Clinical trial NCT03053440
Conditions: Waldenström's Macroglobulinemia
Sponsor: BeiGene
Start date: 2017-01-25; Completion date: 2022-06-21
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the safety, efficacy and clinical benefit of BGB-3111 (zanubrutinib) vs ibrutinib in participants with MYD88 Mutation Waldenström's Macroglobulinemia.

Detailed description:
This open-label, randomized study compared the efficacy and safety of the Bruton's Tyrosine Kinase (BTK) inhibitors BGB-3111 and ibrutinib in participants with Waldenström's Macroglobulinemia who require therapy. Participants had baseline bone marrow samples assayed for sequencing of the MYD88 gene. 201 participants with the MYD88 mutation were enrolled and randomized to receive 160 mg BGB-3111 orally twice per day (PO BID) (treatment Arm A) or to receive 420mg ibrutinib orally once per day (PO QD) (treatment Arm B) until disease progression or unacceptable toxicity.

Arms: arm 1: Participants with the MYD88 mutation received Ibrutinib arm 2: Participants with the MYD88 mutation received zanubrutinib
Interventions: intervention 1: BGB-3111 intervention 2: Ibrutinib
Intervention descriptions: intervention 1: 160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor intervention 2: 420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 3, Randomized, Open-Label, Multicenter Study 
Comparing the Efficacy and Safety of the Bruton’s Tyrosine 
Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects 
with Waldenström’s Macroglobulinemia (WM) 
Protocol Number: 
BGB-3111-302 
Study Phase: 
3 
Investigational Product: 
Zanubrutinib (BGB-3111) 
Original Protocol: 
29 July 2016  
Amendment 1: 
01 November 2016 
Amendment 2: 
08 May 2017 
Amendment 3: 
02 February 2018 
Amendment 4:       
   21 September 2018 
Amendment 5:       
   26 August 2019 
IND No.: 
125326 
EudraCT No.: 
2016-002980-33 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA 94403 
USA 
Medical Monitor: 
NCT03053440




 
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SYNOPSIS 
Name of Sponsor/Company: 
BeiGene USA, Inc. 
Name of Finished Product: 
Zanubrutinib (BGB-3111) 
Name of Active Ingredient: 
Zanubrutinib (BGB-3111) 
Title of Study: 
A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the 
Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Inhibitors 
BGB-3111 and Ibrutinib in Subjects with Waldenström’s 
Macroglobulinemia (WM)  
Protocol No: 
BGB-3111-302 
Study Centers:  
Approximately 82 sites in the United States (US), Australia (AUS), the 
European Union (EU), and others 
Study Phase: 
Phase 3 
Treatment Duration: 
Subjects will receive daily treatment during the study until progressive 
disease (PD), unacceptable toxicity or death, withdrawal of consent, 
loss to follow-up, or study termination by Sponsor. 
Objectives:  
Primary (Cohort 1) 
 
To compare the efficacy of zanubrutinib (also known as BGB-3111) vs ibrutinib in subjects with 
activating mutations in the myeloid differentiation primary response gene 88 (MYD88) 
(MYD88MUT) WM 
Secondary (Cohort 1)  
 
To further compare the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib vs 
ibrutinib in subjects with MYD88MUT WM 
 
To evaluate safety and tolerability of zanubrutinib versus ibrutinib in subjects with MYD88MUT 
WM, as measured by the incidence and severity of adverse events according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 
Exploratory  


 
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Study Design: 
This is a Phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of the 
Bruton’s Tyrosine Kinase (BTK) Inhibitors zanubrutinib and ibrutinib in subjects with Waldenström’s 
Macroglobulinemia (WM) who require therapy according to the consensus panel criteria from the Seventh 
International Workshop on Waldenström’s Macroglobulinemia (Seventh IWWM, Dimopoulos et al 2014). 
The study is composed of an initial Screening Phase (up to 35 days), a Treatment Phase, and a Follow-up 
Phase.  
Approximately 210 subjects will be enrolled on the study. All subjects enrolled on the study will have 
baseline bone marrow samples (bone marrow aspirate and biopsy) collected and assayed at a central 
laboratory for sequencing of the MYD88 gene. Approximately one hundred eighty-eight WM subjects 
(Approximately 150 relapsed/refractory and approximately 38 treatment-naïve subjects) with the MYD88 
mutation (MYD88MUT), which is characteristic of WM and present in approximately 90% of cases, will be 
enrolled onto Cohort 1 and randomized to one of two treatment arms (Cohort 1: zanubrutinib treatment 
[Arm A] or ibrutinib treatment [Arm B]) in a 1:1 ratio and stratified using CXC-chemokine receptor 4 
(CXCR4) gene sequencing status (CXCR4WHIM vs CXCR4WT vs missing ) and prior line of therapy for WM 
(0 vs 1-3 vs >3 lines of therapy).  
Subjects found to have MYD88 wild-type (MYD88WT) by gene sequencing, which is estimated to be 
present in approximately 10% of enrolled subjects, will be enrolled to Cohort 2 and will receive 
zanubrutinib treatment on a third, non-randomized, study arm (Arm C).  In addition, those subjects whose 
MYD88 mutational status is missing or inconclusive will be assigned to Cohort 2, Arm C.  Approximately 
22 total subjects (including relapsed/refractory and treatment-naïve subjects) are anticipated to be enrolled 
in this cohort. 
The primary efficacy analysis will be conducted approximately 12 months after the last relapsed/refractory 
subject is randomized.   
 
Response will be assessed by an independent review committee (IRC) according to an adaptation 
of the response criteria updated at the Sixth International Workshop on Waldenström’s 
Macroglobulinemia (Sixth IWWM, Owen et al 2013 and National Comprehensive Cancer 
Network [NCCN] Guidelines, Lymphoplasmacytic Lymphoma/Waldenström’s 
Macroglobulinemia 2015: v2). Response assessments will occur at the beginning of every cycle 
(i.e., every 4 weeks starting from C2D1) for the first 48 weeks and then every 3 cycles thereafter 
until PD. 
 
Serum IgM and M-protein levels will be measured at Screening, on Day 1 of every cycle for the 
first 48 weeks, then every 3 cycles thereafter (each cycle is 28 days). 
 
For subjects with evidence of extramedullary disease (defined as lymphadenopathy [lymph nodes 
having a long axis of > 1.5 cm] and/or splenomegaly) detected by computed tomography (CT) 
scan at baseline: 
o Response assessment by CT scan will occur every 12 weeks during the first 48 weeks 
beginning on Day 1, Cycle 4, and then every 24 weeks until PD or complete resolution of 
extramedullary disease.  Additionally, a CT scan is also required at the safety follow-up 
visit. 
For response assessments that occur during cycles when a CT scan is not required, the 
results of the most recent CT scan may be used for the response assessment only if the 


 
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prior scan date is within 12 weeks of the response assessment date during the first 
48 weeks of the study and within 24 weeks of the response assessment date thereafter. 
 
QOL will be measured every 12 weeks during the first 48 weeks, and then every 24 weeks 
thereafter by the EORTC QLQ-C30 and EQ-5D in MYD88MUT WM subjects. 
 
Bone marrow involvement by WM will be assessed by aspirate and biopsy at Screening, at the end 
of Cycle 12 (Week 48), at time of suspected complete response (CR), and as clinically indicated. 
 
All subjects will be followed for adverse events (AEs) until 30 days after the last dose of study 
drug. All treatment-related AEs and serious AEs (SAEs) will be followed until resolution or 
stabilization. Efficacy evaluations will continue until documented PD for subjects who 
discontinued for reasons other than PD.  
Planned Number of Subjects: 
Approximately 210 subjects will be enrolled. This includes 
approximately 188 subjects (approximately 150 subjects with 
relapsed/refractory WM and approximately 38 subjects with treatment-
naïve WM) with MYD88MUT enrolled in Cohort 1 and randomized 1:1 to 
either Arm A or Arm B, and approximately 22 total subjects (both 
relapsed/refractory and treatment-naïve) who are MYD88 wild-type 
(MYT88WT) enrolled in Cohort 2, Arm C.   
Study Population 
Inclusion criteria  
1. 
Clinical and definitive histologic diagnosis of WM. Subjects must either have relapsed/refractory 
disease OR be treatment naïve and considered by their treating physician to be unsuitable for 
standard chemoimmunotherapy regimens 
 
For subjects who have received no prior therapy for WM: “Unsuitable” for treatment 
with a standard chemoimmunotherapy regimen must be a physician-determined status 
based on co-morbidities and risk factors. Physicians will need to provide and 
document organ system(s) and specific reason(s) for subject being considered 
unsuitable.  Patient preference does not meet the eligibility requirement for a 
treatment-naïve subject to be unsuitable for treatment with a standard 
chemoimmunotherapy regimen 
2. 
Meeting at least one criterion for treatment according to consensus panel criteria from the 
Seventh IWWM (Dimopoulos et al 2014, Table 4) 
3. 
Measurable disease, as defined by a serum IgM level > 0.5 g/dl 
4. 
Age ≥ 18 years old 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
6. 
Adequate bone marrow function defined as: 
 
Neutrophils ≥ 0.75 x 109/L, independent of growth factor support within 7 days of study 
entry 
 
Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days of 
study entry 


 
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7. 
Creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or estimated 
glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD]) 
based on ideal body mass 
8. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of 
normal (ULN) 
9. 
Bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome) 
10. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time 
(aPTT) ≤ 1.5 x ULN. Subjects with factor inhibitors that prolong PT/aPTT without increasing 
the bleeding risk, or those with lupus anticoagulant or acquired von Willebrand’s syndrome due 
to WM may be enrolled after discussion with the Medical Monitor or designee. 
11. Subjects who relapse after autologous stem cell transplant are eligible if they are at least 3 
months after transplant and are eligible after allogeneic transplant if they are at least 6 months 
post-transplant. To be eligible after either type of transplant, subjects should have no active 
infections or, in the case of allogeneic transplant relapse, no active acute graft versus host 
disease (GvHD) of any grade, and no chronic GvHD other than mild skin, oral, or ocular GvHD 
not requiring systemic immunosuppression  
12. Female subjects of childbearing potential and non-sterile males must practice highly effective 
methods of birth control initiated prior to first dose of study drug, for the duration of the study, 
and for 90 days after the last dose of study drug.  These methods include the following: 
 
A barrier method of contraception (including male and female condoms with or without 
spermicide) plus one of the following hormonal contraceptives: 
o Combined (estrogen and progestogen containing) hormonal contraception 
associated with the inhibition of ovulation 
 
Oral, intravaginal or transdermal 
o Progestogen-only hormonal contraception associated with the inhibition of 
ovulation 
 
Oral, injectable, implantable 
o An intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment, starting the day prior to first dose of 
study drug, for the duration of the study, and for 90 days after the last dose of study drug). 
Total sexual abstinence should only be used as a contraceptive method if it is in line with 
the subjects’ usual and preferred lifestyle. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of 
exposure to investigational medicinal product (IMP), and withdrawal are not acceptable 
methods of contraception. 
13. Of note, barrier contraception (including male and female condoms with or without spermicide) 


 
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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.  Life expectancy of > 4 
months 
14. Able to provide written informed consent and can understand and comply with the requirements 
of the study 
Exclusion criteria  
1. 
Prior exposure to a BTK inhibitor 
2. 
Evidence of disease transformation at the time of study entry 
3. 
Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy given with 
antineoplastic intent, targeted therapy, or radiation therapy within 4 weeks, or antibody-based 
therapy within 4 weeks of the start of study drug 
4. 
Major surgery within 4 weeks of study treatment 
5. 
Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, absolute 
neutrophil count [ANC] and platelets). For ANC and platelets, please follow inclusion criteria #6 
regarding neutrophils and platelets 
6. 
History of other active malignancies within 2 years of study entry, with exception of (1) 
adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell 
carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent 
7. 
Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, 
congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart failure) as defined by 
the New York Heart Association (NYHA) Functional Classification, or history of myocardial 
infarction within 6 months of screening 
8. 
QTcF prolongation (defined as a QTcF > 480 msec)  
9. 
Active, clinically significant Electrocardiogram (ECG) abnormalities including second degree 
atrioventricular (AV) block Type II, or third-degree AV block 
10. Unable to swallow capsules or disease significantly affecting gastrointestinal (GI) function such 
as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory 
bowel disease, or partial or complete bowel obstruction 
11. Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial 
therapy that was completed ≤ 14 days before the first dose of study drug 
12. Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active 
hepatitis B or hepatitis C infection as follows:  
a) Presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibody (anti-
HBc).  Patients with anti-HBc, but absence of HBsAg, are eligible if hepatitis B virus (HBV) 
DNA is undetectable and if they are willing to undergo monthly monitoring for HBV 
reactivation 
b) Presence of hepatitis C virus (HCV) antibody.  Patients with presence of HCV antibody are 
eligible if HCV ribonucleic acid (RNA) is undetectable 


 
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13. Pregnant or lactating women 
14. Any life-threatening illness, medical condition, organ system dysfunction, need for profound 
anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could compromise the 
subject’s safety, or put the study at risk 
15. Inability to comply with study procedures 
16. At time of study entry, taking any medications which are strong cytochrome P450, family 3, 
subfamily A (CYP3A) inhibitors or strong CYP3A inducers. 
17. At time of study entry, taking warfarin or other vitamin K antagonists  
18. Known central nervous system (CNS) hemorrhage or stroke within 6 months prior to study entry 
19. Active CNS involvement by WM. Patients with a previous history of CNS involvement must 
undergo magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology studies to 
document no evidence of CNS disease prior to study entry. 
20. History of intolerance to the active ingredients or other ingredients of either zanubrutinib or 
ibrutinib 
Study Drug:  
Zanubrutinib 160 mg (80 mg x 2 capsules) twice daily (BID), 
administered orally (PO) 
Comparator: 
Ibrutinib 420 mg (140 mg x 3 capsules or in other applicable dose 
forms) once daily (QD), administered PO 
Study Treatment: 
Subjects will be divided into two cohorts according to MYD88 sequencing at Screening.   
Subjects in Cohort 1 (subjects with MYD88 MUT by gene sequencing) will be randomized 1:1 to receive: 
Arm A  
Zanubrutinib 160 mg (80 mg x 2 capsules) administered PO BID at approximately the same time 
each day with at least 8 hours’ interval. A treatment cycle consists of 28 days. 
Arm B  
Ibrutinib 420 mg (140 mg x 3 capsules or in other applicable dose forms) administered PO QD at 
approximately the same time each day. A treatment cycle consists of 28 days. 
Dose Modifications:  
The guidelines set forth in the table below should be followed for dose interruption or modification of 
zanubrutinib or ibrutinib for hematologic or non-hematologic toxicities noted on investigator assessment 
of study drug relatedness.   
Study drug (zanubrutinib or ibrutinib) may be held for a maximum of 2 consecutive cycles and restarted 
upon resolution of toxicity and per investigator discretion.  If, in the investigator’s opinion, it is in the 
subject’s best interest to restart study drug after dose has been held for more than 2 consecutive cycles, 
then written approval must be obtained from the Sponsor Medical Monitor or designee.  More than one 


 
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study drug hold is allowed. 
Zanubrutinib and Ibrutinib Dose Reduction Steps 
Toxicity 
Occurrence 
Dose Level 
Zanubrutinib Dose  
(Arms A and C) 
(Starting dose = 160 mg BID) 
Ibrutinib Dose  
(Arm B) 
(Starting dose = 420 mg QD)
First 
Starting Dose 
Restart at 160 mg BID 
Restart at 420 mg QD 
Second 
Dose Level -1 
Restart at 80 mg BID 
Restart at 280 mg QD 
Third 
Dose Level -2 
Restart at 80 mg QD 
Restart at 140 mg QD 
Fourth 
Discontinue study 
drug 
Discontinue zanubrutinib 
Discontinue ibrutinib 
BID=twice daily; QD=once daily 
Dose Modifications for Hematologic Toxicity for Zanubrutinib 
For zanubrutinib, dosing will be held for hematologic toxicity suspected to be related to study drug 
treatment under any of the following conditions:  
 
Grade 4 neutropenia (lasting >10 days despite the use of growth factors) 
 
Grade 4 thrombocytopenia (lasting > 10 days) 
 
≥ Grade 3 febrile neutropenia 
 
≥ Grade 3 thrombocytopenia associated with significant bleeding 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery of the 
toxicity to ≤ Grade 1 or baseline. If the same event reoccurs, subjects will restart at one dose level lower 
upon recovery of the toxicity to ≤ Grade 1 or baseline. A maximum of 2 dose reductions will be allowed.  
Dose Modifications for Non-Hematologic Toxicity for Zanubrutinib 
For non-hematological toxicities ≥ Grade 3, other than hypertension that is adequately controlled with oral 
medication or asymptomatic laboratory events (laboratory events indicating liver or renal dysfunction will 
not be considered asymptomatic laboratory events) suspected to be related to study drug treatment, study 
drug will be held until recovery to ≤ Grade 1 or baseline, and then restarted at the original dose level. If the 
event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1or baseline and restarted at Dose 
Level -1.  If the event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1or baseline and 
restarted at Dose Level -2.  If the event recurs at ≥ Grade 3 at Dose Level -2, the subject will be 
discontinued from study treatment. For subjects experiencing atrial fibrillation that is symptomatic and/or 
incompletely controlled: after 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 held for any ≥ Grade 3 bleeding.  The drug should be permanently discontinued for 
any related ≥ Grade 3 hemorrhage with the exception of those where the underlying condition can be fully 
treated (e.g. gastric ulcer resulting in gastrointestinal [GI] bleed) and the risk of a re-bleed is deemed 
acceptable. For any intracranial hemorrhage, regardless of grade or relationship to the study drug, the 
study drug should be held and the risk of rebleeding should be assessed. If the risk of rebleeding is deemed 
unacceptable, which is expected in the majority of cases, the study drug should be permanently 
discontinued. Study drug should not be resumed unless event resolution has been demonstrated by CT 
scans or MRI, the risk of rebleeding is deemed low, and the patient does not have a need for concurrent 
anti-coagulation or anti-platelet medications (except low dose aspirin or low molecular weight heparin 


 
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used to prevent venous thromboembolism).  Study drug resumption can only occur after a discussion and 
approval by the study medical monitor. 
Dose Modifications for Ibrutinib 
For dose modification of ibrutinib, local prescribing guidelines (Prescribing Information or Summary of 
Product Characteristics) should be followed throughout the study.  The major dose modifications for 
ibrutinib are described below:   
Ibrutinib should be interrupted for any new onset or worsening of ≥ Grade 3 non-hematologic toxicities, 
≥ Grade 3 neutropenia with infection or fever, or 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, drug dose will be reduced to Dose Level -1 (280 mg orally QD).  A second dose 
reduction to Dose Level -2 (140 mg orally QD) may be considered as needed.  If these toxicities persist or 
recur following 2 dose reductions, the subject will be discontinued for study treatment.   
As with zanubrutinib, ibrutinib should be interrupted for any Grade ≥ 3 bleeding.  The drug should be 
permanently discontinued for any related Grade ≥ 3 hemorrhage with the exception of those where the 
underlying condition can be fully treated (e.g. gastric ulcer resulting in GI bleed) and the risk of a re-bleed 
is deemed acceptable. For any intracranial hemorrhage, regardless of grade or relationship to the study 
drug, the study drug should be held and the risk of rebleeding should be assessed. If the risk of rebleeding 
is deemed unacceptable, which is expected in the majority of cases, the study drug should be permanently 
discontinued. Study drug should not be resumed unless event resolution has been demonstrated by CT 
scans or MRI, the risk of rebleeding is deemed low, and the patient does not have a need for concurrent 
anti-coagulation or anti-platelet medications (except low dose aspirin or low molecular weight heparin 
used to prevent venous thromboembolism).  Study drug resumption can only occur after a discussion and 
approval by the study medical monitor. 
Use of ibrutinib in patients requiring other anticoagulants or medicinal products that inhibit platelet 
function may increase the risk of bleeding, and particular care should be taken if anticoagulant therapy is 
used. 
Concomitant use of ibrutinib with strong and moderate CYP3A4 inhibitors should be avoided.  If the 
benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, ibrutinib dose must be reduced or 
withheld temporarily (7 days or less).  Ibrutinib dose must be reduced when administered with moderate 
CYP3A inhibitors.  Refer to the local prescribing guidelines (Prescribing Information or Summary of 
Product Characteristics) for specific instructions on dose modifications with these inhibitors.  
For patients with mild hepatic impairment (Child-Pugh Class A) and patients with moderate hepatic 
impairment (Child-Pugh Class B), refer to the local prescribing guidelines (Prescribing Information or 
Summary of Product Characteristics) for specific instructions on dose modifications for ibrutinib. It is not 
recommended to administer ibrutinib to patients with severe hepatic impairment (Child-Pugh Class C).  
Concomitant Therapy and Clinical Practice: 
Permitted Concomitant Therapy 
Corticosteroid courses of limited duration (2 weeks or less) are permitted, if used to treat a concomitant 
(non-cancer) medical condition.  
Bisphosphonates can be coadministered with zanubrutinib. 
Infection prophylaxis should be as per institutional standards. 
Prohibited Concomitant Therapy 
Any anticancer chemotherapy, immunotherapy, corticosteroids given with antineoplastic intent, 


