have you carried this mobile device with you when you were active since the 
last time you completed this questionnaire? 
• 
Close to 100% of the time 
• 
More than 50% of the time 
• 
About 50% of the time 
• 
Less than 50% of the time 
• 
Very little or not at all 
 
 


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