 
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experimental therapy, and radiotherapy are prohibited.  Corticosteroid courses of limited duration (2 weeks 
or less) are permitted, if used to treat a concomitant (non-cancer) medical condition. The chronic use of 
corticosteroids at doses equivalent to adrenal replacement (2.5 mg to 7.5 mg prednisone) is prohibited 
without previous discussion and approval from the Medical Monitor or designee.  
Use of warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil or supplements and vitamin E preparations should be avoided.   
Use of preparations containing St. John’s Wort should be avoided. 
Concomitant Use of CYP Inhibiting/Inducing Drugs 
The primary metabolic pathway for both zanubrutinib and ibrutinib involve the cytochrome P450, family 
3, subfamily A (CYP3A) isoform.  Administration of zanubrutinib with strong/moderate CYP3A inhibitors 
or CYP3A inducers (refer to Appendix 3 and Table 2 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/ 
ibrutinib.  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 
guidelines for zanubrutinib in Table 2 and refer to the ibrutinib local prescribing information.  The medical 
monitor should be consulted in these situations. 
Criteria for Evaluation: 
Response will be evaluated using an IRC based on an adaptation of the response criteria updated at the 
Sixth IWWM (Owen et al. 2013 and NCCN Guidelines, Lymphoplasmacytic Lymphoma/Waldenström’s 
Macroglobulinemia 2015:v2). The modified criteria are listed in Appendix 2 with guidelines for special 
clinical or laboratory circumstances including response assessment in the case of drug hold or missing CT 
scans. 
All enrolled subjects will be evaluated clinically and with standard laboratory tests during their 
participation in this study. Safety evaluations will consist of medical interviews, recording of AEs, 
physical examinations, and laboratory measurements (i.e., complete blood count, chemistry, and 
urinalysis).  
Subjects will be evaluated for AEs (all grades, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03 [NCI-CTCAE v4.03]) and SAEs. Subjects who, at 
time of progression, have an ongoing AE that leads to treatment discontinuation will be followed until the 
event resolves, the investigator assesses the event as stable, the subject is lost to follow-up, or the subject 
starts a different antitumor therapy. 
An independent data monitoring committee (DMC) will monitor safety and efficacy data periodically 
throughout the study. One interim analysis is planned, and will occur approximately 6 months after the 
first 50 relapsed/refractory subjects in Cohort 1 are randomized to Arms A or B. This analysis is for 
futility only. A stop in recruitment is not planned for this interim analysis.  At regular safety reviews, data 
review will include but not be limited to deaths, SAEs, adverse events leading to dose reduction, dose 
interruption, or drug discontinuation. The DMC may recommend study modification, including 
termination of the study due to efficacy and safety concerns.  Details of safety data review will be outlined 
in DMC charter.  
Primary Endpoint:  
Cohort 1 Only 
 
Proportion of subjects achieving either CR or very good partial response (VGPR), as determined 
by the IRC using an adaptation of the response criteria updated at the Sixth IWWM (Owen et al. 
2013 and NCCN Guidelines, Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia 


 
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2015: v2).   
Secondary Endpoints: 
Efficacy (Cohort 1): 
 
Major response rate (MRR) as assessed by the IRC, defined as the proportion of subjects 
achieving CR, VGPR, or partial response (PR)  
 
Duration of response (DOR) as assessed by the IRC, defined as the time from first determination 
of response (CR, VGPR or PR) (per modified IWWM criteria) until first documentation of 
progression (per modified IWWM criteria) or death, whichever comes first 
 
Rate of CR or VGPR as assessed by the Investigator 
 
DOR as assessed by the Investigator, defined as the time from first determination of response (CR, 
VGPR or of PR) (per modified IWWM criteria) until first documentation of progression (per 
modified IWWM criteria) or death, whichever comes first 
 
Progression-free survival (PFS) as assessed by the IRC, defined as time from randomization to the 
first documentation of progression (per modified IWWM criteria) or death, whichever occurs first 
 
PFS as assessed by the Investigator, defined as time from randomization to the first documentation 
of progression (per modified IWWM criteria) or death, whichever occurs first 
 
Resolution of treatment-precipitating symptoms, defined as the absence of the symptoms that 
triggered initiation of study treatment (per the IWWM treatment guidelines) at any point during 
study treatment  
 
Anti-lymphoma effect, defined as any reduction in bone marrow involvement by 
lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT 
scan, at any time during the course of study treatment  
Safety (Cohort 1): 
 
The incidence, timing, and severity of treatment-emergent AEs (TEAE) according to NCI-CTCAE 
v4.03 
Exploratory Endpoints: 


 
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Statistical Methods:  
All inferential statistics described in this Section refer to the efficacy comparisons of Arms A and B in 
Cohort 1, which represent the primary/secondary objectives of the study. Separate descriptive statistics in 
Cohort 2 will be used to report the efficacy and safety of zanubrutinib in Arm C.  
Analysis Sets: 
The Intent to Treat analysis set (ITT) includes all enrolled subjects who are assigned to a treatment arm. 
The Relapsed/Refractory analysis set (a subset of the ITT analysis set) includes all randomized subjects 
with at least 1 prior line of therapy as determined by the Interactive Response Technology system. The 
Relapsed/Refractory analysis set for Cohort 1 will be the primary analysis set used for efficacy analyses.  
The Safety analysis set includes all subjects who received any dose of zanubrutinib or ibrutinib. Subjects 
will be assigned to the treatment arms as treated. The Safety analysis set will be used for all safety 
analyses. 
The Per-Protocol analysis set (PP) includes subjects who received any dose of study medication and had 
no major protocol deviations. Criteria for exclusion from the PP analysis set will be determined and 
documented before the database lock for the primary analysis. The PP analysis set will be the secondary 
analysis set for efficacy analyses.   
The PK analysis set includes all subjects who have at least one post-dose zanubrutinib concentration.  
Primary Efficacy Analysis: 
The primary endpoint of CR/VGPR rate will be assessed by an IRC, based upon the best overall response 
(BOR), defined as the best response recorded from the cohort assignment date until data cut or start of new 
antineoplastic treatment, and will be analyzed in the Relapsed/Refractory analysis set and ITT analysis set 
of Cohort 1. 
Comparison of the primary endpoint between Arm A and Arm B in Cohort 1 will be tested using 
hierarchical fixed-sequence procedure under the null and alternative hypotheses as follows: 
H0: RRA=RRB 
Ha: RRA> RRB 
where RRA is the CR/VGPR rate in relapsed/refractory subjects in Arm A (zanubrutinib) and RRB is the 
CR/VGPR rate in relapsed/refractory subjects in Arm B (ibrutinib).  
Testing for above hypotheses will be performed in the Relapsed/Refractory analysis set first at 1-sided 
alpha of 0.025. If the result is in the Relapsed/Refractory analysis set is statistically significant, the 
primary objective has been met and further testing will be performed in the ITT analysis set at 1-sided 
alpha of 0.025. 
A Cochran-Mantel-Haenszel (CMH) test of rate difference adjusting for stratification factors (CXCR4 


 
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status [WHIM vs WT/missing] and prior line of therapy [1-3 vs >3 for Relapsed/Refractory analysis set 
analysis and 0 vs 1-2 vs >3 in ITT analysis set analysis]) will be performed for hypothesis testing at the 
level of 0.025 (1-sided) in corresponding analysis sets.  
A CMH 95% stratified confidence interval (CI) of rate difference (RRA-RRB) with each rate weighted by 
the number of subjects in each stratification factor combination will be constructed. A Clopper-Pearson 
95% CI of CR/VGPR rate within each arm will be constructed. 
The primary efficacy analysis in Cohort 1 will be conducted approximately 12 months after the cohort 
assignment of the last relapsed/refractory subject.  
Secondary Efficacy Analyses:  
If the primary efficacy analysis is significant in Cohort 1, secondary endpoints will be tested in the 
analysis set where the null hypothesis for primary efficacy endpoint is rejected. 
MRR will be tested for non-inferiority (NI) (Arm A vs Arm B). The null and alternative hypotheses of 
MRR are set as follows: 
H0: MRRA-MRRB≤-8% 
Ha: MRRA- MRRB>-8% 
where MRRA is the major response rate in Arm A (zanubrutinib) and MRRB is the major response rate in 
Arm B (ibrutinib).  
MRR assessed by IRC will be compared between Arms A and B.  It will be analyzed using the same 
methods as described for the primary endpoint, based upon the best overall response, defined as the best 
response recorded from the date of cohort assignment until data cut or start of new antineoplastic 
treatment.  Subjects with no post-baseline response assessment (regardless of reason) will be considered 
non-responders for best overall response.   
A CMH test of rate difference adjusting for stratification factors (CXCR4 status [WHIM vs WT/missing] 
and prior line of therapy [1-3 vs >3 for Relapsed/Refractory analysis set and 0 vs 1-2 vs >3 in ITT analysis 
set]) will be performed for hypothesis testing.  Non-inferiority will be concluded when the one-sided p-
value is less than or equal to 0.025, or equivalently, when the 2-sided 95% CI for the weighted rate 
difference (weighted by the number of subjects in each stratification factor combination) excludes -8%. 
Furthermore, superiority can be claimed if the lower limit excludes 0.    
Justification of non-inferiority margin 
Since no randomized trial has been conducted in WM, the ibrutinib treatment benefit over placebo can 
only be estimated from the single-arm ibrutinib Phase 2 trial in which the MRR is 0.73 with 95% CI (0.60, 
0.83). As a ≥ 50% reduction of IgM is impossible without treatment, MRR can be considered 0% in the 
placebo treated subject. Therefore, the lower bound of 95% CI (i.e., 60%) can be used as the treatment 
effect of ibrutinib over placebo (M1). A NI margin of 8% (M2) is proposed assuming 86.7% of the 
ibrutinib benefit over a placebo is retained. With close to 90% of the ibrutinib effect preserved, the 8% NI 
margin in MRR is clinically justified. The loss of the ibrutinib treatment benefit is well within the 
clinically acceptable range.  It is worth noting that the NI of MRR will only be performed after the 
superiority of zanubrutinib over ibrutinib in CR/VGPR rate, which is closely correlated with MRR, has 
been demonstrated. Hence, a numerically higher MRR in zanubrutinib is certainly expected if the NI test 
of MRR is to be performed. The inclusion of the NI test of MRR is mainly based on the sample size 
consideration in a rare disease setting where statistical significance might not be shown in a superiority test 
with a clinically meaningful MRR difference (e.g., 12% higher MRR in zanubrutinib over ibrutinib) in 150 
randomized relapsed/refractory subjects. 


 
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The proportion and its corresponding Clopper-Pearson 95% CI for each of the response categories (CR, 
VGPR, PR, Minor Response, stable disease [SD], and PD) by both independent review and investigator 
assessment will be presented. 
Progression-free survival (PFS) will be estimated using the Kaplan-Meier (KM) method. PFS censoring 
rule will follow FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics (2007). 
A stratified log-rank test with CXCR4 mutational status and number of prior lines of therapy as strata will 
be used to test the PFS differences between Arms A and B. The Cox regression will be used to estimate 
the hazard ratio (HR) of PFSA vs PFSB. A 95% CI of HR in PFS will be constructed.   
Median PFS, if estimable, will be estimated using the KM method. Its 2-sided 95% CI, if estimable, will 
be constructed with a generalized Brookmeyer and Crowley method.  KM estimates of PFS will be plotted 
over time.  The PFS at 12 and 18 months, defined as the percentages of subjects in the analysis set who 
remain alive and progression-free at the specified time points, will be estimated using KM method along 
with the corresponding 95% CI constructed using Greenwood’s formula.  
The duration of CR/VGPR/PR within subjects who have achieved a major response will be analyzed 
similarly as PFS. 
Indications for initiation of therapy (see Table 4) will be documented for all subjects at baseline visit.  
Symptoms that triggered treatment will be followed at, during, and end of treatment visits until resolution. 
Percentages of subjects with resolution of each and all baseline symptom(s) will be summarized; and 
compared between Arms A and B using Fisher’s Exact test. 
Maximum decrease in percentage of lymphoplasmacytoid lymphocytes by bone marrow studies will be 
compared using analysis of variance model with treatment arm (A vs. B) as group variable. Percentage of 
subjects with decreased percentage of lymphoplasmacytoid lymphocytes after the start of study medication 
will also be compared using Fisher’s Exact test. Percentages of subjects with resolution and/or reduction of 
pretreatment lymphadenopathy and/or splenomegaly according to CT scan will be summarized separately; 
and compared using Fisher’s Exact test. 
Exploratory Efficacy Analyses: 


 
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Safety Analysis: 
Safety analysis will be performed by treatment arm, as well as by combining Arms A and C. 
Drug exposure will be summarized by treatment arm, including duration, dosage, and dose intensity.   
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA®) terms and graded according to the NCI-CTCAE v4.03. All treatment-emergent AEs (TEAEs) 
will be summarized.  A TEAE is defined as an AE that had an onset date on or after the first dose of study 
drug up to 30 days following study drug discontinuation or was worsening in severity from baseline 
(pretreatment) or initiation of new anticancer therapy, whichever comes first.  SAEs, deaths, TEAEs with 
Grade 3 or above, related TEAEs and TEAEs that led to treatment discontinuation, dose reduction or dose 
interruption will be summarized. 
Multiple occurrences of the same event will be counted once at the maximum severity within a system 
organ class (SOC) and preferred term (PT). 
Clinical laboratory data with values outside of the normal ranges will be identified.  Select laboratory data 
will be summarized by grade. Vital signs will also be summarized by visit.  
Correlation between trough plasma zanubrutinib concentration and safety endpoints may be explored. 
Sample Size: 
The sample size calculation is based on the comparison of the primary endpoint CR/VGPR rate in 
relapsed/refractory subjects in Cohort 1. Assuming RRA=0.35 and RRB=0.15, seventy-five subjects per 
arm (approximately 150 total) provide a power of 0.814 in testing RRA versus RRB in the 
Relapsed/Refractory analysis set in Cohort 1 using a normal approximation to binomial test with a two-
sided significance of 0.05. Assuming MRRA=0.90 and MRRB=0.80, the power of demonstrating NI of 
zanubrutinib in the Relapsed/Refractory analysis set is 85.5% when a NI margin of 0.08 is used.  
In addition to 150 replased/refractory subjects, approximately 20% (38) treatment-naïve subjects with 
MYD88MUT will be enrolled in Cohort 1.  
Assuming MYD88MUT mutation is present in 90% of the enrolled subjects, approximately a total of 
210 subjects will be enrolled in this study.   


 
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TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ............................................................................................1 
SIGNATURES ...........................................................................................................................2 
SYNOPSIS .................................................................................................................................3 
TABLE OF CONTENTS .........................................................................................................17 
LIST OF TABLES ...................................................................................................................21 
LIST OF FIGURES .................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................22 
1 
INTRODUCTION .......................................................................................................27 
1.1 
Current Status of Waldenström’s Macroglobulinemia ....................................27 
1.2 
Ibrutinib............................................................................................................28 
1.2.1 
Pharmacokinetics and Drug Interactions ................................................28 
1.3 
Zanubrutinib (BGB-3111) ...............................................................................29 
1.3.1 
Non-Clinical Data ...................................................................................29 
1.3.2 
Pharmacokinetics and Drug Interactions ................................................29 
1.3.3 
Safety Pharmacology ..............................................................................30 
1.3.4 
Clinical Pharmacology ............................................................................30 
1.4 
BTK Inhibitors in the Treatment of Waldenström’s Macroglobulinemia 
Study Rationale and Risk/Benefit Assessment ................................................32 
2 
OBJECTIVES ..............................................................................................................35 
2.1 
Primary Objective (Cohort 1) ..........................................................................35 
2.2 
Secondary Objectives (Cohort 1) .....................................................................35 
2.3 
Exploratory Objectives ....................................................................................35 
3 
STUDY ENDPOINTS .................................................................................................36 
3.1 
Primary Endpoint .............................................................................................36 
3.2 
Secondary Endpoints .......................................................................................36 
3.3 
Exploratory Endpoints .....................................................................................37 
4 
STUDY DESIGN.........................................................................................................38 
4.1 
Summary of Study Design ...............................................................................38 
5 
STUDY POPULATION ..............................................................................................42 
5.1 
Inclusion Criteria .............................................................................................42 
5.2 
Exclusion Criteria ............................................................................................44 
6 
STUDY TREATMENT PHASE AND FOLLOW-UP PHASE ..................................46 
6.1 
Study Treatment and Dose Rationale ..............................................................46 
6.2 
Study Treatment Preparation and Dispensation ...............................................46 
6.2.1 
Packaging and Labeling ..........................................................................46 
6.2.2 
Handling and Storage ..............................................................................46 
6.2.3 
Compliance and Accountability ..............................................................47 


 
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6.2.4 
Disposal and Destruction ........................................................................47 
6.3 
Subject Numbering and Treatment Assignment ..............................................47 
6.3.1 
Subject Numbering and Screening..........................................................47 
6.3.2 
Treatment Assignment ............................................................................48 
6.3.3 
Treatment Blinding .................................................................................49 
6.4 
Dosage and Administration..............................................................................49 
6.5 
Dose Interruption and Modification.................................................................50 
6.5.1 
Dose Modifications for Hematologic Toxicity for Zanubrutinib ...........50 
6.5.2 
Dose Modifications for Non-Hematologic Toxicity for 
Zanubrutinib ............................................................................................51 
6.5.3 
Dose Modifications for Zanubrutinib when Co-adminstered with 
Strong/Moderate CYP3A Inhibitors/Inducers ........................................52 
6.5.4 
Dose Modifications for Ibrutinib ............................................................53 
6.6 
Concomitant Medications and Non-Drug Therapies .......................................54 
6.6.1 
Permitted Medications ............................................................................54 
6.6.2 
Prohibited Medications ...........................................................................54 
6.6.3 
Medications to be Used with Caution .....................................................55 
6.6.4 
Surgery and Procedures ..........................................................................56 
6.7 
End of Treatment .............................................................................................56 
6.8 
Follow-Up Phase ..............................................................................................56 
6.8.1 
Safety Follow-Up ....................................................................................56 
6.8.2 
Efficacy Follow-Up ................................................................................57 
6.8.3 
Survival Follow-Up ................................................................................57 
6.9 
End of Study ....................................................................................................57 
7 
STUDY ASSESSMENTS ...........................................................................................59 
7.1 
Study Flow and Visit Schedule ........................................................................59 
7.2 
Subject Demographics/Other Baseline Characteristics ...................................67 
7.2.1 
Demography ............................................................................................67 
7.2.2 
Medical History ......................................................................................67 
7.2.3 
Other Baseline Characteristics ................................................................67 
7.3 
Efficacy ............................................................................................................68 
7.3.1 
Physical Examination..............................................................................71 
7.3.2 
Radiological Tumor Assessment ............................................................71 
7.3.3 
Bone Marrow Assessment ......................................................................73 
7.3.4 
Biopsy for Amyloidosis ..........................................................................73 
7.3.5 
Biopsy for Suspected Disease Transformation .......................................73 
7.4 
Safety ...............................................................................................................73 
7.4.1 
Adverse Events .......................................................................................73 
7.4.2 
Physical Examination, Vital Signs, Height, Weight, Assessment of 
B symptoms, Re-evaluation of Baseline Reason(s) for Initiation of 
Therapy, and Review for Arrhythmia Signs/Symptoms .........................74 
7.4.3 
ECOG Performance Status .....................................................................74 
7.4.4 
Electrocardiogram ...................................................................................74 
7.4.5 
ECHO/MUGA ........................................................................................75 
7.4.6 
Quality of Life Assessment and Medical Resource Utilization ..............75 


 
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7.5 
Laboratory Evaluations ....................................................................................75 
7.5.1 
Hematology Studies ................................................................................75 
7.5.2 
Clinical Chemistry ..................................................................................76 
7.5.3 
Quantitative Serum Immunoglobulins and β2-microglobulin ................76 
7.5.4 
Serum Immunoelectrophoresis with M-Protein Quantitation by 
Densitometry (SPEP) and Serum Immunofixation .................................76 
7.5.5 
Cold Agglutinins, Cryoglobulin, Anti-MAG, Serum Viscosity .............76 
7.5.6 
Iron, Total Iron Binding Capacity (TIBC), and Ferritin Tests ................77 
7.5.7 
Coagulation .............................................................................................77 
7.5.8 
Urinalysis with Dipstick .........................................................................77 
7.5.9 
Pregnancy Test ........................................................................................77 
7.5.10 
HIV and Hepatitis B/C Testing ...............................................................78 
7.6 
Pharmacokinetics .............................................................................................79 
7.6.1 
Pharmacokinetic Blood Samples ............................................................79 
7.6.2 
Effects of Plasmapheresis on PK of Zanubrutinib ..................................80 
7.7 
 
7.8 
Appropriateness of Measurements ...................................................................81 
8 
DATA HANDLING AND QUALITY ASSURANCE ...............................................82 
8.1 
Data Collection ................................................................................................82 
8.2 
Data Management/Coding ...............................................................................82 
8.3 
Quality Assurance ............................................................................................82 
9 
SAFETY MONITORING AND REPORTING...........................................................84 
9.1 
Adverse Events ................................................................................................84 
9.1.1 
Definitions and Reporting .......................................................................84 
9.1.1.1 
Assessment of Severity ................................................................85 
9.1.1.2 
Assessment of Causality ...............................................................85 
9.1.1.3 
Follow-Up of Adverse Events and Serious Adverse Events ........86 
9.1.2 
Laboratory Test Abnormalities ...............................................................87 
9.2 
Serious Adverse Events ...................................................................................87 
9.2.1 
Definitions...............................................................................................87 
9.2.2 
Reporting.................................................................................................88 
9.2.2.1 
Timeframes for Submitting Serious Adverse Events ...................88 
9.2.2.2 
Completion and Transmission of the Serious Adverse Event 
Report Form .................................................................................88 
9.2.2.3 
Regulatory Reporting Requirements for Serious Adverse 
Events ...........................................................................................89 
9.2.2.4 
Adverse Event Reporting Period ..................................................89 
9.2.2.5 
Specific Instructions for Recording Adverse Events and 
Serious Adverse Events ................................................................89 
9.2.2.6 
Serious Adverse Event Related to Study Participation ................90 
9.2.2.7 
Expedited Reporting to Health Authorities, Investigator, 
Institutional Review Boards and Ethics Committees ...................90 
9.3 
Pregnancies ......................................................................................................90 
9.4 
Lack of Efficacy ...............................................................................................91 


 
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9.5 
Data Monitoring Committee ............................................................................91 
10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .........................92 
10.1 
Primary, Secondary and Exploratory Study Endpoints ...................................92 
10.2 
Statistical Analysis ...........................................................................................92 
10.2.1 
Analysis Sets ...........................................................................................92 
10.2.2 
Subject Disposition .................................................................................92 
10.2.3 
Demographics and Other Baseline Characteristics .................................93 
10.2.4 
Prior and Concomitant Therapy ..............................................................93 
10.2.5 
Efficacy Analyses ...................................................................................93 
10.2.5.1 
Primary Efficacy Analysis ............................................................93 
10.2.5.2 
Secondary Efficacy Analysis ........................................................94 
10.2.5.3 
Exploratory Efficacy Analysis .....................................................96 
10.2.6 
Pharmacokinetic Analyses ......................................................................97 
10.2.7 
 
10.3 
Safety Analyses ................................................................................................97 
10.3.1 
Extent of Exposure ..................................................................................98 
10.3.2 
Adverse Events .......................................................................................98 
10.3.3 
Laboratory Analyses ...............................................................................98 
10.3.4 
Vital Signs ...............................................................................................99 
10.3.5 
Electrocardiogram ...................................................................................99 
10.4 
Sample Size Consideration ..............................................................................99 
10.5 
Interim Analysis ...............................................................................................99 
10.6 
Other Statistical Issues ...................................................................................100 
11 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............101 
11.1 
Regulatory Authority Approval .....................................................................101 
11.2 
Investigator Responsibilities ..........................................................................101 
11.2.1 
Good Clinical Practice ..........................................................................101 
11.2.2 
Ethical Conduct of the Study and Ethics Approval ..............................101 
11.2.3 
Informed Consent..................................................................................102 
11.2.4 
Investigator Reporting Requirements ...................................................102 
11.2.5 
Confidentiality ......................................................................................103 
11.2.6 
Case Report Forms ................................................................................103 
11.2.7 
Drug Accountability..............................................................................104 
11.2.8 
Inspections ............................................................................................104 
11.2.9 
Protocol Adherence ...............................................................................104 
11.3 
Sponsor Responsibilities ................................................................................104 
11.3.1 
Protocol Modifications..........................................................................104 
11.3.2 
Study Report and Publications ..............................................................105 
11.4 
Study and Study Center Closure ....................................................................105 
11.5 
Records Retention and Study Files ................................................................106 
11.5.1 
Study Files and Retention of Records ...................................................106 
11.6 
Information Disclosure and Inventions ..........................................................107 
11.7 
Joint Investigator/Sponsor Responsibilities ...................................................108 
11.7.1 
Access to Information for Monitoring ..................................................108 


 
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11.7.2 
Access to Information for Auditing or Inspections...............................108 
12 
REFERENCES ..........................................................................................................109 
13 
APPENDICES ...........................................................................................................111 
Appendix 1: 
Signature of Investigator ............................................................112 
Appendix 2: 
WM Response Assessment ........................................................113 
Appendix 3: 
CYP3A Inhibitors and Inducers .................................................118 
Appendix 4: 
Sensitive CYP2C8, CYP2C19 Substrates or CYP2C8, and 
CYP2C19 Substrates with a Narrow Therapeutic Index ...............................119 
Appendix 5: 
ECOG Performance Status .........................................................120 
Appendix 6: 
List of Country Specific Amendments .......................................121 
 
LIST OF TABLES 
Table 1. 
Zanubrutinib and Ibrutinib Dose Reduction Steps..................................................... 50 
Table 2. 
Dose Modification for Zanubrutinib when Co-Administered with Strong/Moderate 
CYP3A Inhibitors or Inducers ................................................................................................... 52 
Table 3. 
Study Assessments and Procedures Schedule............................................................ 60 
Table 4. 
Indications for Initiation of Therapy in Patients with WMa ...................................... 68 
Table 5. 
Active hepatitis B (HBV) or hepatitis C (HCV) infection (detected positive by 
polymerase chain reaction [PCR]) ............................................................................................. 79 
Table 6. 
Timeframe for Reporting Serious Adverse Events to the Sponsor ............................ 88 
 
LIST OF FIGURES 
Figure 1. 
Schema for Study BGB-3111-302 ............................................................................. 41 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
activated B-cell 
ADCC 
antigen-dependent cell-mediated cytotoxicity 
AEs 
adverse events 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
ATP 
adenosine triphosphate 
AUC 
area under the plasma concentration-time curve 
AUS 
Australia 
AV 
Atrioventricular 
BCR 
B-cell receptor 
BID 
twice a day 
BOR 
best overall response 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CBC 
complete blood count 
CERT 
Center for Education and Research on Therapeutics 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CI 
confidence interval 
CL 
apparent total body clearance of the drug from plasma 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
computed tomography 
CXCR4 
CXC-chemokine receptor 4 
CYP 
Cytochrome 


 
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CYP3A 
cytochrome P450, family 3, subfamily A 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DLBCL 
diffuse large B-cell lymphoma 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOMR 
duration of major response 
DOR 
duration of response 
ECHO 
echocardiogram 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EQ-5D 
EuroQol five dimensions questionnaire 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of treatment 
eGFR 
estimated glomerular filtration rate  
EGFR 
epithelial growth factor receptor 
EU 
European Union 
F 
bioavailability (systemic availability of the administered dose) 
FDA 
Food and Drug Administration 
FGR 
Garden-Rasheed feline sarcoma viral (v-fgr) oncogene homolog 
FRK 
fyn-related kinase 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GvHD 
graft versus host disease 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 


 
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IB 
Investigator’s Brochure 
IC50 
50% maximum inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference of Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgM 
immunoglobulin M 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRAK 
interleukin-1-receptor associated kinase 
IRB 
Institutional Review Board 
IRC 
independent review committee  
IRT 
interactive response technology 
ITK 
interleukin-2-inducible T cell kinase 
ITT 
Intent to Treat analysis set 
IWWM 
International Workshop for Waldenström's Macroglobulinemia 
JAK3 
Janus kinase 3 
KM 
Kaplan-Meier 
LCK 
lymphocyte-specific protein tyrosine kinase 
LDH 
lactate dehydrogenase 
LDi 
longest diameter 
MCL 
mantle cell lymphoma 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minor response 
MRI 
magnetic resonance imaging 
MRR 
Major response rate 
MUT 
Mutated 
MUGA 
Multiple Gated Acquisition scan 
MYD88 
myeloid differentiation primary response gene 88 
MYDMUT 
activating mutations in the MYD88 gene 
MYD88WT 
wild-type MYD88 gene 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NF-κB 
nuclear factor-kappa B 


 
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NI 
non-inferiority 
NTI 
narrow therapeutic index 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PLCβ2 
phospholipase C-beta-2 
PO 
per os (orally) 
PP 
Per-Protocol analysis set 
PR 
partial response 
PT 
preferred term or prothrombin time 
QD 
once daily 
QLQ 
Quality of Life Questionnaire-Core 30 
QOL 
quality of life 
QT 
interval between the beginning of the QRS complex to the end 
of the T wave 
RBC 
red blood cell 
R-CHOP 
rituximab-cyclophosphamide, doxorubicin, vincristine, and 
prednisone  
RNA 
ribonucleic acid 
SAEs 
serious adverse events 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
stable disease 
SDF-1a 
stromal-derived factor 1a 
SDi 
shortest diameter 
SOC 
system organ class 
SOPs 
standard operating procedures 
SPEP 
Serum immunoelectrophoresis, with M-protein quantitation by 
densitometry 
TEAEs 
treatment-emergent adverse events 
TEC 
tyrosine kinase expressed in hepatocellular carcinoma 
TIBC 
total iron binding capacity 
TLS 
tumor lysis syndrome 


 
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TMD-8 
transmembrane domain 8 
TSTM 
too small to measure 
TTNT 
time-to-next-treatment 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
VGPR 
very good partial response 
WBC 
white blood cell 
WHIM 
Warts, Hypogammaglobulinemia, Immunodeficiency, and 
Myelokathexis syndrome 
WHO-DD 
World Health Organization Drug Dictionary 
WM 
Waldenström’s macroglobulinemia  
WT 
wild type 
X 
to be performed 
zanubrutinib 
BGB-3111 


 
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1 
INTRODUCTION 
1.1 
Current Status of Waldenström’s Macroglobulinemia 
Waldenström’s macroglobulinemia (WM) is a rare B-cell malignancy, characterized by bone 
marrow infiltration with monoclonal immunoglobulin M secreting lymphoplasmacytic cells.  The 
incidence is 5-8 cases per million, with about 1000-1500 new patients diagnosed in the USA 
annually.  Incidence increases with age with a median age at diagnosis of 70 years for Caucasians, 
and slightly lower in other ethnic groups. There is a male to female preponderance, and an incidence 
higher in Caucasians than Africans or Asians (Gertz et al 2000; Gertz et al 2015).  Activating 
mutations in the MYD88 gene (MYD88MUT), which trigger downstream interleukin-1-receptor 
associated kinase (IRAK)-mediated nuclear factor -kappa B (NF-κB) signaling (Treon et al 2012), 
are seen in approximately 90% of cases.  A second set of mutations with prognostic significance is 
found at CXC-chemokine receptor 4 (CXCR4), the receptor for stromal-derived factor 1a (SDF-1a), 
which are either frameshift or nonsense mutations, are similar to those seen in the 
immunodeficiency syndrome WHIM (warts, hypogammaglobulinemia, infections and 
myelokathexis), and also lead to constitutive activation. Either or both of these mutations can be 
found in patients and lead to different clinical pictures, outcomes, and response to therapy with best 
response to the BTK inhibitor ibrutinib found in MYD88MUT CXCR4WT(Treon et al 2015a).  
According to the International Prognostic scoring system for WM (ISSWM), patients are stratified 
into low, intermediate, and high risk groups with respective 5-year survival rates of 87%, 68%, and 
36%, based upon age, IgM level, β2-microglobulin level, hemoglobin, and platelet count. (Morel et 
al 2009). 
About 75% of initially asymptomatic WM patients will require therapy within 15 years of follow-
up, with a median time to initiation of therapy of over 7 years; a lower hemoglobin (Hgb), extensive 
bone marrow infiltration, serum M-spike, and β2-microglobulin levels are significant predictors of 
an eventual need for therapy (Gertz et al 2015). Indications for treatment as per the IWWM-7 
consensus meeting are either clinical symptoms or laboratory findings. Clinical indications for 
treatment include any of the following: fever, night sweats, weight loss and fatigue, hyperviscosity 
syndrome, bulky/symptomatic lymphadenopathy, significant hepatomegaly or splenomegaly, other 
symptomatic organomegaly, or peripheral neuropathy.  Laboratory indications for therapy include 
symptomatic cryoglobulinemia, cold agglutinin anemia, immune hemolytic cytopenias, 
nephropathy, amyloidosis, or significant anemia/thrombocytopenia due to marrow replacement.  
Current treatment strategies include single agent rituximab or rituximab plus cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) (Jacobson et al 2013).  Bendamustine plus 
rituximab has been shown to be an active agent with similar overall response rates to R-CHOP but 
with enhanced progression-free survival and better tolerability (Rummel et al 2013). Experimental 
agents studied in WM include bortezomib, lenalidomide, everolimus, enzastaurin, and panobinostat. 


 
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Recently, the BTK inhibitor ibrutinib was approved for the treatment of patients with WM by the 
FDA and by the European Medicines Agency (EMA) in adults who have received prior treatment 
for their disease, or in previously untreated patients for whom treatment with chemoimmunotherapy 
is not suitable.  
1.2 
Ibrutinib  
Bruton’s tyrosine kinase (BTK) is a signaling molecule within the B-cell antigen receptor (BCR) 
and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results 
in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical 
studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell 
migration and substrate adhesion in vitro. 
Ibrutinib is a first-generation small-molecule BTK inhibitor that forms a covalent bond to cysteine 
at position 481 in the BTK active site, leading to inhibition of BTK phosphorylation at Tyr223 and 
thus inhibiting enzymatic activity.  
1.2.1 
Pharmacokinetics and Drug Interactions 
Ibrutinib is absorbed after oral administration with a median time to maximum observed plasma 
concentration (Tmax) of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The 
steady-state area under the plasma concentration time curve (AUC) (mean ± standard deviation) 
observed in patients at 560 mg is 953 ± 705 ng⋅h/mL and in patients at 420 mg is 680 ± 517 
ng⋅h/mL.  Administration with food increased ibrutinib maximum observed plasma concentration 
(Cmax) and AUC by approximately 2- to 4- and 2-fold, respectively, compared with administration 
of ibrutinib after overnight fasting. The oral clearance is approximately 2000 and 1000 L/h in fasted 
and fed condition. The half-life of ibrutinib is 4 to 6 hours. The 420 mg dosage was selected to treat 
WM.  
Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of 
ibrutinib was administered in non-cancer subjects, ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, 
respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with 
normal liver function. Thus, subjects with moderate and severe liver impairment should avoid using 
ibrutinib.  Ibrutinib is not significantly cleared renally, the exposure of ibrutinib is not altered in 
patients with creatinine clearance (CrCL) >25 mL/min.  Ibrutinib can cause fetal harm when 
administered to a pregnant woman; it must not be taken during pregnancy and pregnancy should be 
avoided for 1 month after cessation of therapy.   
Ibrutinib is metabolized to several metabolites primarily by cytochrome P450 (CYP), CYP3A, and 
to a minor extent by CYP2D6. Refer to updated Imbruvica® (Ibrutinib) Prescribing Information, 
August 2018, as well as Section 6.6.2 for further discussion of drug-drug interactions with ibrutinib.  


 
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1.3 
Zanubrutinib (BGB-3111) 
Zanubrutinib (also known as BGB-3111) is a novel second-generation small-molecule oral BTK 
inhibitor, which forms an irreversible covalent bond at Cys481 within the adenosine triphosphate 
(ATP) binding pocket of the BTK protein.  Zanubrutinib is highly potent against BTK; however, as 
opposed to ibrutinib, zanubrutinib has significantly less epithelial growth factor receptor 
(EGFR)/Janus kinase 3 (JAK3)/tyrosine kinase expressed in hepatocellular carcinoma 
(TEC)/interleukin-2-inducible T cell kinase (ITK) inhibitory activity.  
1.3.1 
Non-Clinical Data 
Zanubrutinib inhibits BTK with a 50% maximum inhibitory concentration (IC50) of 0.3 nanomolar 
(nM) in biochemical assays.  Cellular assays confirmed that zanubrutinib inhibited BCR 
aggregation-triggered BTK autophosphorylation, and blocked downstream phospholipase C-beta-2 
(PLCβ2) signaling in mantle cell lymphoma (MCL) cell lines. Zanubrutinib potently and selectively 
inhibited cellular growth of several MCL cell lines (REC-1, Mino, and JeKo-1) and activated B-cell 
(ABC) type of diffuse large B-cell lymphoma (DLBCL) cell line transmembrane domain 8 
(TMD-8), with IC50s from 0.36 nM to 20 nM, while inactive in many other hematologic cancer cell 
lines.   
In vivo studies showed that zanubrutinib induced dose-dependent antitumor effects against REC-1 
MCL xenografts engrafted either subcutaneously or systemically in mice.  Zanubrutinib was more 
selective than ibrutinib for inhibition of kinase activity of BTK vs. EGFR, Garden-Rasheed feline 
sarcoma viral (v-fgr) oncogene homolog (FGR), fyn-related kinase (FRK), human epidermal growth 
factor receptor (HER)2, HER4, ITK, JAK3, lymphocyte-specific protein tyrosine kinase (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 antigen-dependent cell-mediated cytotoxicity (ADCC).  Zanubrutinib was shown 
to be at least 10-fold weaker than ibrutinib in inhibiting rituximab-induced ADCC, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity than 
ibrutinib in both biochemical and cellular assays, thus preventing the potential for antagonism with 
rituximab that has been seen preclinically with other BTK inhibitors. Refer to the Investigator’s 
Brochure (IB) for more detailed information on zanubrutinib. 
1.3.2 
Pharmacokinetics and Drug Interactions 
In the Phase 1 study, PK was linear between 40 mg and 320 mg daily.  The absorption of 
zanubrutinib is rapid with median time to maximum plasma concentration (Cmax) of 2 hours.  
Preliminary results from the food effect study revealed that zanubrutinib exposure was not altered 
by high-fat breakfast, and was increased by 30-60% 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 QD administered in the ongoing Phase 1 study, which did not lead to 


 
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additional safety findings. The terminal elimination half-life is approximately 4 hours at 320 mg 
daily. 
Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all subjects in the 
study, while occupancy in lymph node tissue was assessed only at 160 mg BID and 320 mg daily.  
At the 160 mg BID 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 indications 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 BID and 320 mg daily dose; both schedules show a high level of activity without 
compromise of the tolerability profile as compared to lower doses of zanubrutinib.   
Cytochrome P450, family 3, subfamily A (CYP3A) was the major CYP isoform responsible for 
zanubrutinib metabolism.  Based on in vitro data, zanubrutinib is a moderate inhibitor for CYP2C8 
(IC50 = 4.03 µM).  Zanubrutinib is not a time-dependent CYP inhibitor of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A.    Zanubrutinib is not an inducer of human 
CYP1A2 or CYP2B6 but has weak CYP3A induction potential at a concentration equal to or higher 
than 3 µM in primary human hepatocytes.   
1.3.3 
Safety Pharmacology 
The potential risk of zanubrutinib on QT interval prolongation was assessed using a battery of 
preclinical studies. A GLP compliant hERG assay was conducted.  Based on the clinical steady-
state, unbound Cmax of 0.042 μM (total Cmax 346 ng/mL; plasma protein binding 94.2%) observed 
at the recommended Phase 2 dose (RP2D) of 160 mg BID, there is more than a 200-fold exposure 
margin compared with the hERG IC50 of 9.11 μM.   
No effects on blood pressure, heart rate, or electrocardiogram (ECG) findings, including QT and 
QTc intervals, were noted in telemetry-instrumented conscious dogs following single doses of 
zanubrutinib up to 100 mg/kg.  In addition, no abnormal changes in ECG or cardiovascular function 
were noted in 28- and 91-day repeat-dose toxicity studies in dogs at doses up to 100 mg/kg.  In 
these studies, the systemic exposure of zanubrutinib was 10-fold higher than that observed at the 
human therapeutic dose.   
1.3.4 
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 ECG parameters, including QTc intervals and other ECG intervals.  


 
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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 clnical drug-drug interaction study (BGB-3111-104) indicate that 
coadministration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg every day for 8 
days) decreased exposure of zanubrutinib by 13.5-fold for AUC0-∞, and 12.6-fold for maximum 
observed plasma concentration (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, 
preliminary simulations from a physiologically-based pharmacokinetic (PBPK) model suggest that 
coadministration of multiple doses of a moderate CYP3A inhibitor (eg, diltiazem, erythromycin, 
and fluconazole) may increase the Cmax and AUC of zanubrutinib by approximately 2-fold.  For 
coadministration with a moderate CYP3A inducer (eg, efavirenz), PBPK simulations suggest that 
the Cmax and AUC of zanubrutinib may decrease 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 mild induction effect on CYP3A and CYP2C19 
enzymes, but not an inhibitor of CYP2C19.  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 AUC 0-t and 34% for Cmax.  
Based a validated PBPK model to simulate the effect of zanubrutinib on the pharmacokinetics of 
CYP2B6 sensitive substrate, the potential for zanubrutinib to induce CYP2B6 is considered low. 
Based on results of two clinical DDI studies above, a validated PBPK model was developed and 
was employed to simulate the effect of zanubrutinib on the pharmacokinetics of sensitive CYP2C8, 
and CYP2B6 substrates.  The simulation findings show that concomitant use of zanubrutinib has a 
minimal or no effect on the exposure of CYP2C8 substrate (eg, rosiglitazone) or CYP2B6 substrate 
(eg, bupropion).  The predicted AUC ratios of repaglinide and bupropion (with versus without 
zanubrutinib coadministration) are predicted to be close to 1.  
Refer to the Investigator’s Brochure (IB) for more detailed information of zanubrutinib.  


 
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1.4 
BTK Inhibitors in the Treatment of Waldenström’s Macroglobulinemia 
Study Rationale and Risk/Benefit Assessment 
Bruton’s tyrosine kinase, a member of the TEC family kinases, is a critical component of BCR 
signaling cascade.  Inhibition of BTK has emerged as a promising strategy for targeting B-cell 
malignancies. 
Ibrutinib, given at a dose of 420 mg PO daily, was evaluated in a 63-patient single-arm Phase 2 
study. The responses were assessed by reduction in serum IgM levels from baseline according to a 
modification of the Sixth IWWM response criteria. (IWWM, Owen et al 2013 and NCCN Guidance 
Insights, 2012). The MRR (defined as achieving partial response or better at any time over the 
course of study treatment) was 61.9%. No patients achieved a CR. A very good partial response 
(VGPR; a > 90% reduction in IgM) occurred in 11.1% of patients and a partial response (PR; 50-
89% reduction in IgM) in 50.8%. The median time to response was 1.2 months (range 0.7-13.4 
months). In this trial, the median reduction in IgM level was from 3520 mg/dl to 880 mg/dl, and 
median improvement in hemoglobin was from 10.5 g/dl to 13.8 g/dl. However, there are limitations 
to ibrutinib in the treatment of WM. By IgM criteria, 27% of subjects failed to achieve a response, 
and the nadir IgM level exceeded 3000 mg/dl in 10% of responding subjects. Only 25/35 (71%) 
subjects presenting with adenopathy had reduction in adenopathy by CT, 4/7 (57%) subjects 
presenting with splenomegaly had reduction in spleen size, and the bone marrow response was 
usually incomplete (median reduction in bone marrow lymphoplasmacytoid cell percentage from 
60% to 25%). In the initial report of this study, 2 of 7 (29%) of subjects with wild-type MYD88 
(MYD88WT) by, were reported to have achieved a major response to ibrutinib; however, a 
subsequent report (Treon et al 2015b) noted that activating non-MUT mutations were found in both 
responding patients. Therefore, to date, major responses have not been reported in patients with 
wild-type MYD88 WM. Of adverse events (AEs) potentially associated with ibrutinib treatment, 
Grade 2 or greater bleeding occurred in 6% of patients and atrial fibrillation was reported in 5% of 
patients. Six percent of patients discontinued treatment due to adverse events and dose reduction 
due to adverse events occurred in 11% of patients.  In addition, 52 cases of ventricular 
tachyarrhythmia were reported in post-marketing settings of which the role of ibrutinib could not be 
ruled out in 2 cases. (EMA CHMP scientific conclusions for ibrutinib, 2017). 
Zanubrutinib is a novel second-generation, potent, specific and irreversible BTK inhibitor.  In the 
ongoing first-in-human Phase 1 study of zanubrutinib (BGB-3111-AU-003) in subjects with 
advanced B-cell malignancies, as of 03 November 2017, a total of 67 subjects with WM were 
enrolled in the study. All 67 subjects with WM were fully evaluable for safety and 51 subjects were 
evaluable for efficacy.  The median follow-up in these patients was 15.5 months (0.1 to 
37.6 months).  No subjects had CR, 43% had very good PR (VGPR), and 37% had PR, for a major 
response rate (CR+VGPR+PR) of 80%.  Preliminary gene sequencing data was available for all 51 


 
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patients evaluable for efficacy and suggests a high frequency of deep responses in patients with 
MYD88MUT WM, with 16 of 30 (53%) MYD88MUT WM patients achieving VGPR (Tam et al 2018). 
Zanubrutinib was well tolerated across histologies and dosages.  As of 15 September 2017, the most 
common (≥ 10%) treatment-emergent adverse events (TEAEs) for 58 subjects with WM were upper 
respiratory tract infection (39.7%); contusion (32.8%); constipation (20.7%); diarrhea (19.0%); 
cough (15.5%); nausea, back pain, headache, anemia, urinary tract infection (13.8% each), and rash 
(12.1%).  Of the 58 evaluable subjects with WM, 6 subjects (10.3%) discontinued BGB- 3111 due 
to adverse events (AEs).  No deaths were considered related to treatment.  Refer to the 
Investigator’s Brochure (IB) for more detailed information on zanubrutinib. 
Zanubrutinib was designed to be a more specific inhibitor of the Bruton’s tyrosine kinase than 
ibrutinib.  Preclinical data in cell lines and primary patient samples show specific BTK inhibition 
with less inhibition of off-target kinases such as EGFR, ITK, JAK3, HER2 and TEC than the 
first-generation BTK inhibitor ibrutinib.  We hypothesize that this improved selectivity may result 
in a better safety profile than ibrutinib.  Based on safety data of zanubrutinib above we perceive the 
risk of taking zanubrutinib to be similar or superior to those of ibrutinib and the benefit to be 
potentially greater.  However, to minimize the risks associated with BTK inhibitors we have put 
rules in place.  To minimize the risk of bleeding, subjects will hold study drug for 3 to 7 days pre- 
and post- surgery depending on the type of surgery and the risk of bleeding.  Subjects will be 
closely monitored for infection and drug will be held and may be subsequently reduced, depending 
on recurrence, in the event of Grade 3/4 thrombocytopenias associated with significant bleeding as 
well as grade 4 thrombocytopenias lasting > 10 days, Grade 4 neutropenia (lasting > 10 days despite 
use of growth factors), and ≥ Grade 3 febrile neutropenia.  Furthermore, study drug will be held for 
any ≥ Grade 3 bleeding, and permanently discontinued for any related ≥ Grade 3 hemorrhage with 
the exception of those where the underlying condition can be fully treated (e.g. gastric ulcer 
resulting in gastrointestinal [GI] bleed) and the risk of a re-bleed is deemed acceptable. For any 
intracranial hemorrhage, regardless of grade or relationship to the study drug, the study drug should 
be held and the risk of rebleeding should be assessed. If the risk of rebleeding is deemed 
unacceptable, which is expected in the majority of cases, the study drug should be permanently 
discontinued. Study drug should not be resumed unless event resolution has been demonstrated by 
CT scans or MRI, the risk of rebleeding is deemed low, and the patient does not have a need for 
concurrent anti-coagulation or anti-platelet medications (except low dose aspirin or low molecular 
weight heparin used to prevent venous thromboembolism).  Study drug resumption can only occur 
after a discussion and approval by the study medical monitor. Subjects will be monitored for these 
adverse events. 
We hypothesize that zanubrutinib will have sustained tissue penetration that may result in a deeper 
response than ibrutinib.  Twice-daily zanubrutinib dosing results in high plasma exposure of 
zanubrutinib.  Close to 100% sustained BTK occupancy was found in studies where paired patient 


 
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lymph node biopsies and blood samples were examined suggesting a deep tissue penetration of the 
drug.  Phase 1 clinical data presented at the European Hematology Association meeting support this 
hypothesis.  With a median follow up of 15.5 months (range, 0.1-37.6), an overall response rate of 
92% (47 of 51), a major response rate of 81% (41 of 51), and a VGPR in 43% (22 of 51) of subjects 
with WM (Tam et al, 2018).  To test these hypotheses more formally we have designed this head to 
head Phase 3 study to compare the efficacy and safety of zanubrutinib to ibrutinib.   


 
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2 
OBJECTIVES 
2.1 
Primary Objective (Cohort 1) 
 To compare the efficacy of zanubrutinib vs ibrutinib in subjects with MYD88MUT WM 
2.2 
Secondary Objectives (Cohort 1) 
 To further compare the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib 
vs ibrutinib in subjects with MYD88MUT WM  
 To evaluate safety and tolerability of zanubrutinib versus ibrutinib in subjects with 
MYD88MUT WM, as measured by the incidence and severity of adverse events according to 
the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) 
v4.03. 
2.3 
Exploratory Objectives 


 
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3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint is the proportion of subjects in Cohort 1 achieving either CR or VGPR, as 
determined by independent review committee (IRC) using an adaptation of the response criteria 
updated at the Sixth IWWM (Owen et al. 2013 and NCCN Guidelines, Lymphoplasmacytic 
Lymphoma/Waldenström’s Macroglobulinemia 2015: v2). 
3.2 
Secondary Endpoints 
Efficacy (Cohort 1): 
 Major response rate (MRR) as assessed by the IRC, defined as the proportion of subjects 
achieving CR, VGPR, or PR  
 Duration of response (DOR) as assessed by the IRC, defined as the time from first 
determination of response (CR, VGPR or PR) (per modified IWWM criteria) until first 
documentation of progression (per modified IWWM criteria) or death, whichever comes 
first 
 Rate of CR or VGPR as assessed by the Investigator 
 DOR as assessed by the Investigator, defined as the time from first determination of 
response (CR, VGPR or of PR) (per modified IWWM criteria) until first documentation of 
progression (per modified IWWM criteria) or death, whichever comes first 
 Progression-free survival (PFS) as assessed by the IRC, defined as time from randomization 
to the first documentation of progression (per modified IWWM criteria) or death, whichever 
occurs first 
 
PFS as assessed by the Investigator, defined as time from randomization to the first 
documentation of progression (per modified IWWM criteria) or death, whichever occurs 
first 
 Resolution of treatment-precipitating symptoms, defined as the absence of the symptoms 
that triggered initiation of study treatment (per the IWWM treatment guidelines) at any point 
during study treatment  
 Anti-lymphoma effect, defined as any reduction in bone marrow involvement by 
lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by 
CT scan, at any time during the course of study treatment  


 
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Safety (Cohort 1) 
 The incidence, timing, and severity of treatment-emergent AEs (TEAE) according to NCI-
CTCAE v.03 
3.3 
Exploratory Endpoints 
 
 


 
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4 
STUDY DESIGN 
4.1 
Summary of Study Design 
This is a Phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of 
the Bruton’s Tyrosine Kinase (BTK) Inhibitors zanubrutinib and ibrutinib in subjects with 
Waldenström’s Macroglobulinemia (WM) who require therapy according to the consensus panel 
criteria from the Seventh International Workshop on Waldenström’s macroglobulinemia 
(Dimopoulos et al 2014).  Subjects may be treatment-naïve (TN) or have relapsed or been refractory 
to prior therapy.  Relapsed means a subject previously achieved a CR or VGPR/PR but after a 
period of 6 months or more showed progressive disease. Refractory means a subject experienced 
prior treatment failure or disease progression within 6 months of therapy initiation. Subjects with no 
prior therapy (TN) will comprise no more than 20% of the study analysis set in Cohort 1.  The study 
is composed of an initial Screening Phase (up to 35 days), a Treatment Phase, and a Follow-up 
Phase.  The study schema is presented in Figure 1.  
Approximately 210 subjects will be enrolled on the study. All subjects enrolled on the study will 
have the MYD88 gene sequenced by a central laboratory using the baseline bone marrow.  
Approximately one hundred and eighty-eight WM subjects (150 relapsed/refractory subjects and 
approximately 38 treatment-naïve subjects) who have the MYD88MUT mutation, which is 
characteristic of WM and present in approximately 90% of cases, will be enrolled on to Cohort 1 
and randomized to one of two treatment arms (Cohort 1; zanubrutinib treatment [Arm A] or 
ibrutinib treatment [Arm B]) in a 1:1 ratio using CXCR4 mutational status (CXCR4WHIM vs. 
CXCR4WT vs missing) and number of prior lines of therapy for WM (0 vs. 1-3 vs. >3 prior therapies) 
as stratification factors.  Subjects found to have MYD88WT by gene sequencing, which is estimated 
to be present in approximately 10% of enrolled subjects, will be enrolled to Cohort 2 and will 
receive zanubrutinib treatment on a third, non-randomized study arm (Arm C).  This non-
randomized arm is aimed to evaluate the efficacy of zanubrutinib in MYD88WT WM subjects, among 
whom suboptimal efficacy has been observed (i.e., shorter median survival and lower MRR and 
CR/VGPR rates versus MYD88MUT) when treated with ibrutinib. In addition, those subjects whose 
MYD88 mutational status is missing or inconclusive will be assigned to Cohort 2, Arm C.  Arm C 
will enroll approximately 22 subjects.  
The primary efficacy analysis will be conducted approximately 12 months after the last 
relapsed/refractory subject in Cohort 1 is randomized.  Tumor response will be assessed every cycle 
(every 4 weeks) for the first 48 weeks and then every 3 cycles thereafter by an independent review 
committee (IRC) according to an adaptation of the response criteria updated at the Sixth IWWM 
(Owen et al 2013; NCCN Guidelines, Lymphoplasmacytic Lymphoma/Waldenström’s 
Macroglobulinemia 2015: v2). Serum IgM and M-protein levels will be measured at Screening, on 
Day 1 of every cycle for the first 48 weeks (12 cycles) then every 3 cycles thereafter. For subjects 


 
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with evidence of extramedullary disease (lymphadenopathy and/or splenomegaly) by computed 
tomography (CT) scan at baseline, assessment by CT scan will occur every 12 weeks (starting from 
C4D1) during the first 48 weeks (until C13D1), then every 24 weeks until PD or complete 
resolution of extramedullary disease.  A CT scan is also required at the safety follow-up visit.  Bone 
marrow will be assessed by aspirate and biopsy at Screening, after 12 cycles (C13D1), at time of 
suspected CR, and as clinically indicated. 
Response assessments will occur in all subjects at the beginning of every cycle (every 4 weeks) 
starting from C2D1 during the first 12 cycles (48 weeks), and then every 3 cycles (every 12 weeks) 
thereafter e.g., C2D1, C3D1, etc. For those with extramedullary disease at baseline response 
assessments must occur in conjunction with CT scans until resolution of extramedullary disease.  
For response assessments that occur during cycles where a CT scan is not required then results from 
prior scans (up to 12 weeks/3 cycles during the first 48 weeks/12 cycles and up to 24 weeks/6 cycles 
thereafter) can be carried forward in those subjects with extramedullary disease at baseline.  Quality 
of life (QOL) will be measured every 12 weeks during the first 48 weeks, and then every 24 weeks 
thereafter by the EORTC QLQ-C30 and EQ-5D in MYD88MUT WM subjects (Cohort 1). 
All subjects will be followed for AEs for 30 additional days after the last dose of study drug.  All 
treatment-related AEs and serious AEs (SAEs) will be followed until resolution or stabilization. 
Efficacy evaluations will continue until documented PD for subjects who discontinued for reasons 
other than PD.   
Screening Phase: Screening evaluations will be performed within 35 days prior to the 
randomization, with the exception of a fresh bone marrow biopsy, which may be performed up to 
42 days prior to randomization, as long as no intervening therapy has been administered.  A fresh 
bone marrow aspirate is required for flow cytometry and the MYD88 and CXCR4 mutational 
analyses at Screening.  If subject enrolls based on a bone marrow biopsy that was obtained within 
the 42 days of randomization, then a fresh bone marrow aspirate will still be required during the 
Screening period.  Subjects who agree to participate will sign the informed consent form prior to 
any screening evaluations.  Screening procedures are outlined in Table 3.  Screening evaluations can 
be repeated within the screening period.  
Treatment Phase:  Subjects will be assigned to either Cohort 1 (MYD88MUT) or Cohort 2 
(MYD88WT/missing) based on the mutational status of the MYD88 gene.  Cohort 1 subjects will be 
randomized using an Interactive Response Technology (IRT) system by the status of stratification 
factors to receive the first dose of zanubrutinib or ibrutinib at Cycle 1 Day 1. Cohort 2 subjects 
(MYD88WT/missing) will be assigned by the IRT to receive zanubrutinib. Subjects randomized to Arm 
A will take 160 mg (80 mg x 2 capsules) of zanubrutinib PO BID.  Subjects randomized to Arm B 
will take 420 mg (140 mg x 3 capsules, or in other applicable dose forms) of ibrutinib PO QD.  
Subjects assigned to Cohort 2 (Arm C) will take zanubrutinib 160 mg (80 mg x 2 capsules) PO BID.  


 
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All subjects will continue to be treated and followed by the defined schedules in Table 3 for IgM, 
radiologic assessments and bone marrow, etc. until PD, unacceptable toxicity, death, withdrawal of 
consent, lost to follow-up, end of treatment duration or the study is terminated by the sponsor, 
whichever comes first.  A treatment cycle consists of 28 days.   
Follow-up Phase:  In all study arms, subjects will return approximately 30 days after the last dose 
of study drug for Safety Follow-up Visit(s) for the collection of AEs and SAEs that may have 
occurred after the subject discontinued from the study.  For subjects that had extramedullary disease 
at baseline, a CT scan is also required at the Safety Follow-up Visit.  All treatment-related SAEs 
will be followed until resolution or stabilization.  The investigator or his/her designee will also 
continue to collect information on new anticancer therapy given after the last dose of study drug.  
Efficacy evaluations will continue until documented PD.  If study drug is discontinued due to 
reasons other than PD, serum IgM and M-protein levels will continue to be followed every 12 
weeks while other efficacy evaluations will be followed as per investigator’s discretion. Efficacy 
assessments will be continued, as per protocol, until PD, withdrawal of consent, death, lost to 
follow-up, end of study or study termination by sponsor, whichever occurs first.  Follow-up will 
continue to occur even though a subject may have started a new anticancer therapy after the last 
dose of study drug.  For full efficacy assessment schedules, please refer to Section 7.3 and Table 3.  
Subjects will be followed for survival and further anticancer therapy information after progression 
of disease via phone contact (with the subject’s guardian, if applicable) every 12 weeks until study 
end.  
Post Study: Subjects assigned to Arms A and C (zanubrutinib) who, in the opinion of the 
investigator, continue to benefit from zanubrutinib or ibrutinib at study closure may continue 
treatment with zanubrutinib by enrolling on the zanubrutinib Long Term Extension Study. This 
study is a rollover study for subjects who wish to continue receiving zanubrutinib. 


 
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Figure 1. 
Schema for Study BGB-3111-302  
 
 
 


 
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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Clinical and definitive histologic diagnosis of WM. Subjects must either have 
relapsed/refractory disease OR be treatment naïve and considered by their treating physician 
to be unsuitable for standard chemoimmunotherapy regimens. 
 For subjects who have received no prior therapy for WM: “Unsuitable” for 
treatment with a standard chemoimmunotherapy regimen must be a physician-
determined status based on co-morbidities and risk factors. Physicians will need 
to provide and document organ system(s) and specific reason(s) for subject being 
considered unsuitable.  Patient preference does not meet the eligibility 
requirement for a treatment-naïve subject to be unsuitable for treatment with a 
standard chemoimmunotherapy regimen 
2. Meeting at least one criterion for treatment according to consensus panel criteria from the 
Seventh International Workshop on Waldenström’s Macroglobulinemia (Dimopoulos et al 
2014, detailed in Table 4, Section 7.2) 
3. Measurable disease, as defined by serum IgM level > 0.5 g/dL 
4. Age ≥ 18 years old  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2  
6. Adequate bone marrow function defined as: 
 Neutrophils ≥ 0.75 x 109/L, independent of growth factor support within 7 days of study 
entry 
 Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days 
of study entry 
7. Creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or 
estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease 
[MDRD]) based on ideal body mass (EMA 2014; FDA 2010) 
8. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of 
normal (ULN) 
9. Bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome) 
10. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time 
(aPTT) ≤ 1.5 x ULN. Subjects with factor inhibitors that prolong PT/aPTT without 


 
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increasing the bleeding risk or those with lupus anticoagulant or acquired von Willebrand’s 
syndrome due to WM may be enrolled after discussion with the Medical Monitor or 
designee. 
11. Subjects who relapse after autologous stem cell transplant are eligible if they are at least 3 
months after transplant, and are eligible after allogeneic transplant if they are at least 6 
months post-transplant.  To be eligible after either type of transplant, subjects should have 
no active infections or in the case of allogeneic transplant relapse, no active acute graft 
versus host disease (GvHD) of any grade, and no chronic GvHD other than mild skin, oral, 
or ocular GvHD not requiring systemic immunosuppression. 
12. Female subjects of childbearing potential and non-sterile males must practice highly 
effective methods of birth control initiated prior to first dose of study drug, for the duration 
of the study, and for 90 days after the last dose of study drug.  These methods include the 
following: 
 A barrier method of contraception (including male and female condoms with or 
without spermicide) plus one of the following hormonal contraceptives  
o Combined (estrogen and progestogen containing) hormonal contraception 
associated with the inhibition of ovulation 
 Oral, intravaginal or transdermal 
o Progestogen-only hormonal contraception associated with the inhibition of 
ovulation 
 Oral, injectable, implantable 
o An intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day prior to first 
dose of study drug, for the duration of the study, and for 90 days after the last dose of 
study drug). Total sexual abstinence should only be used as a contraceptive method if 
it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 


 
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abstinence for the duration of exposure to the investigational medicinal product 
(IMP), 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. 
13. Life expectancy of > 4 months 
14. Able to provide written informed consent and can understand and comply with the 
requirements of the study 
5.2 
Exclusion Criteria 
Subjects will be excluded from the study for any of the following reasons: 
1. Prior exposure to a BTK inhibitor. 
2. Evidence of disease transformation at the time of study entry. 
3. Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy, targeted 
therapy, or radiation therapy within 4 weeks, or antibody-based therapy within 4 weeks of 
the start of study drug. 
4. Major surgery within 4 weeks of study treatment. 
5. Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, absolute 
neutrophil count [ANC] and platelets). For ANC and platelets, please follow inclusion 
criteria #6 [neutrophils] and [platelets]). 
6. History of other active malignancies within 2 years of study entry, with exception of (1) 
adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell 
carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
7. Currently active, clinically significant cardiovascular disease such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart 
failure) as defined by the New York Heart Association (NYHA) Functional Classification, 
or history of myocardial infarction within 6 months of screening. 
8. QTcF prolongation (defined as a QTcF > 480 msec). 
9. Active, clinically significant Electrocardiogram (ECG) abnormalities including second 
degree atrioventricular (AV) block Type II, or third degree AV block.  


 
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10. Unable to swallow capsules or disease significantly affecting gastrointestinal function such 
as malabsorption syndrome, resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
11. Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial 
therapy that was completed ≤ 14 days before the first dose of study drug. 
12. Known infection with human immunodeficiency virus (HIV), or serologic status reflecting 
active hepatitis B or hepatitis C infection as follows: 
a) Presence of hepatitis B surface antigen (HbsAg) or anti-hepatitis core antibody (anti-
HBc).  Patients with presence of anti-HBc, but absence of HBsAg, are eligible if 
hepatitis B virus (HBV) DNA is undetectable and if they are willing to undergo 
monthly monitoring for HBV reactivation.   
b) Presence of hepatitis C virus (HCV) antibody.  Patients with presence of HCV 
antibody are eligible if HCV ribonucleic acid (RNA) is undetectable. 
13. Pregnant or lactating women. 
14. Any life-threatening illness, medical condition, organ system dysfunction, need for profound 
anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could 
compromise the subject’s safety, or put the study at risk. 
15. Inability to comply with study procedures. 
16. At time of study entry, taking any medications which are strong cytochrome P450, family 3, 
subfamily A (CYP3A) inhibitors or strong CYP3A inducers. 
17. At time of study entry, taking warfarin or other vitamin K antagonists.  
18. Known CNS hemorrhage or stroke within 6 months prior to study entry.  
19. CNS involvement by WM. Patients with a previous history of CNS involvement must 
undergo magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology studies 
to document no evidence of CNS disease prior to study entry.  
20. History of intolerance to the active ingredients or other ingredients of either zanubrutinib or 
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6 
STUDY TREATMENT PHASE AND FOLLOW-UP PHASE  
6.1 
Study Treatment and Dose Rationale 
Subjects randomized to Arm A or assigned to Arm C will receive zanubrutinib 160 mg (80 mg x 2 
white capsules) PO BID.  The dose of 320 mg total daily, given as divided dose of 160 mg PO BID 
was selected as the recommended Phase 3 dose based on PK/PD data, sustained target occupancy, 
high rates of objective response in multiple histologies, and a favorable safety and tolerability 
profile. Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all subjects 
starting at 40 mg zanubrutinib in the Phase 1/2 study, while occupancy in lymph node tissue was 
assessed only at 160 mg BID and 320 mg daily. At the 160 mg BID 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 
indications 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 BID dose; which shows a high 
level of activity without compromise of the tolerability profile as compared to lower doses of 
zanubrutinib.  
Subjects randomized to Arm B will receive ibrutinib 420 mg (140 mg x 3 capsules, or in other 
applicable dose forms) PO QD as per prescribing information.  For example, as available, one 
420 mg tablet or 140 mg x 3 tablets.  
6.2 
Study Treatment Preparation and Dispensation 
6.2.1 
Packaging and Labeling 
Zanubrutinib capsules will be provided in a child-resistant high-density polyethylene (HDPE) bottle 
with induction seal and bottle label.  Commercial supplies of ibrutinib will be provided by the 
sponsor or via local procurement by the site. In the case of local procurement, the cost for provision 
of ibrutinib may be covered by a patient’s insurance or via reimbursement by the sponsor.  The 
contents of study treatment labels will be in accordance with all applicable local regulatory 
requirements. 
All study treatments will be consistent with those described in the Pharmacy Manual for this study. 
6.2.2 
Handling and Storage 
Interactive Response Technology (IRT) system will be used for drug supply management. The 
study drug will be dispatched to a study center only after receipt of the required documents in 
accordance with applicable regulatory requirements and the sponsor’s procedures. The Investigator 
or pharmacist/designated personnel is responsible for maintaining the drug supply inventory and 
acknowledgment receipt of all study drug shipments. All study drug must be stored in a secure area 


 
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with access limited to the investigator and authorized study center personnel and under physical 
conditions that are consistent with study drug-specific requirements. The study drug must be kept at 
the condition as specified on the labels. Zanubrutinib bottles must be stored at room temperature 
15ºC to 30ºC.  For ibrutinib, each country should follow the storage condition instructions on the 
local drug label. Study drug must be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study may receive study drug, in accordance with all 
applicable regulatory requirements.  Only authorized study center personnel may supply or 
administer study drug.   
6.2.3 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel by reviewing the patient 
diary and information provided by the subject and/or guardian.  
The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed  All subjects enrolled in the study will be provided with patient diaries.  The subject is 
responsible for maintaining the patient diary.  The subject will record the number of capsules (or in 
other dose forms as applicable, eg, tablets) taken and if any were missed.  The site personnel 
responsible for drug accountability will record the quantity of drug dispensed and quantity of drug 
returned at periodic visits by the patient, or at any cycle visit if dosing non-compliance is suspected.  
The patient diaries and the pharmacist record of drug dispensation will be assessed by the 
Investigator/study personnel at each visit.  The investigator is responsible for study drug 
accountability, reconciliation, and record maintenance.  In accordance with all applicable regulatory 
requirements, the investigator or designated study center personnel must maintain study drug 
accountability records throughout the course of the study. This person will document the amount of 
study drug received from the sponsor, the amount supplied, and/or administered to and returned by 
subjects, if applicable. 
6.2.4 
Disposal and Destruction 
At appropriate times during the conduct of the study or after completion of the study, all unused 
zanubrutinib and ibrutinib will be inventoried and packaged for return shipment by the hospital unit 
pharmacist or other designated study center personnel. The inventoried supplies can be destroyed on 
site or at the depot according to institutional policies, after receiving written sponsor approval.  
6.3 
Subject Numbering and Treatment Assignment 
6.3.1 
Subject Numbering and Screening  
Subjects will be identified by a subject number.  Each subject enrolled in this study will receive a 
unique subject number which will be assigned by the IRT system when the subject is screened in the 
study.  Subject number will be assigned in chronological order starting with the lowest number.  
Once a subject number has been assigned to a subject, it cannot be reassigned to any other subject.  


 
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Repeating the screening procedures or tests within the original screening window is allowed if the 
subject did not previously meet the inclusion and exclusion criteria.  A new informed consent is not 
required and the subject shall maintain the same subject number as originally assigned.  Within the 
screening window, a failed screening test can only be repeated one time.  
The Investigator is responsible for ensuring that the patient meets the eligibility criteria for this 
study.  An eligibility packet which contains checklist of the inclusion/exclusion criteria and scanned 
copies of subject’s source data/documents will need to be provided to the Medical Monitor or 
designee for review during the screening period.  Medical Monitor or designee will confirm whether 
the subject is eligible for the study and confirmation will be sent to the site.  Subject can not be 
randomized until confirmation from the Medical Monitor or designee is received. 
6.3.2 
Treatment Assignment 
After a subject has completed all screening procedures and meets the eligibility criteria, study center 
personnel can enroll the subject. Based on MYD88 gene sequencing, the subject will be enrolled into 
either Cohort 1 (MYD88MUT) or Cohort 2 (MYD88WT). Those subjects with either missing or 
inconclusive MYD88 gene sequencing results will be assigned to Cohort 2 by default. 
Approximately 210 subjects will be enrolled into the study. Aproximately 188 subjects from 
Cohort 1 (MYD88MUT), including 150 subjects with relapsed refractory WM and approximately 
38 subjects with treatment-naïve WM, will be randomized in a 1:1 ratio using the IRT system to 
receive either zanubrutinib (Arm A) or ibrutinib (Arm B).  Stratification factors include CXCR4 
mutational status (CXCR4WHIM vs. CXCR4WT vs missing) and the number of prior lines of therapy 
for WM (0 vs. 1-3 vs. >3).  A computer-generated randomization list including stratification factor 
values and treatment arm assignments will be produced, reviewed and approved by an independent 
statistician. The randomization scheme and identification for each subject will be included in the 
final clinical study report (CSR) for this study. Subjects from Cohort 2 (approximately 22 subjects 
who are MYD88WT/missing) will be assigned to Arm C using IRT to receive zanubrutinib capsules. 
Cohort 2 assignment and stratified randomization of Cohort 1 will be performed centrally by the 
IRT system on or immediately prior to Cycle 1 Day 1. The investigator or his/her delegate will call 
the IRT after confirming that the subject has fulfilled all the eligibility criteria. At randomization, 
the IRT will assign each subject a unique number. This unique patient number will be used to 
identify the patient in the electronic data capture (EDC) system and other data sources. The 
randomization list will be kept by the IRT vendor in their secure system and will not be accessible 
to the study center, responsible (or designee) monitors, project statisticians, or to the project team at 
BeiGene.  The time from randomization of the subject to the initiation of therapy should be no more 
than 5 days. 


 
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6.3.3 
Treatment Blinding 
This is an open-label study. The IRC will be blinded to study treatment.  The independent data 
monitoring committee (DMC) will not be blinded. 
6.4 
Dosage and Administration 
Zanubrutinib or ibrutinib will be dispensed by the study center personnel to subjects at scheduled 
study visits to ensure adequate drug supply for administration at home throughout the Treatment 
Phase.  The investigator is to instruct the subject to take the study drug exactly as prescribed and at 
the same time each day of dosing.  Subjects will be requested to bring their unused medication 
including empty bottles to the center at each visit.  All dosages prescribed and dispensed to the 
subject and all dose changes including reason for dose changes during the study must be recorded 
on the appropriate electronic case report form (eCRF). 
Subjects randomized or assigned to zanubrutinib (Arms A and C) will be instructed to take 160 mg 
(80 mg x 2 capsules) orally with a glass of water twice a day at approximately the same time each 
day. The time difference between two consecutive doses should be a minimum of 8 hours.  Subjects 
randomized to ibrutinib (Arm B) will be instructed to take 420 mg (140 mg x 3 capsules or in other 
applicable dose forms) orally with a glass of water, once a day at the approximately same time each 
day.   
Zanubrutinib (Arms A and C) or ibrutinib (Arm B) should be taken within 5 days from the time of 
subject randomization. 
Subjects are not required to fast before or after the administration of either zanubrutinib or ibrutinib. 
Zanubrutinib or ibrutinib will be taken as prescribed from Cycle 1 Day 1 until PD, unacceptable 
toxicity or death, withdrawal of consent, loss to follow-up, or termination of the study by the 
sponsor, whichever comes first. Zanubrutinib capsules or ibrutinib in any applicable dose forms 
should not be opened, broken, or chewed at any time.  
In subjects undergoing pharmacokinetics (PK) blood sampling, study drug administration for 
subjects randomized or assigned to Arms A and C (zanubrutinib) will occur on the specified days 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 subject not to self-
administer the study drug prior to the office visit on those days.   
Subjects on Arms A and C (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 subjects vomit after taking the capsules, they 
should not repeat that dose. 


 
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Subjects on Arm B (ibrutinib) should be instructed that if a dose of the study drug is not taken at the 
scheduled time, it can be taken as soon as possible on the same day with a return to normal dosing 
the next day, or to take ibrutinib according to local prescribing guidelines.  The patient should not 
take extra capsules (or in other applicable dose forms) to make up the missed dose.  If subjects 
vomit after taking the capsules, they should not repeat that dose.  
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose.  
AEs associated with an overdose of study drug should be recorded as an AE in the patient's chart 
and on the appropriate eCRF.  Any SAEs associated with an overdose are required to be reported 
within 24 hours of awareness via SAE reporting process as described in Section 9.2.2.  There is no 
specific antidote for either zanubrutinib or ibrutinib. In an event of an overdose, subjects should be 
closely monitored and given appropriate supportive treatment. 
6.5 
Dose Interruption and Modification 
The guidelines set forth in Table 1 should be followed for dose interruption or modification of 
zanubrutinib or ibrutinib for hematologic (Section 6.5.1) or non-hematologic (Section 6.5.2) 
toxicities based on investigator assessment of study drug relatedness.   
Study drug may be held for a maximum of 2 consecutive cycles and restarted upon resolution of 
toxicity and per investigator discretion.  If, in the investigator’s opinion, it is in the subject’s best 
interest to restart treatment after being held for more than 2 consecutive cycles, then written 
approval must be obtained from the Sponsor’s Medical Monitor or designee. More than one study 
drug hold is allowed. 
Table 1. 
Zanubrutinib and Ibrutinib Dose Reduction Steps 
Toxicity 
Occurence 
Dose Level 
Zanubrutinib Dose (Arms A & C) 
(Starting dose = 160 mg BID) 
Ibrutinib Dose (Arm B) 
(Starting dose = 420 mg QD) 
First 
0 = starting dose 
Restart at 160 mg BID 
Restart at 420 mg QD 
Second 
-1 dose level 
Restart at 80 mg BID 
Restart at 280 mg QD 
Third 
-2 dose level 
Restart at 80 mg QD 
Restart at 140 mg QD 
Fourth 
Discontinue Study Drug 
Discontinue zanubrutinib 
Discontinue ibrutinib 
BID=twice daily; QD=once daily 
 
6.5.1 
Dose Modifications for Hematologic Toxicity for Zanubrutinib 
For zanubrutinib, dosing will be held for hematologic toxicity suspected to be related to study drug 
treatment under any of the following conditions: 


 
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 Grade 4 neutropenia (lasting >10 days despite the use of growth factors)  
 Grade 4 thrombocytopenia (lasting >10 days) 
 Grade ≥ 3 febrile neutropenia 
 Grade ≥ 3 thrombocytopenia associated with significant bleeding 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery of 
the toxicity to ≤ Grade 1 or baseline.  If the same event reoccurs, subjects will restart at one dose 
level lower upon recovery of the toxicity to ≤ Grade 1 or baseline.  A maximum of 2 dose 
reductions will be allowed.  
6.5.2 
Dose Modifications for Non-Hematologic Toxicity for Zanubrutinib 
For non-hematological toxicities ≥ Grade 3, other than hypertension that is adequately controlled 
with oral medication or asymptomatic laboratory events (laboratory events indicating liver or renal 
dysfunction will not be considered asymptomatic laboratory events) suspected to be related to study 
drug treatment, study drug will be held until recovery to ≤ Grade 1 or baseline, and then restarted at 
the original dose level.  If the event recurs at ≥ Grade 3, drug will be held until recovery to 
≤  Grade 1 or baseline and restarted at Dose Level -1.  If the event recurs at ≥ Grade 3 at Dose 
Level -1, drug will be held until recovery to ≤ Grade 1 or baseline and restarted at Dose Level -2.  If 
the event recurs at ≥ Grade 3 at Dose Level -2, the subject will be discontinued from study 
treatment.  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 held for any ≥ Grade3 bleeding.  The drug should be permanently 
discontinued for any related ≥ 3 Grade hemorrhage with the exception of those where the 
underlying condition can be fully treated (e.g. gastric ulcer resulting in GI bleed) and the risk of a 
re-bleed is deemed acceptable. For any intracranial hemorrhage, regardless of grade or relationship 
to the study drug, the study drug should be held and the risk of rebleeding should be assessed. If the 
risk of rebleeding is deemed unacceptable, which is expected in the majority of cases, the study 
drug should be permanently discontinued. Study drug should not be resumed unless event 
resolution has been demonstrated by CT scans or MRI, the risk of rebleeding is deemed low, and the 
patient does not have a need for concurrent anti-coagulation or anti-platelet medications (except low 
dose aspirin or low molecular weight heparin used to prevent venous thromboembolism).  Study 
drug resumption can only occur after a discussion and approval by the study medical monitor. 




 
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6.5.4 
Dose Modifications for Ibrutinib 
For dose modification of Ibrutinib, local prescribing guidelines (Prescribing Information or 
Summary of Product Characteristics) should be followed throughout the study.  The major dose 
modifications for ibrutinib are described below:   
Ibrutinib should be interrupted for any new onset or worsening ≥ Grade 3 non-hematologic 
toxicities, ≥ Grade 3 neutropenia with infection or fever, or 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, drug dose will be reduced to Dose Level -1 (280 
mg orally QD).  A second dose reduction to Dose Level -2 (140 mg orally QD) may be considered 
as needed.  If these toxicities persist or recur following 2 dose reductions, the subject will be 
discontinued for study treatment.   
As with zanubrutinib, ibrutinib should be interrupted for any ≥ Grade3 bleeding.  The drug should 
be permanently discontinued for any related ≥ Grade 3 hemorrhage with the exception of those 
where the underlying condition can be fully treated (e.g. gastric ulcer resulting in GI bleed) and the 
risk of a re-bleed is deemed acceptable. For any intracranial hemorrhage, regardless of grade or 
relationship to the study drug, the study drug should be held and the risk of rebleeding should be 
assessed. If the risk of rebleeding is deemed unacceptable, which is expected in the majority of 
cases, the study drug should be permanently discontinued. Study drug should not be resumed unless 
event resolution has been demonstrated by CT scans or MRI, the risk of rebleeding is deemed low, 
and the patient does not have a need for concurrent anti-coagulation or anti-platelet medications 
(except low dose aspirin or low molecular weight heparin used to prevent venous 
thromboembolism).  Study drug resumption can only occur after a discussion and approval by the 
study medical monitor. 
Use of ibrutinib in patients requiring other anticoagulants or medicinal products that inhibit platelet 
function may increase the risk of bleeding, and particular care should be taken if anticoagulant 
therapy is used.  
As described in Section 6.6.2, concomitant use of ibrutinib with strong and moderate CYP3A4 
inhibitors should be avoided.  If the benefit outweighs the risk and a strong CYP3A4 inhibitor must 
be used, ibrutinib dose must be reduced or withheld temporarily (7 days or less).  Ibrutinib dose 
must be reduced when administered with moderate CYP3A inhibitors.  Refer to the local 
prescribing guidelines (Prescribing Information or Summary of Product Characteristics) for specific 
instructions on dose modifications with these inhibitors. 
For patients with mild hepatic impairment (Child-Pugh Class A) and patients with moderate hepatic 
impairment (Child-Pugh Class B), refer to the local prescribing guidelines (Prescribing Information 
or Summary of Product Characteristics) for specific instructions on dose modifications of ibrutinib. 


 
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It is not recommended to administer ibrutinib to patients with severe hepatic impairment (Child-
Pugh Class C).  
6.6 
Concomitant Medications and Non-Drug Therapies 
6.6.1 
Permitted Medications 
All concomitant medications taken during the study will be recorded in the eCRF with indication 
and dates of administration.   
Subjects with high tumor burden should be monitored closely and prophylactic measures, including 
allopurinol, may be instituted per institutional standards. Tumor Lysis Syndrome (TLS) has not 
been currently reported with zanubrutinib treatment, but has been reported rarely with ibrutinib.  
Corticosteroid courses of limited duration (2 weeks or less) are permitted, if used to treat a 
concomitant (non-cancer) medical condition.  
Bisphosphonates can be coadministered with zanubrutinib. 
Patients with hematologic malignancies, particularly those having received prior lymphodepleting 
chemotherapy or having prolonged corticosteroid exposure,  are predisposed to opportunistic 
infections as a result of a number of disease and treatment-related factors.  In patients with a high 
risk of opportunistic infections, including pneumocystis jiroveci pneumonia (PJP), prophylaxis 
should be considered as per institutional standards. 
6.6.2 
Prohibited Medications 
Subjects should not receive other anticancer therapy (cytotoxic, biologic, or hormone other than for 
replacement) while on treatment in this study.  Other anticancer therapy, experimental therapy and 
radiotherapy are prohibited and should not be administered until PD (as per clinical practice 
standards at the study center), unmanageable toxicity, or no further clinical benefit occurs which 
requires permanent discontinuation of the study drug.  
Any anticancer chemotherapy, immunotherapy, corticosteroids given with antineoplastic intent, 
experimental therapy, and radiotherapy are prohibited.  
Corticosteroid courses of limited duration (2 weeks or less) are permitted, if used to treat a 
concomitant (non-cancer) medical condition. The chronic use of corticosteroids at doses equivalent 
to adrenal replacement (2.5 mg to 7.5 mg prednisone) is prohibited without previous discussion with 
and approval from the Medical Monitor or designee.   
Use of warfarin or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib.  Supplements such as fish oil or supplements and vitamin E preparations should be 
avoided.   
Use of preparations containing St. John’s Wort should be avoided.  


 
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The primary metabolic pathway for ibrutinib involve the CYP3A isoform.  Administration of 
ibrutinib with strong CYP3A inhibitors or CYP3A inducers should be avoided and consider using 
alternative agents. In addition, star fruit, pomegranate and grapefruit and their juices and Seville 
oranges (bitter oranges) should be avoided since they are known to affect the CYP3A pathway.  
Co-administration of strong or moderate CYP3A4 inhibitors with ibrutinib may lead to increased 
ibrutinib exposure and consequently a higher risk for toxicity.  On the contrary, co-administration 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.  
If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the ibrutinib 
dose or withhold treatment temporarily (for 7 days or less).  If a moderate CYP3A4 inhibitor must 
be used, reduce ibrutinib treatment for the duration of the inhibitor use.  Refer to the local 
prescribing guidelines (Prescribing Information or Summary of Product Characteristics) for specific 
guidelines on dose modifications.   
Refer to Appendix 3 for examples of strong and moderate CY3A4 inhibitors or inducers. Please 
refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list. 
6.6.3 
Medications to be Used with Caution 
Ibrutinib is metabolized to a minor extent by CYP2D6. Other than strong or moderate CYP3A4 
inhibitor and inducers, CYP 450 enzyme class drug is not restricted in ibrutinib prescribing 
information Zanubrutinib is primarily metabolized by CYP3A (see Section 1.3.4), 
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers (refer 
to Table 2 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 2.  The 
medical monitor should be consulted in these situations. Please refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list.  
Based on in vitro data, zanubrutinib may have the potential to affect the human isoenzymes 
CYP2C8 activity (Section 1.3.2).  A clinical drug-drug interaction study (Study BGB-3111-108) 
indicated that zanubrutinib does not inhibit CYP2C9, however, is a mild inducer of CYP3A4 and 
CYP2C19 (Section 1.3.4).  Narrow therapeutic index drugs that are metabolized by CYP3A4 
(alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus 
and tacrolimus), and CYP2C19 (eg, S-mephenytoin) or CYP2C8 should be used with caution 
(Appendix 4), 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 


 
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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 5.1).  
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 1.3.4). 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. 
6.6.4 
Surgery and Procedures 
Susceptibility to bleeding has been observed with BTK inhibitors. Study treatment for either 
zanubrutinib or ibrutinib should be held for 3 to 7 days pre- and post-surgery depending upon the 
type of surgery and the risk of bleeding, if a subject is to undergo surgery during Treatment Phase.  
6.7 
End of Treatment 
All subjects, regardless of reason for discontinuation of study treatment will undergo an End of 
Treatment (EOT) visit within 7 days of stopping study drug.  A visit should be scheduled as soon as 
possible, at which time all of the assessments listed for the EOT visit will be performed (see Table 
3).  The reason for discontinuation from treatment will be recorded on the eCRF. 
Subjects may discontinue study drug for any one of the following reasons: 
 Disease progression 
 Adverse event(s) 
 Subject withdrew consent 
 Investigator Decision  
 Other 
Subjects may voluntarily withdraw consent from treatment at any time.  Subjects will continue into 
the Follow-up Phase if subject withdraws consent from the Treatment Phase.   
Subjects who are continuing to receive benefit from zanubrutinib after disease progression may 
remain in the study upon discussion with the Medical Monitor or designee.  These subjects that 
remain in the study will continue to follow the required assessments during the treatment phase.  
6.8 
Follow-Up Phase 
6.8.1 
Safety Follow-Up 
All subjects who discontinue study drug and agree to a follow-up visit will have a safety follow-up 
visit approximately 30 days after the last dose of study drug to collect AEs and SAEs that may have 
occurred after the subject discontinued from the study treatment.  All treatment-related SAEs will be 


 
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followed until resolution or stabilization.  The investigator or his/her designee will also continue to 
collect information on new anticancer therapy given after the last dose of study drug.  For subjects 
that had extramedullary disease at baseline, a CT scan is also required at this visit.  A laboratory 
assessment is only required if the subject had an ongoing laboratory abnormality at the previous 
visit that the investigator considered to be related to study drug.  If the subject is unable to return to 
the clinic and no laboratory assessment is necessary, the investigator or his/her designee will contact 
the subject or guardian to collect this information.  
6.8.2 
Efficacy Follow-Up 
Subjects who are discontinued from study drug for any reason other than PD will be followed every 
12 weeks (±14 days) until disease progression, withdrawal of consent, death, lost to follow-up, end 
of study or study termination by sponsor, whichever occurs first. Follow-up will continue to occur 
even though a subject may have started a new anticancer therapy after the last dose of study drug.  
IgM will continue to be followed every 12 weeks while other efficacy evaluations will be followed 
as per investigator’s discretion.  
For full efficacy assessment schedules, please refer to Section 7.3 and Table 3.  If the subject 
refuses to return for these visits or is unable to do so, every effort should be made to contact them or 
subject’s guardian by telephone to determine the subject’s disease status and survival.  
6.8.3 
Survival Follow-Up 
Subjects will be followed for survival and further anticancer therapy information post progression 
via phone contact (with the subject’s guardian, if applicable) every 12 weeks (±14 days) as per 
Section 4.1 until study end. 
6.9 
End of Study 
Premature discontinuation from the study (including all follow-up visits) will occur under the 
following circumstances: 
 Subject withdrew consent 
 Lost to follow-up 
 Death  
 Study termination by sponsor 
 Other 
Subjects may voluntarily withdraw consent from the study at any time.  


 
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Subjects lost to follow-up should be recorded as such in the eCRF. For subjects who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the subject, e.g., dates of telephone calls, registered letters, etc. 


 
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7 
STUDY ASSESSMENTS 
7.1 
Study Flow and Visit Schedule 
The study-specific assessments and procedures are shown in Table 3.  


 
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Table 3. 
Study Assessments and Procedures Schedule  
 
Pre- 
treatment 
Treatment 
Each cycle = 28 days 
End of 
Treatment 
 
Follow-up 
 
Screening1 
Cycle 1 
Cycle 2 
C3-13 
C16, C19, C22+ 
(every 3 cycles) 
Subjects must come 
every cycle for 
CBC, study drug, 
and patient diary 
review  
EOT 
Safety Follow-
up Visit 18 
Follow-up 
(every 12 
weeks) 
Day of cycle 
-35 to -1 
D1 
D1±4 
D1±4 
D1±7 
≤7 days 
after last dose 
30 days after 
last dose 
≤ 14 days  
Informed consent 
X 2 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 3 
 
 
 
 
 
 
 
Demography 
X 4 
 
 
 
 
 
 
 
Medical/surgical history/current 
medical conditions 
X 5 
 
 
 
 
 
 
 
WM diagnosis  
X 6 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
Randomization via IRT 
X 7 
 
 
 
 
 
 
 
12-lead ECG 8 
X 
X  
X 
X (Every 4 
cycles) 
X (Every 4 cycles) 
X 
 
 
ECHO/MUGA 
X 9 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
Height (cm) 
X 
 
 
 
 
 
 
 
Weight (kg) 10 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs / physical examination / 
B symptoms assessment/ review and 
documentation of baseline reasons 
for treatment initiation and review 
for arrhythmia signs/symptoms 10  
X 
X 
X 
X 
X 
X 
X 
 
Complete Blood Count (CBC) 11 
X 
X 
X 
X 
X (every cycle) 
X 
 
 
Chemistry and β2-microglobulin 11 
X 
X 
X 
X 
X 
X 
 
 
Coagulation 11 
X 
 
 
 
 
 
 
 
Urinalysis 11 
X 
X 
X 
X 
X 
X 
 
 


 
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Table 3. 
Study Assessments and Procedures Schedule (continued) 
 
Pre- 
treatment 
Treatment 
Each cycle = 28 days 
End of 
Treatment  
 
Follow-up 
 
Screening1 
Cycle 1 
Cycle 2 
C3-13 
C16, C19, C22+ 
(every 3 cycles) 
Subjects must 
come every cycle 
for CBC, study 
drug, and patient 
diary review 
EOT 
Safety Follow-
up Visit 18 
Follow-up 
(every 12 
weeks) 
Day of cycle 
-35 to -1 
D1 
D1±4 
D1±4 
D1±7 
≤7 days 
after last dose 
30 days after 
last dose 
≤ 14 days 
from last visit 
Quantitative serum 
immunoglobulins11 (starting at 
end of Cycle 1/start of Cycle 2) 
X 
X  
(pre-dose) 
X 
X 
X 
X 
 
X11 
Response Assessment11 
 
 
X 
X 
X 
X 
 
X 
Serum immunoelectrophoresis, 
with M-protein quantitation by 
densitometry (SPEP) and serum 
immunofixation11 
X 
X 
(pre-dose) 
X 
X 
X 
X 
 
X11 
Cold agglutinins11 
X 
For any abnormal result, the abnormal test should be 
repeated every cycle for the first 48 weeks, then every 3 
cycles, and at time of suspected CR. Once normalized, to be 
repeated every 3 cycles and at time of suspected CR 
 
 
 
Cryoglobulin11 
X 
 
 
 
Anti-MAG (myelin associated 
glycoprotein) 11 
X 
 
 
 
Serum viscosity11 
X 
 
 
 
Iron, TIBC and Ferritin11 
X 
 
 
 
 
 
 
 
Hepatitis B/C testing 11 
X 
Subj negative for HBsAg, HBcAb positive, and HBV DNA 
negative must undergo monthly HBV DNA screening by PCR. 
Subj positive for HCV antibody but negative for HCV RNA 
must undergo monthly HCV RNA screening. 
 
 
 
Pregnancy test (if applicable) 11  
X 
(within 7 days of 
randomization) 
X  
(Day 1 
and Day 
28) 
Every 4 weeks (Day 28 of each cycle)  
Every 4 weeks (cycle) for at least 90 days after the 
last dose of study drug 
Pharmacokinetics 12 
 
X  
X 
 
 
 
 
 
Study drug administration  
(zanubrutinib or ibrutinib) 13 
 
X 
Continuous dosing in 28-day cycles  
(28-day ± 3 day cycles after C13) until PD, 
unacceptable toxicity, or withdrawal of consent  
 
 
 


 
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Table 3. 
Study Assessments and Procedures Schedule (continued) 
 
Pre- 
treatment 
Treatment 
Each cycle = 28 days 
End of 
Treatment  
 
Follow-up 
 
Screening1 
Cycle 1 
Cycle 2 
C3-13 
C16, C19, C22+ 
(every 3 cycles) 
Subjects must 
come every 
cycle for CBC, 
study drug, and 
patient diary 
review 
EOT 
Safety Follow-
up Visit 18 
Follow-up 
(every 12 
weeks) 
Day of cycle 
-35 to -1 
D1 
D1±4 
D1±4 
D1±7 
≤7 days 
after last dose 
30 days after last 
dose 
≤ 14 days 
from last 
visit 
Biopsy for amyloidosis (e.g., Fat 
pad/bone marrow) 14 
 
At time of suspected CR only in subjects with known amyloidosis 
 
 
Bone marrow biopsy/aspiration15 
X15 
At 48 weeks (C13D1), at time of suspected CR, and as clinically indicated. 
Optional bone marrow aspiration collection for correlative study in subjects with 
progressive disease 
 
 
Imaging 16 
X 
Every 12 weeks (starting C4D1) during the first 48 weeks (ending C13D1), then 
every 24 weeks (i.e., every 6 cycles) thereafter (±7 days) 
X16  
X16 
QOL (EORTCQLQ-C30) and 
EQ-5D 17  
X 
Every 12 weeks (starting C4D1) during the first 48 weeks (ending C13D1), then 
every 24 weeks (i.e., every 6 cycles) thereafter 
 
 
Brain CT/MRI scan with contrast 
As clinically indicated 
Concomitant medications and 
medical resource utilization17 
Throughout study 
 
AEs/SAEs19 
Throughout study 
 
Antineoplastic therapies since 
discontinuation of study drug 
 
 
 
 
 
 
X20 
X20 
Survival follow-up  
 
 
 
 
 
 
 
X20 
Patient diary21 
 
X 
X 
X 
X (every cycle) 
X 
 
 
Abbreviations:  AEs: adverse events; CBC: complete blood count; CR: complete response; CT: computed tomography; ECG: electrocardiogram; ECHO/MUGA; 
echocardiogram/Multiple Gated Acquisition scan; ECOG: Eastern Cooperative Oncology Group; EOT: End of Treatment; Ig: immunoglobulin; IRT: Interactive Response 
Technology; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; QOL: quality of life; SAEs: serious adverse events; TIBC: total iron binding capacity; WM: 
Waldenström’s Macroglobulinemia; X: to be performed  


 
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Windows:  Days allowed for reschedule of an entire visit due to logistic reasons (e.g., Public Holidays)  
Assessments scheduled on Cycle 1 Day 1 (C1D1) should be performed prior to the administration of the first dose of zanubrutinib or ibrutinib. Screening blood and urine tests 
performed within 72 hours of the first administration of study drug do not need to be repeated on C1D1. Please refer to Section 7.5 for the requirements of central or local analysis 
regarding blood laboratory assessments. 
1. 
The center must register the subject at screening.in the IRT system.  
2. 
Written informed consent form(s) must be signed by the subject before any study-specific procedures are performed. 
3. 
Screening evaluations will be performed and completed within 35 days of the randomization. The results of all screening assessments and evaluations must be completed 
and reviewed by the investigator prior to C1D1.  The investigator will review and ensure that the subject meets all of the inclusion and none of the exclusion criteria and 
that MYD88 gene sequence has been assessed by central laboratory (MYD88MUT, MYD88WT, or indeterminant). 
4. 
Demography includes gender, date of birth (or age), and race/ethnicity. 
5. 
Relevant medical history (i.e., previous diagnoses, diseases, or surgeries) not pertaining to the study indication, started before signing the informed consent, and 
considered relevant for the subject’s study eligibility, and current medical conditions. 
6. 
Diagnosis and extent of cancer, includes background information such as history of disease and current disease status, staging (at time of diagnosis and at time of 
treatment), bone marrow involvement, sites of disease, prior anticancer therapies, and prior medications/significant non-drug therapies will be collected.  
7. 
The center will utilize the IRT system for Cohort 1 to randomize subjects to Arm A or Arm B, or for Cohort 2 to assign subjects to Arm C in the trial upon completion of 
the all screening activities. Randomization of Cohort 1 can occur on or immediately prior to C1D1. The time from randomization of the subject to the initiation of 
therapy should be no more than 5 days. 
8. 
Perform a 12-lead ECG in triplicate at Screening for all subjects.  For subjects assigned to the zanubrutinib arm, perform a 12-lead ECG in triplicate at pre-dose (within 
30 min prior to dose), 2 hours (± 30 min) post-dose on C1D1 and C2D1, and then continue to one 12-lead ECG in triplicate every 4 cycles thereafter [at C6D1, C10D1, 
etc] until EOT (this can be performed at either pre-dose or post-dose).  For subjects assigned to the ibrutinib arm, perform a 12-lead ECG in triplicate at C1D1 and C2D1 
and every 4 cycles thereafter (C6D1, C10D1 etc.) until EOT (this can be performed at either pre-dose or post-dose).  Subjects should be in the semi-recumbent or supine 
position.  
9. 
Perform ECHO/MUGA at the local lab at Screening, and when clinically indicated. 
10. Physical examination, vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, and temperature), weight, B symptoms examination, and 
review for arrhythmia signs/symptoms will be performed at the time points specified. In addition, baseline reason(s) for treatment initiation must be reviewed and 
documented at each visit.  Symptoms that triggered treatment will be followed at, during, and end of treatment until resolutions. A complete physical exam includes 
assessments of cardiovascular, respiratory, and neurological systems as well as the examination of the abdomen, lymph nodes, spleen, skin, oropharynx and extremities. 
Clinical suspicion of PD at any time will require a physical examination to be performed promptly, rather than waiting for the next scheduled radiological assessment. B 
symptoms include unexplained weight loss > 10% over previous 6 months, fever (≥38°C), and/or drenching night sweats.  The review for arrhythmia signs/symptoms 
for all subjects will be conducted by the Investigators by providing a questionnaire to be completed by all subjects enrolled in the study.  These questions will include 
signs and symptoms of ventricular dysfunction (e.g., shortness of breath, dizziness, or fainting).  The completed questionnaire will be provided back to the investigator 
for review and the Investigator will monitor the subjects at every clinic visit as part of the routine AE monitoring.  Data collected at each visit (Day 1 of each cycle 
during the first 48 weeks [until C13D1], then every 3 cycles [every 12 weeks], and at EOT and Safety Follow-up Visits) will be recorded in the eCRF.).   
11. Laboratory assessments include the following:  
a. 
Screening clinical laboratory assessments performed within 72 hours of the first administration of study drug do not need to be repeated on Cycle 1 Day 1. 
Screening quantitative serum immunoglobulin (IgG, IgM, IgA), β2-microglobulin and serum immunoelectrophoresis, with M-protein quantitation by 
densitometry (SPEP), performed within 14 days of the first administration of study drug do not need to be repeated on Cycle 1 Day 1. 
b. 
Complete Blood Count is required to be performed every cycle (every 4 weeks) during the Treatment Phase. Clinical Chemistry and urinalysis tests will follow 
the same schedule to be performed at Screening, on every cycle (every 4 weeks) for the first 48 weeks and every 3 cycles (every 12 weeks) thereafter.  
c. 
Complete Blood Count includes red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, absolute differential count (neutrophils, 
eosinophils, lymphocytes, monocytes, basophils) and platelet count.  In the event of neutropenia (absolute neutrophil count [ANC] < 750/mm3) or 


 
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thrombocytopenia (platelets of less than 50,000/mm3), these assessments will be conducted as frequently as the investigator feels it necessary and until toxicity 
resolves to ≤ Grade 2 or baseline (ANC ≥ 750/mm3). 
d. 
Clinical chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN) or urea, creatinine, calcium, phosphate, magnesium, total 
bilirubin, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase and 
uric acid.  In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequently as the investigator feels it necessary and until 
toxicity resolves to ≤ Grade 2. The Screening β2-microglobulin, if performed within 14 days of the first administration of study drug, does not need to be 
repeated on C1D1. 
e. 
Coagulation profile will be performed at Screening only includes prothrombin time (PT), which will also be reported as international normalized ratio (INR).  
f. 
Quantitative serum immunoglobulins (IgG, IgM, IgA) and β2-microglobulin will be measured at Screening Visit, pre-dose on C1D1, on Day 1 of every cycle 
for the first 48 weeks through and including Day 1 of Cycle 13, then on Day 1 of every 3 cycles starting on Cycle 16 (C16, C19, C22 etc.).  If a subject 
discontinues study drug due to reasons other than PD, the screening serum immunoglobulins (IgG, IgM, IgA) and β2-microglobulin will continue to be 
followed every 12 weeks. The Screening serum immunoglobulin (i.e.,ie, IgG, IgM, IgA) and β2-microglobulin, if performed within 14 days of the first 
administration of study drug, do not need to be repeated on C1D1. Response assessments will be documented every cycle (starting from C2D1) for the first 48 
weeks (12 cycles) then every 12 weeks (3 cycles) thereafter as indicated in Section 7.3. Assessments will be based on physical examination (in cases in which 
organomegaly is present), laboratory evaluations, quantitative immunoglobulins and SPEP, radiologic assessment, and bone marrow studies. For response 
assessments during cycles when a CT scan is not required, the results of the most recent CT scan(s) may be used for the response assessment only if the prior 
scan date is within 12 weeks of the response assessment date during the first 48 weeks of the study and within 24 weeks of the response assessment date 
thereafter. 
g. 
SPEP and serum immunofixation will be performed at Screening Visit, on Day 1 of every cycle for the first 48 weeks until Day 1 of Cycle 13 with the C1D1 
sample drawn at pre-dose, then every 3 cycles starting on Cycle 16 (C16, C19, C22 etc.) and thereafter. The Screening serum immunoelectrophoresis, with 
M-protein quantitation by densitometry (SPEP), performed within 14 days of the first administration of study drug do not need to be repeated on C1D1.   
h. 
Cold agglutinins, cryoglobulin; anti-MAG (myelin associated glycoprotein) and serum viscosity will be performed at Screening. If there are abnormal findings 
for any of these laboratory assessments at Screening, follow-up is required every cycle (every 4 weeks) for the first 48 weeks, then every 3 cycles (every 12 
weeks) starting on Cycle 16 (C16, C19, C22, etc.) and at time of suspected CR. Once these labs have normalized, they should be repeated every 3 cycles and at 
time of suspected CR.  Of note, subjects that have cryoglobulinemia at Screening and confirmed by the central test should be tested for the presence of 
cryoglobulins at the local laboratory prior to C1D1.  The C1D1 sample will serve as the baseline. The test for cryoglobulinemia should always be performed 
under warm conditions.  The local laboratory should be used to test for cryoglobulinemia throughout the study to ensure that the same methodology is used 
throughout the study.  In addition, serum immunoglobulins should be retested using the residual cryoglobulin blood sample, which is to be collected and 
processed under warm conditions at the local laboratory throughout the study. If serum immunoglobulins cannot be quantified, the serum 
immunoelectrophoresis sample will need to be re-collected, processed, and analyzed at the local laboratory under warm conditionsThese blood samples 
(cryoglobulin/serum IgM/SPEP/serum immunofixation) are to be collected and processed under warm conditions. 
i. 
Iron, TIBC, and Ferritin will be performed at Screening only. If abnormal, iron supplementation should be provided per investigator’s discretion prior to 
initiation of study treatment. 
j. 
Hepatitis B/C serologic markers and viral load will be tested at Screening only.  The hepatitis B testing includes hepatitis B surface antibody (HBsAb), 
hepatitis B core antibody (HBcAb), and hepatitis B surface antigen (HBsAg) as well as hepatitis B virus (HBV) DNA by PCR if the subject is negative for 
HBsAg but HBcAb positive (regardless of HBsAb status). The hepatitis C testing includes Hepatitis C virus (HCV) antibody as well as HCV RNA by PCR if 
the subject is HCV antibody positive. Subjects with positive HBsAg and/or detectable level of HBV DNA or detectable level of HCV RNA are not eligible.  
Subjects negative for HBsAg, HBcAb positive, and HBV DNA negative must undergo monthly HBV DNA screening by PCR.  Subjects positive for HCV 
antibody but negative for HCV RNA must undergo monthly HCV RNA screening. Subjects with known HIV are excluded from the study. 
k. 
Urinalysis will be assessed using urine dipstick.  Urine microscopy will be performed if urine dipstick is abnormal (may be at investigator discretion except 
when urine protein ≥ 2+).  Urinalysis includes pH, glucose, protein, ketones, bilirubin, blood, and specific gravity.  If urine protein is ≥ 2+ by dipstick, a 
24-hour urine for total protein and a random urine for total protein and creatinine will be obtained and evaluated. All these tests will be performed in a local 
laboratory.  


 
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l. 
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at Screening within 7 days of 
randomization.  Laboratory-based highly sensitive pregnancy tests (urine or serum) will be performed on Cycle 1 Day 1, then on Day 28 of every cycle (which 
can be performed on Day 1 of the following cycle).  Any female subject who is pregnant will not be eligible for the study.  Urine or serum pregnancy tests must 
be continued every 4 weeks (cycle) for at least 90 days after the last dose of study drug.  At the last dose of study drug, a serum pregnancy test is required 
(EOT).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
12. Pharmacokinetic samples will be collected from select subjects randomized to Arms A and C (zanubrutinib) at the following time points:  pre-dose (within 30 min of 
dose), 2 hours (±30 min) post-dose and before subject discharge (3-6 h post-dose) on Cycle 1 Day 1 and Cycle 2 Day 1. The time of study drug administration on the day 
prior to Cycle 2 Day 1 must be recorded on the eCRF.  Additionally, subjects who receive plasmapheresis (in Cycle 1 or Cycle 2 or beyond) will be evaluated for the 
effects of plasmapheresis on PK, including collection of additional PK samples immediately before the start of plasmapheresis, approximately an hour after the start of 
the procedure, and 30 min after the end of procedure (please also see Section 7.6.2).  Subjects are recommended to receive zanubrutinib in the clinic on day of 
plasmapheresis and plasmapheresis is to commence between 2 to 3 hours (Tmax) following zanubrutinib dosing.   
13. Zanubrutinib and ibrutinib will be dispensed by the study center personnel on scheduled study visits, approximately every 4 weeks (every cycle), to ensure adequate drug 
supply for each cycle throughout the Treatment Phase. Subjects randomized to Arm A, or assigned to Arm C will receive zanubrutinib at a dose of 160 mg (80 mg x 2 
white opaque capsules) PO BID. Subjects randomized to Arm B will receive ibrutinib at a dose of 420 mg (e.g.140 mg x 3 capsules). Zanubrutinib or ibrutinib will be 
administered on a 28-day cycle and will continue until PD, unacceptable toxicity or death, withdrawal of consent, or study terminated by sponsor for any reason.  All 
subjects will have an end of treatment (EOT) visit within 7 days after stopping study drug.  All subjects will have a follow-up visit 30 days after the last dose of the study 
drug to collect AEs and SAEs that may have occurred after the subject discontinued from the study. The investigator or his/her designee will also continue to collect 
information on new anticancer therapy given after the last dose of study drug. 
14. Fat pad biopsy or biopsy of other relevant tissue (e.g., bone marrow) for subjects with a previous biopsy positive for amyloidosis will be collected at the time of 
suspected CR by IgM response. 
15. Screening bone marrow biopsy samples is allowable within 42 days prior to randomization unless intervening therapy; however, a fresh bone aspirate must be collected 
during the Screening period for the flow cytometry and the mutation analyses.  A bone marrow aspirate and biopsy must be performed for all subjects at 48 weeks, 
(C13D1), at time of suspected CR, and as clinically indicated. An aliquot of bone marrow specimen from Screening will be used for mutation analysis, including but not 
limited to MYD88 and CXCR4.  Optional bone marrow aspiration will be collected in subjects with progressive disease for studying the resistance mechanism.  With 
Medical Monitor (or designee) approval, archival tissue from a prior bone marrow biopsy may be sent to the central lab for assessment of mutation status; this will be 
allowed only if the fresh bone marrow biopsy/aspirate result in an indeterminate mutation result by the central lab. 
16. CT scans should encompass neck, chest, abdomen, pelvis and include oral and/or intravenous contrast. An MRI of the head is required if clinically indicated.  An MRI 
may be used in place of CT for anatomic lesions which cannot be adequately visualized by CT or for subjects who cannot undergo CT (e.g., due to inability to take 
contrast).  The CT portion of a PET/CT scan can also be performed.  In Germany, an MRI may be used in place of CT in all subjects.  However, in all cases the same 
modality should be used throughout the study. All efforts will be made to ensure that the imaging equipment, contrast agent, and person (investigator or radiologist) 
performing the evaluation is kept constant throughout a subject’s course on study.  For subjects with evidence of extramedullary disease (lymphadenopathy and/or 
splenomegaly) by CT scan at baseline, assessment by CT or scan will occur every 12 weeks starting on Day 1 of Cycle 4 (C7, C10 and C13 etc.) during the first 48 
weeks, then every 24 weeks (C19, C25 etc.) starting on Cycle 19 until PD, resolution of extramedullary disease, or EOT, whichever comes first.  Additionally, for 
subjects with extramedullary disease at baseline, a CT scan is also required at the safety follow-up visit.  Unscheduled response assessments may be performed based on 
physical examination or laboratory findings, at the discretion of the investigator.  CT scans for post treatment follow-up will be performed as per investigator’s discretion 
for subjects discontinued due to the reasons other than PD.  
17. In Cohort 1 (Arm A and Arm B only) quality of life (QOL) will be measured at C1D1 pre-dose (to avoid having subjects in Cohort 2 having to complete this at 
Screening) and every 3 cycles during the first 12 cycles then every 6 cycles thereafter throughout the study using the EORTC QLQ-C30, and EQ-5D.  In addition, in 
Cohort 1, medical resource utilization will be recorded at each visit, including Screening and C1D1, including hospitalizations, emergency room visits, transfusion 
support, intravenous antibiotic use, and growth factor support. 
18. Laboratory assessments for safety follow-up is only required if the subject had an ongoing laboratory abnormality at the previous visit that the investigator considered to 
be related to study drug.  Additionally, all treatment-related SAEs will be followed until resolution or stabilization.  For subjects that had extramedullary disease at 
baseline, a CT scan is also required at this visit. 


 
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19. The investigators should ask for signs and symptoms of ventricular dysfunction as part of the routine AE monitoring for each cycle.   
20. Information on survival and new anticancer therapy after last dose of study drug will be collected via telephone call every 12 weeks (± 14 days).  Follow-up will continue 
to occur even though a subject may have started a new anticancer therapy after the last dose of study drug.     
21. All drug supplies and associated documentation will be periodically reviewed and verified by the Study Monitor over the course of the study.  A patient diary will be 
provided to each subject to record the study drug dose taken each day.  Any missed doses with explanation should be recorded in the diary.  The diary should be returned 
to the study personnel for review, and will be reviewed by the Study Coordinator on a regular basis. 
 


 
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7.2 
Subject Demographics/Other Baseline Characteristics 
Refer to Table 3 for all windows for assessments.   
7.2.1 
Demography 
Demographic data will include gender, date of birth (or age), and race/ethnicity. 
7.2.2 
Medical History 
Clinically significant medical history findings (i.e., previous diagnoses, diseases or surgeries) not 
pertaining to the study indication, started before signing of the informed consent, and considered 
relevant for the subject’s study eligibility will be collected and captured, including baseline severity 
if ongoing, in the eCRF. “Clinically significant” is defined as any events, diagnoses or laboratory 
values requiring treatment, follow-up or the presence of signs or symptoms that require medical 
intervention. Concurrent medical signs and symptoms must be documented to establish baseline 
severities.  All conditions ongoing at the time of first study drug dose and all relevant conditions 
that may have resolved prior to the first dose of study drug should be recorded. 
7.2.3 
Other Baseline Characteristics 
Other background information including history of disease, including the date of initial diagnosis 
and current disease status, staging at diagnosis and time of entry on this study, sites of disease, prior 
anticancer therapies, dates administered, responses and duration of response to these treatments will 
also be recorded. Prior medications/significant non-drug therapies will also be collected. 
Not all patients with a diagnosis of WM need immediate therapy. Criteria for the initiation of 
therapy (Seventh IWWM) are presented in Table 4.  Subjects who do not fulfill the criteria in Table 
4 at Screening and in whom only laboratory evidence may indicate a possible development of 
symptomatic disease (such as a minor decrease in hemoglobin level, but >10 g/dL or mild increases 
in IgM or mild increase of lymphadenopathy or splenomegaly without discomfort for the patient) 
are not eligible for the study. 


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Table 4. 
Indications for Initiation of Therapy in Patients with WMa 
Clinical indications for initiation of therapy  
 Recurrent fever, night sweats, weight loss, fatigue  
 Hyperviscosity  
 Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum diameter)  
 Symptomatic hepatomegaly and/or splenomegaly  
 Symptomatic organomegaly and/or organ or tissue infiltration  
 Peripheral neuropathy due to WM 
Laboratory indications for initiation of therapy  
 Symptomatic cryoglobulinemia  
 Cold agglutinin anemia  
 Immune hemolytic anemia and/or thrombocytopenia  
 Nephropathy related to WM  
 Amyloidosis related to WM  
 Hemoglobin ≤10 g/dL  
 Platelet count <100 × 109/L  
a Dimopoulos et al, 2014, Seventh IWWM 
Information will also be collected regarding childbearing potential and any other assessments that 
are done for the purpose of eligibility for inclusion into the study (physical examination, vital signs, 
complete blood count [CBC] and blood chemistry, urinalysis, pregnancy test, ECG, and 
ECHO/MUGA).  For further details on eligibility assessments, please see Table 3. 
7.3 
Efficacy 
Response will be evaluated using an adaptation of the consensus panel criteria updated at the Sixth 
International Workshop (Owen et al 2013, NCCN Guidance Insights, 2012). Response will be 
assessed both with and without considering extramedullary disease (ie, IWWM-6 Including 
Extramedullary Disease and IWWM-6 “IgM-based”).  Please refer to Appendix 2 for categorical 
response definitions and guidelines for special clinical and laboratory circumstances including 
response assessment in the case of dose hold or missing CT scans.  Response categories include CR, 
VGPR, PR, Minor Response, SD, and PD. Additionally an IgM flare can be assigned during periods 
of study drug withholding (see Appendix 2 and guidelines for specific clinical or laboratory 
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Response assessments will be performed, for both every 4 weeks (every cycle) starting from C2D1 
for the first 48 weeks (12 cycles) then every 12 weeks (every 3 cycles) thereafter as indicated in 
Table 3, based on physical examination (in cases in which organomegaly is present), laboratory 
evaluations, quantitative serum immunoglobulins and serum immunoelectrophoresis with M-protein 
quantitation by densitometry (SPEP), radiologic assessment and bone marrow studies.  All response 
assessments should be performed at the required visits as described above and should be entered 
into the eCRF.  The data can be entered retrospectively in the eCRF according to the most recent 
version of the protocol. 
Radiological assessment for extramedullary disease for those who have findings at baseline, by 
either IRC or investigator, will occur every 12 weeks for the first 48 weeks and then every 24 weeks 
thereafter until CT scan has normalized.  Additionally, for subjects who had extramedullary disease 
at baseline, a CT scan is also required at the safety follow-up visit. For response assessments that 
occur during cycles where a CT scan is not required then results from prior scans (as long as within 
up to 12 weeks during the first 48 weeks and up to 24 weeks thereafter) can be carried forward in 
those subjects with extramedullary disease at baseline. 
Change in serum IgM level from baseline will be based upon the IgM value from the central 
quantitative serum immunoglobulin assay, unless for assay limitations this is not possible, in which 
case the central M-protein level by densitometry (SPEP) will be used.   
The serum IgM value (quantitative serum immunoglobulin/SPEP methodology) at C1D1 will serve 
as the baseline (last value prior to drug administration) for all assessments throughout the study 
except for patients who have undergone plasmapheresis. For patients who have undergone 
plasmapheresis, the pre-plasmapheresis serum IgM value (if available at screening) should be used. 
In the case of multiple prior consecutive plasmapheresis procedures during screening, the highest 
predose value (least confounded by plasmapheresis) should be used as the baseline.   
For patients with cryoglobulinemia, blood samples (cryoglobulins/serum IgM/SPEP/serum 
immunofixation) should be collected and processed under warm conditions for baseline assessment 
and throughout the study.   
Response assessments should be performed using results based on the same methodology in the 
same laboratory i.e., central or local throughout the study. Of note, all local labs, e.g. local serum 
IgM/SPEP or serum immunofixation or cryoglobulin results should be reported in the eCRF.   
Per IWWM criteria, PD by increase in IgM requires a confirmatory blood draw which should be 
obtained at next scheduled IgM draw, or at a minimum of 4 weeks from the previous draw.  In 
addition, PD requires a total increase of IgM of at least 500 mg/dL from lowest nadir. Subjects 
should remain on study drug until the central laboratory IgM testing confirms PD.  Transformation 
of WM to large cell lymphoma (Richter’s transformation) is considered as progressive disease and 
should not be recorded in the eCRF as an adverse event.  


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For patients with new disease symptoms, every effort should be made to obtain and document 
objective evidence of disease progression according to the disease-specific response criteria 
Appendix 2.  Of note, progressive disease cannot be determined solely by the presence of 
B symptoms.  Disease progression due to new symptomatic disease must be accompanied by 
objective evidence (e.g., imaging, laboratory value, biopsy, or bone marrow histology) consistent 
with the disease and associated response criteria for progression.  For example, in the absence of 
IgM increase or other objective measures of disease progression, new B symptoms alone should not 
be the sole reason to discontinue a patient from study treatment.  
If there is a rapid rise in serum IgM level or an increase in known extramedullary disease leading to 
an “apparent” response of PD (e.g. an increase in serum IgM level of at least 25% and 500 mg/dL 
from lowest nadir) after the study drug has been held for at least 7 consecutive days, an assessment 
response of IgM flare will be assigned instead of PD. The period to which this is applicable begins 
on the day of the first missed dose and ends when the subject has IgM levels or extramedullary 
disease that no longer qualify as “apparent” PD (e.g., there is a drop in serum IgM level to below 
25% and 500 mg/dL from lowest nadir) or the subject has a confirmed response of PD whichever 
comes first.  During and following periods of study drug withholding, response assessments that 
would otherwise qualify as PD will initially be recorded as IgM Flare and NOT be considered as 
progressive disease.  See Appendix 2 for all conditions and timing that must be met when assigning 
response for IgM Flare.  Subjects may undergo plasmapheresis, when clinically indicated, during 
the first two cycles of study treatment.  IgM response and nadir determination should be at least 
4 weeks following the last plasmapheresis procedure.  Subjects requiring plasmapheresis after 
Cycle 2 will be adjudged to have progressive disease. 
At Screening, a bone marrow biopsy/aspirate, and CT scanning of the neck, chest, abdomen, and 
pelvis (including oral and/or intravenous contrast) will be conducted.  If a bone marrow biopsy was 
performed within 42 days prior to randomization, the specimen will be sent for
 analysis 
as described in Section 7.7.  If a bone marrow biopsy is collected within 42 days of randomization, a 
fresh bone marrow aspirate must still be collected during the Screening period for flow cytometry 
and MYD88 and CXCR4 mutational analyses. With Medical Monitor (or designee) approval, 
archival tissue from a prior bone marrow biopsy may be sent to the central lab for assessment of 
mutation status; this will be allowed only if the fresh bone marrow biopsy/aspirate result in an 
indeterminate mutation result by the central lab. Quantitative serum immunoglobulins (IgM, IgG, 
IgA), serum immunoelectrophoresis with quantification of M-protein by densitometry and serum 
immunofixation, and β2-microglobulin will be drawn at Screening and followed as primary 
endpoints through the study. Complete blood count (CBC) will be drawn at Screening and followed 
every cycle.  Cold agglutinins, cryoglobulins, anti-MAG (myelin associated glycoprotein), and 
serum viscosity will be drawn at Screening and followed if positive as markers of associated 
symptoms. 


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Bone marrow aspirate and biopsy will be obtained at Screening as described above and at 48 weeks 
(C13D1).  Bone marrow aspirate and biopsy will also be repeated to confirm a CR if the subject has 
absence of M-protein and normal serum IgM level during the course of study treatment.   
For subjects with evidence of extramedullary disease (lymphadenopathy and/or splenomegaly) by 
CT scan at Screening/baseline, the CT scan will be repeated every 12 weeks during the first 
48 weeks beginning on C4D1 and every 24 weeks thereafter until PD or resolution of 
extramedullary disease, as well as at the safety follow-up visit. Please refer to Section 7.3.2. 
Quantitative serum immunoglobulins (IgM, IgG, IgA) and serum immunoelectrophoresis with 
quantification of M-protein by densitometry and serum immunofixation will be performed on Day1 
of every cycle for first 48 weeks with the Cycle 1 Day1 sample drawn at pre-dose, then every 3 
cycles and thereafter. Please refer to Section 7.5.3 and Section 7.5.4. 
In the event that cold agglutinins, cryoglobulin, anti-MAG (myelin associated glycoprotein), or 
serum viscosity are found to be abnormal at Screening, then the abnormal laboratory test will be 
repeated every cycle for the first 48 weeks (12 cycles), then every 3 cycles, and at time of suspected 
CR.  Once these labs have normalized, they should be repeated every 3 cycles and at the time of a 
suspected CR. For subjects with previous biopsy positive for amyloidosis, a fat pad biopsy or biopsy 
of other relevant tissue will be collected at the time of suspected CR by IgM response.  
7.3.1 
Physical Examination 
Enlargement of lymph nodes and spleen is included in the physical examination at each visit for 
efficacy. Body systems (e.g. cardiovascular, respiratory etc.) should be evaluated at each visit when 
a physical examination is performed and any abnormalities recorded. See Section 7.4.2 for details of 
physical examination.  
7.3.2 
Radiological Tumor Assessment 
Baseline radiological tumor assessment should be performed within 35 days of the randomization.  
All subjects must have baseline CT scan with contrast of neck, chest, abdomen, and pelvis and any 
other disease sites. An MRI of the head is required if clinically indicated.  The CT portion of a 
PET/CT scan can also be performed as long as the same modality is used throughout the study. 
For subjects with evidence of extramedullary disease (lymphadenopathy [note lymph nodes must 
measure >15mm in longest diameter (LDi)] and/or splenomegaly [measured craniocaudally 
> 130mm]) by CT scan at baseline, the CT scan will be repeated every 12 weeks during the first 
48 weeks beginning on C4D1 and every 24 weeks thereafter until documented PD or complete 
resolution of extramedullary disease during the Treatment Phase by investigator according to 
consensus panel criteria updated at the Sixth International Workshop (Owen et al 2013 and 
Appendix 2; NCCN Guidance Insights, 2012).  CT scans for post treatment efficacy follow-up will 
be performed for subjects discontinued due to the reasons other than PD at the follow-up visit.  A 


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CT scan will also be repeated to confirm a CR if the subject has absence of serum monoclonal IgM 
protein and normal serum IgM level and had extramedullary disease at baseline and at the discretion 
of the investigator.  At least one post-baseline CT scan is also required in situations where the 
baseline extramedullary disease assessment was determined to be absent by investigator and present 
by the IRC.  The first follow-up CT scan for such patient should be performed within 30 days upon 
notification, ie, by the next clinic visit regardless of the protocol defined CT scan schedule and/or 
achievement of CR. Afterwards, follow-up CT scans should be obtained per the protocol schedule 
(with a minimum of 12 weeks between scans, at investigator’s discretion). 
All lesions found by imaging will be recorded at baseline as target (up to 10 lesions in 
extramedullary CRF) or non-target.  Measureable lesions will be recorded in the eCRF at each 
imaging timepoint in 2 perpendicular dimensions: LDi and short diameter (SDi).  SDi is defined as 
the longest diameter perpendicular to LDi. 
Target lesions may become “too small to measure” (TSTM).  While on study, all lesions (nodal and 
extranodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on a CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the eCRF.  If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm.  If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well).    
An MRI may be used in place of CT only for anatomic lesions which cannot be adequately 
visualized by CT, or for subjects who cannot undergo CT.  The CT portion of a PET/CT scan can 
also be used.  In Germany, an MRI may be used in place of CT in all subjects.  However, in all 
cases the same modality should be used throughout the study. All efforts will be made to ensure that 
the imaging equipment, contrast agent, and person (investigator or radiologist) performing the 
evaluation is kept constant throughout a subject’s course on study.   
All CT scans, and MRIs obtained during the study will be collected and reviewed by a central 
imaging vendor identified to this trial. De-identified copies of all scans and radiology reports 
(including those from screening) must be provided to the sponsor or designee (e.g., central imaging 
vendor). 


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7.3.3 
Bone Marrow Assessment 
A unilateral bone marrow biopsy at Screening (within 42 days of the randomization, as long as no 
intervening therapy is administered) and a fresh bone marrow aspirate taken during Screening, 
followed by aspirate and biopsy at 48 weeks, at time of suspected CR, and as clinically indicated 
will be used to assess for bone marrow involvement by WM. Bone marrow for post treatment 
efficacy follow-up will be performed as per investigator’s discretion for subjects discontinued due 
to the reasons other than PD.   
All pathology samples will undergo central pathology review. 
An aliquot of bone marrow specimen from Screening will be used for the mutation analysis, 
including but not limited to MYD88 and CXCR4 gene sequencing. 
Optional bone marrow aspiration will be collected in subjects with progressive disease for studying 
the resistance mechanism. 
7.3.4 
Biopsy for Amyloidosis 
For subjects with a known history of amyloidosis (based on screening bone marrow studies and 
indication of treatment initiation [Table 4]), fat pad biopsy or biopsy of other relevant tissue (e.g., 
bone marrow) will be collected at the time of suspected CR by IgM response. 
7.3.5 
Biopsy for Suspected Disease Transformation 
Biopsy confirmation is necessary for subjects suspected to have disease transformation.  
7.4 
Safety 
Safety assessments should be performed at all site visits throughout the study. Please see Table 3 for 
the schedule of the assessments and windows for assessments.   
7.4.1 
Adverse Events 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported.  All AEs and SAEs, regardless of the relationship to the study drug, will be 
collected from the time of first dose of study drug.  Secondary malignancies will be recorded as AEs 
and should be reported to the sponsor. Transformation of WM to large cell lymphoma (Richter’s 
transformation) is considered as progressive disease and should not be recorded in the eCRF as an 
adverse event.  
All subjects will be followed for safety 30 additional days after the last dose of study drug.  All 
treatment-related AEs and SAEs will be followed until resolution or stabilization. The accepted 
regulatory definition for an AE is provided in Section 9.1.  Important additional requirement for 
reporting SAEs are explained in Section 9.2.  


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In addition, arrhythmia signs/symptoms will be reviewed at every cycle.  This will involve the 
investigators asking subjects for signs and symptoms of ventricular dysfunction via a brief 
questionnaire, as part of the routine AE monitoring for each cycle.  
7.4.2 
Physical Examination, Vital Signs, Height, Weight, Assessment of B symptoms, 
Re-evaluation of Baseline Reason(s) for Initiation of Therapy, and Review for 
Arrhythmia Signs/Symptoms 
Physical examination, vital signs (sitting blood pressure, pulse rate, and body temperature), weight, 
B symptoms examination will be performed at the timepoints specified (See Table 3).  Additionally, 
a brief questionnaire to review signs and symptoms of ventricular arrhythmia (e.g., shortness of 
breath, dizziness, or fainting) will be completed by all patients for both cohorts and the data will be 
recorded in the eCRF.  These signs and symptoms will be monitored throughout the study at every 
visit.  Height (cm) is determined at Screening only.  B symptoms includes unexplained weight loss 
> 10% over previous 6 months, fever (≥ 38°C), and/or drenching night sweats.  
Body systems (e.g. cardiovascular, respiratory etc.) should be evaluated at each visit when a 
physical examination is performed and any abnormalities recorded. A complete physical exam 
includes assessments of cardiovascular, respiratory, and neurological systems as well as the 
examination of the abdomen, lymph nodes, spleen, skin, oropharynx and extremities.  As part of the 
tumor assessment, physical examination should also include the evaluation of the presence and 
degree of enlarged lymph nodes and splenomegaly.  For a lymph node to be considered enlarged, 
the longest diameter should measure > 1.5 cm. Spleen should be measured craniocaudal. 
In addition, baseline reason(s) for treatment initiation must be reviewed and documented at each 
visit (Day 1 of each cycle during the first 48 weeks [until C13D1), then every 3 cycles (every 
12 weeks), and at EOT and Safety Follow-up Visits).  Symptoms that triggered treatment will be 
followed until resolution(s) through the end of treatment.  
7.4.3 
ECOG Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed at the Screening Visit, 
each visit during study treatment, the End of Treatment Visit, and the Safety Follow-up Visit.  
Appendix 5 will be used to assess performance status. 
7.4.4 
Electrocardiogram  
A 12-lead ECG will be performed locally in triplicate at Screening for all subjects. Subjects should 
be in the semi-recumbent or supine position.   
For subjects assigned to the zanubrutinib arm, a 12-lead ECG in triplicate will be performed at pre-
dose (within 30 min prior to dose) and at 2 hours (± 30 min) post-dose on C1D1 and C2D1, and one 
12-lead ECG in triplicate performed at every 4 cycles thereafter (at C6D1, C10D1, etc.) until EOT.  
Where not specified, triplicate ECGs can be performed at either pre-dose or post-dose.   


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For subjects assigned to the ibrutinib arm, a 12-lead ECG in triplicate will be performed at C1D1, 
C2D1, and every 4 cycles thereafter (at C6D1, C10D1, etc) until EOT.  The triplicate ECGs can be 
performed at either pre-dose or post-dose.  
7.4.5 
ECHO/MUGA 
An ECHO/MUGA will be performed at the local lab at Screening, and when clinically indicated.  
7.4.6 
Quality of Life Assessment and Medical Resource Utilization 
Subject in Cohort 1 (MYD88MUT) must have quality of life assessed by EORTC QLQ-C30 and 
EQ-5D.  Assessments will occur on Cycle 1 Day 1 (pre-dose) and every 12 weeks during the first 
48 weeks, and then every 24 weeks thereafter.  In addition, in Cohort 1, medical resource utilization, 
including the number of hospitalizations, length of hospital stay, and supportive care (e.g., 
transfusions, growth factor support, intravenous antibiotics) will be evaluated every cycle, including 
at Screening and Cycle 1 Day 1. 
7.5 
Laboratory Evaluations 
Samples for CBC, Chemistry, and coagulation profiles will be drawn and analyzed locally. All other 
required blood samples (See Table 3) will be sent to central laboratory for analysis throughout the 
study.  Windows for assessments are outlined in Table 3.   
A detailed description of the procedures for sample collection, handling, storage, and shipment of 
the laboratory samples and all material such as test tubes and labels is provided in the Study 
Procedure Manual or in the Central Laboratory Manual. 
 
Clinical chemistry, CBC, coagulation, urinalysis, serum immunoglobulin, and β2-microglobulin, 
will be performed at the time points specified in Table 3 and may also be performed as medically 
necessary.  On Cycle 1 Day 1, laboratory assessments should be done before the study drug 
administration.  Screening blood and urine tests performed within 72 hours of the first study drug 
administration do not need to be repeated on Cycle 1 Day 1.   
7.5.1 
Hematology Studies 
CBC with differential is required to be performed every cycle during the Treatment Phase. CBC 
include hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white blood cell (WBC) 
count with differential including neutrophils (including bands), lymphocytes, monocytes, 
eosinophils, and basophils. In the event of neutropenia (absolute neutrophil count < 750/mm3) or 
thrombocytopenia (platelets of less than 50,000/mm3), these assessments will be conducted as 
frequently as the investigator feels it necessary until toxicity resolves to ≤ Grade 2 or baseline (ANC 
≥ 750/mm3). 


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7.5.2 
Clinical Chemistry 
Clinical chemistry includes albumin, alkaline phosphatase, AST, ALT, bicarbonate, blood urea 
nitrogen (BUN) or urea, calcium, chloride, creatinine, LDH, magnesium, phosphate, potassium, 
sodium, total bilirubin, total protein, and uric acid.  In the event of ≥ Grade 3 clinical chemistry 
toxicity, these assessments will be conducted as frequently as the investigator feels it necessary until 
toxicity resolves to ≤ Grade 2.  
7.5.3 
Quantitative Serum Immunoglobulins and β2-microglobulin 
Quantitative serum immunoglobulins (IgG, IgM, IgA) and β2-microglobulin will be measured at the 
Screening Visit, on Day 1 of every cycle for the first 48 weeks with Cycle 1 Day 1 sample drawn at 
pre-dose, then every 3 cycles during the Treatment Phase. If subjects discontinue study drug due to 
reasons other than PD, serum immunoglobulin (i.e., IgG, IgM, IgA) will continue to be followed 
every 12 weeks. If serum immunoglobulin and β2-microglobulin performed at the screening are 
performed within 14 days of the first administration of study drug, they do not need to be repeated 
on Cycle 1 Day 1. It is recommended that sequential response assessments for individual subjects 
are performed in the same laboratory using the same methodology.  
7.5.4 
Serum Immunoelectrophoresis with M-Protein Quantitation by Densitometry 
(SPEP) and Serum Immunofixation 
Serum immunoelectrophoresis with M-protein quantitation by densitometry (SPEP) and serum 
immunofixation will be performed at Screening, on Day 1 of every cycle for the first 48 weeks with 
Cycle 1 Day 1 sample drawn at pre-dose, then every 3 cycles during the Treatment Phase. If 
subjects discontinue study drug due to reasons other than PD, serum immunoelectrophoresis will 
continue to be followed every 12 weeks. If serum immunoelectrophoresis at the Screening is 
performed within 14 days of the first administration of study drug, it does not need to be repeated on 
Cycle 1 Day 1.  Additionally, see note below in Section 7.5.5 regarding retesting serum 
immunoglobulins in subjects with cryoglobulinemia. 
7.5.5 
Cold Agglutinins, Cryoglobulin, Anti-MAG, Serum Viscosity 
Cold agglutinins, cryoglobulin, anti-MAG (myelin associated glycoprotein), serum viscosity blood 
tests will be performed at Screening.  If there are abnormal findings for any of these laboratory 
assessments at Screening, follow-up is required every cycle for the first 48 weeks, then every 3 
cycles starting C13D1 and at time of suspected CR.  
Subjects who have cryoglobulinemia at Screening and are confirmed by the central test, should be 
tested for the presence of cryoglobulins at the local laboratory prior to C1D1.  The C1D1 sample 
will serve as the baseline.  Repeat testing is required at every visit at the local laboratory or central 
laboratory until cryoglobulin testing has normalized (negative result), and then be assessed every 3 
cycles and at time of suspected CR.  When samples are collected and tested at local laboratories, the 
local results should be recorded in the eCRF.  In addition, the serum immunoglobulins/SPEP and 


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serum immunofixation assays should also be retested prior to C1D1, using the residual cryoglobulin 
blood sample if available, at the local laboratory, which should be collected and processed similarly 
to the cryoglobulins under warm conditions.  Only when serum immunoglobulins cannot be 
quantified, the serum immunoelectrophoresis sample will need to be re-collected, processed, and 
analyzed at the local laboratory under warm conditions. If neither the local laboratory baseline 
serum IgM nor SPEP M-protein was available, then the central laboratory serum IgM should be 
collected in addition and may be used for response assessment throughout the study. If central 
serum IgM has shown to be reliable despite the cryoglobinemia, the local laboratory serum IgM 
may no longer be required.   
The samples (cryoglobulin and serum immunoglobulins) should always be collected and processed 
under warm conditions at the local or central laboratory throughout the study to ensure that the same 
methodology is used throughout the study.  The results of all local testing should be entered into the 
EDC once they are available.  If it is not possible to perform the cryoglobulin or serum 
immunoglobulin testing at the local laboratory, the Clinical Research Associate or BeiGene should 
be contacted as soon as possible.   
7.5.6 
Iron, Total Iron Binding Capacity (TIBC), and Ferritin Tests 
Iron, TIBC and ferritin tests will be performed at Screening only. If abnormal, iron supplementation 
should be provided per investigator’s discretion prior to initiation of study treatment. 
7.5.7 
Coagulation 
The coagulation profile includes prothrombin time (PT), which will also be reported as international 
normalized ratio (INR).  The coagulation profile will be performed at Screening only.   
7.5.8 
Urinalysis with Dipstick 
Urinalysis will be assessed using urine dipstick.  Urine microscopy will be performed if urine 
dipstick is abnormal (may be at investigator discretion except when urine protein ≥ 2+). Urinalysis 
includes pH, glucose, protein, ketones, bilirubin, blood, and specific gravity. If urine protein is ≥ 2+ 
by dipstick, a 24-hour urine for total protein and a random urine for total protein and creatinine will 
be obtained and evaluated. All these tests will be performed in local laboratory. 
7.5.9 
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 subject who is pregnant will not be 
eligible for the study.  Laboratory-based highly sensitive pregnancy tests (urine or serum) will be 
performed on Cycle 1 Day 1, and then on Day 28 of every cycle (which can be performed on Day 1 
of the following cycle).  Pregnancy tests must be continued every 4 weeks (cycle) for at least 90 
days after the last dose of study drug.  At the last dose of study drug, a serum pregnancy test is 
required (for practicality, it will be performed at End of Treatment Visit).  If a urine pregnancy test 


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is positive, it must be confirmed by a serum pregnancy test.  A subject who has a positive pregnancy 
test result at any time after the study drug administration will be immediately withdrawn from 
participation in the study.  
7.5.10 
HIV and Hepatitis B/C Testing 
Hepatitis B/C serologic markers and/or viral load will be tested at Screening.  The hepatitis B 
testing includes hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and 
hepatitis B surface antigen (HBsAg) as well as hepatitis B virus (HBV) DNA by polymerase chain 
reaction (PCR) if the subject is negative for HBsAg but HBcAb positive (regardless of HBsAb 
status). The hepatitis C testing includes Hepatitis C virus (HCV) antibody as well as HCV RNA by 
PCR if the subject is HCV antibody positive.  Subjects with positive HBsAg and/or detectable level 
of HBV DNA or detectable level of HCV RNA are not eligible.  Subjects HBsAg negative, HBcAb 
positive and HBV DNA negative must undergo monthly HBV DNA Screening PCR.  If, during 
monthly monitoring of HBV DNA by PCR, the value is between 20 IU/mL and 100 IU/mL then the 
HBV DNA level should be rechecked within 2 weeks.  Study drug should be held and anti-viral 
therapy initiated if the repeat level is between 20 IU/mL and 100 IU/mL.  If the HBV DNA by PCR 
is 100 IU/mL or higher then study drug should be stopped and anti-viral therapy initiated.  Subjects 
positive for HCV antibody but negative for HCV RNA must undergo monthly HCV RNA 
Screening.  Subjects with known HIV are excluded from the study.  Subjects with detected HCV 
RNA should stop study drug and anti-viral therapy should be initiated.  The Medical Monitor or 
designee should be informed of any suspected hepatitis B or hepatitis C reactivation. 
Table 5 below, shows how the results for HBV, and HBV testing at Screening relate to inclusion 
and exclusion criteria. 
 


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Table 5. 
Active hepatitis B (HBV) or hepatitis C (HCV) infection (detected positive by 
polymerase chain reaction [PCR])  
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA “Not detected”1 
 
Perform monthly monitoring of HBV DNA  
HBsAg (-) and HBcAb (+) 
HBV DNA detected1 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not detected” 1  
 
Perform monthly monitoring of HCV RNA  
Antibody (+) 
HCV RNA Detected1  
DNA: deoxyribonucleic acid; HBsAg: Hepatitis B surface antigen; HBcAb: Hepatitis B core antibody; HBV: Hepatitis B 
virus; HCV: Hepatitis C virus; RNA: ribonucleic acid 
1. 
Please refer to Section 7.5.10 above. 
7.6 
Pharmacokinetics 
Blood will be collected to characterize the PK of zanubrutinib and/or its major metabolites from all 
subjects on Arms A and C. Close monitoring of zanubrutinib drug concentrations may be needed by 
taking additional unscheduled PK samples in the event of suspected drug-drug interactions (eg, 
when a strong or moderate CYP3A inducer must be used for control of infection). 
7.6.1 
Pharmacokinetic Blood Samples 
Pharmacokinetic samples will be collected from subjects randomized to Arms A and C 
(zanubrutinib) only at the following time points: pre-dose (within 30 min prior to dose), 2 hours 
(± 30 min) post-dose and before subject discharge (3-6 h post-dose) on Cycle 1 Day 1 and Cycle 2 
Day 1. The time of study drug administration on the day prior to Cycle 2 Day 1 must be recorded on 
the eCRF. 
Blood samples (2 mL) for PK analysis will be collected via the intravenous cannula pre-dose and at 
the time points specified in Table 3.  The actual time each sample was collected will be captured to 
the nearest minute in the eCRF and recorded in the database. 
Details concerning handling of the PK plasma samples, including labeling and shipping instructions 
will be provided in the Study Manual.   
Samples will be shipped to the central laboratory where they will be stored and batch shipped to 
designated bioanalytical lab for quantification of plasma zanubrutinib concentrations using a 
validated method. 


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7.6.2 
Effects of Plasmapheresis on PK of Zanubrutinib 
For subjects receiving plasmapheresis (in Cycle 1 or Cycle 2 or beyond), below are additional 
procedures to follow: 
 Subjects are recommended to come in the clinic to receive zanubrutinib dosing on the day of 
plasmapheresis.  To properly assess the impact of plasmapheresis on zanubrutinib PK, 
plasmapheresis session is to commence between 2 to 3 hours (Tmax) following zanubrutinib 
dosing.  
 Zanubrutinib dosing time and the start and end time of each plasmapheresis session must be 
recorded in the database. 
 For subjects receiving plasmapheresis, additional PK samples (in addition to those noted in 
Section 7.6.1) will be collected at the following time points: immediately before the start of 
plasmapheresis, approximately an hour after the start of the procedure, and 30 min after the 
end of the procedure.  PK collection time will be recorded in the database. 
 For each plasmapheresis session, the volume of removed plasma will be measured and 
recorded in eCRF and an aliquot will be stored at a temperature of -20ºC or lower until 
analysis. 
 Zanubrutinib concentrations in both circulating and removed plasma will be measured using 
a validated method. 


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Additionally, the Sponsor would like to retain/archive/save any residual or extra samples that are 
not analyzed in Study BGB-3111-302 for additional exploratory 
 studies and analyses that 
may be conducted at a later time.  The samples will be used only for studies related to WM.  
The biological samples will be labeled with a unique code and be stored under BeiGene’s control 
for up to 20 years, at which point they will be destroyed. During and after the study, the subject has 
the right to have any remaining sample material destroyed by the Sponsor or returned to the 
subject’s Study Doctor at any time.  Any 
 generated from the additional research 
during the study or after the study is completed will belong to the Sponsor and will not become part 
of the patient’s medical record.  
Disclosure of any data obtained from the optional studies will be restricted.  Site monitors, auditors, 
ethics committees and/or regulatory authorities may also access the patient data in connection with 
such additional research. Patient data will be retained as long as it is useful for such purposes. If the 
results of such studies are published or presented in a meeting, the patient’s identity will not be 
disclosed. 
7.8 
Appropriateness of Measurements 
All safety and PK assessments used in this study are standard, and generally recognized as reliable, 
accurate, and relevant.  
 


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8 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.  Site audits will be made periodically by the sponsor’s or the contract research 
organization’s (CRO’s) qualified compliance auditing team, which is an independent function from 
the study team responsible for conduct of the study.   
8.1 
Data Collection 
Data required by the protocol will be collected on the eCRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by International 
Conference of Harmonisation (ICH) guidelines, the CRF is a printed, optical, or electronic 
document designed to record all of the protocol-required information to be reported to the sponsor 
on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 1572 
must sign the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs 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. 
8.2 
Data Management/Coding 
All software applications used in the collection of data will be properly validated following standard 
computer system validation that is compliant with all regulatory requirements.  All data, both CRF 
and external data (e.g., laboratory data), will be entered into a clinical system. 
The Data Management Plan defines and documents the procedures necessary to ensure data quality.  
These activities must be followed to ensure that data are properly entered, validated, coded, 
integrated, reconciled, and reviewed. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
Version 18.1 or higher.  Concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD).  Concomitant diseases/medical history will be coded 
using the MedDRA® Version 18.1 or higher. 
8.3 
Quality Assurance 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the sponsor may conduct a quality assurance audit.  Regulatory agencies may also 


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conduct a regulatory inspection of this study.  Such audits/inspections can occur at any time during 
or after completion of the study.  If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her 
time and the time of his/her personnel to the auditor/inspector to discuss findings and any relevant 
issues. 
 


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9 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the monitoring and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  During the study, when there is a 
safety evaluation, the investigator or study center personnel will be responsible for detecting AEs 
and SAEs, as detailed in this section of the protocol.  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. All AEs and SAEs will be followed until resolution, stabilization, the event is otherwise 
explained, or the subject is lost to follow-up. 
9.1 
Adverse Events 
9.1.1 
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 
medicinal product, whether or not considered related to the medicinal product. 
The investigator or designee will ask about adverse events by asking the following standard 
questions: 
 How are you feeling? 
 Have you had any medical problems since your last visit? 
 Have you taken any new medicines since your last visit? 
Examples of an AE include: 
 Worsening of chronic or intermittent pre-existing condition including an increase in severity, 
frequency, duration, and/or has an association with a significantly worse outcome.   
 New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study.  
 Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concurrent medication.  
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the AE or SAE.  The 
investigator will then record all relevant information regarding an AE or SAE in the eCRF.  
However, there may be instances when copies of medical records for certain cases are requested by 


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the sponsor.  In this instance, all subject identifiers will be blinded on the copies of the medical 
records prior to submission to the sponsor. 
9.1.1.1 
Assessment of Severity 
The investigator will make an assessment of severity for each AE and SAE reported during the 
study.  When applicable, AEs and SAEs should be assessed and graded based upon the 
NCI-CTCAE v4.03.  
Toxicities that are not specified in the NCI-CTCAE v4.03 will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
 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 9.2. 
9.1.1.2 
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 event to the study drug will be considered and 
investigated.  The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information to 
include in the initial report to the sponsor.  However, it is very important that the investigator 
always makes an assessment of causality for every event prior to transmission of the SAE report to 
the sponsor, 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.   


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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 (i.e., there are facts, evidence, or arguments to suggest possible 
causation). A number of factors should be considered in making this assessment, including:  
 Temporal relationship of the AE to the administration of study treatment/study procedure 
 Whether an alternative etiology has been identified  
 Mechanism of action of the study drug  
 Biological plausibility 
An AE should be considered ‘related’ to study drug if any of the following are met, otherwise the 
event should be assessed as not related: 
 There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out 
 There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely 
 There is some evidence to suggest a causal relationship (e.g., 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 (e.g., the subject’s clinical condition or other 
concomitant AEs). 
9.1.1.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each subject 
and provide further information to the sponsor on the subject’s condition. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, the subject is lost to follow-up, or the subject withdraws consent. The 
investigator will ensure that follow-up includes any supplemental investigations as may be indicated 
to elucidate the nature and/or causality of the AE or SAE.  This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the 
AE or SAE.  The investigator is obligated to assist.  If a subject dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
post-mortem findings, including histopathology.  


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New or updated information will be recorded on the originally completed SAE report form, with all 
changes signed and dated by the investigator.  The updated SAE report form should be resent to the 
sponsor within the time frames outlined in Section 9.2.2.1 and the eCRF should be updated 
accordingly.  
9.1.2 
Laboratory Test Abnormalities 
Abnormal laboratory findings (e.g., clinical chemistry, CBC, coagulation, urinalysis) or other 
abnormal assessments (e.g., ECGs, X-rays, vital signs, etc.) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE (as 
defined in Section 9.1.1) or an SAE (as defined in Section 9.2).  The definition of clinically 
significant abnormal laboratory findings is left to the judgment of the investigator.  In general, these 
are the laboratory test abnormalities that are associated with clinical signs or symptoms, require 
medical intervention, lead to dose interruption or discontinuation, require close observation, more 
frequent follow-up assessments, or require further diagnostic investigation.  The investigator will 
exercise his/her medical and scientific judgment in deciding whether an abnormal laboratory finding 
or other abnormal assessment is clinically significant. 
9.2 
Serious Adverse Events 
9.2.1 
Definitions 
An SAE is any untoward medical occurrence that, at any dose: 
 Results in death. 
 Is life-threatening.  
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
 Requires hospitalization or prolongation of existing hospitalization. 
NOTE:  In general, hospitalization signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out. 
 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 (e.g., sprained ankle) which may interfere or prevent everyday life functions, 
but do not constitute a substantial disruption. 


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 Is a congenital anomaly/birth defect. 
 Is considered a significant medical AE by the investigator based on medical judgment (e.g., may 
jeopardize the subject 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 consideration 
 Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience 
9.2.2 
Reporting 
9.2.2.1 
Timeframes for Submitting Serious Adverse Events  
Serious adverse events must be reported within 24 hours of investigator’s first knowledge to the 
sponsor as described in Table 6 once the investigator determines that the event meets the protocol 
definition of a SAE. 
Table 6. 
Timeframe for Reporting Serious Adverse Events to the Sponsor 
Type  
Timeframe for 
Initial SAE 
Report 
Documentation 
Method 
Timeframe for 
Follow-up SAE 
Report 
Documentation 
Method 
Reporting Method 
All SAEs  
Within 24 hours 
of first 
knowledge of the 
SAE 
SAE report form 
As expeditiously 
as possible 
Updated SAE 
report form 
Email or fax SAE 
report form*  
SAE:  Serious Adverse Event;  
*The SAE must also be reported in the EDC System by completing the electronic Case Report Form.  
9.2.2.2 
Completion and Transmission of the Serious Adverse Event Report Form 
Once an investigator becomes aware that an SAE has occurred in a subject, he/she will report the 
information to the sponsor within 24 hours as outlined in Section 9.2.2.1.  The SAE report form will 
always be completed as thoroughly as possible with all available details of the event, signed by the 
investigator (or designee), and forwarded to the sponsor or designee within the designated 
timeframes.  
If the investigator does not have all information regarding an SAE, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE and completing the 
form.  The form will be updated when additional information is received. 


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The investigator will always provide an assessment of causality for each SAE as described in 
Section 9.1.1.2. 
The sponsor will provide contact information for the SAE report form receipt. The SAE must also 
be reported in the EDC System by completing the electronic Case Report Form.  
9.2.2.3 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 9.2.2.2.  The sponsor has a legal responsibility to notify, as appropriate, both the 
local regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation.   
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  
When a study center receives an initial or follow-up safety report or other safety information (e.g., 
revised IB) from the sponsor, the investigator or designated responsible person according to local 
requirements is required to promptly notify his/her IRB or IEC.  
9.2.2.4 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last study treatment of zanubrutinib or ibrutinib. After this period, 
the investigator should report any SAEs that are believed to be related to prior study drug treatment. 
A post-study AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period 
defined above.  Investigators are not obligated to actively seek AEs or SAEs in former subjects.  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the SAE related to the study drug, the 
investigator will notify the sponsor. 
9.2.2.5 
Specific Instructions for Recording Adverse Events and Serious Adverse Events 
Disease Progression 
Disease progression (including fatal disease progression) is expected in this study population, and is 
measured as an efficacy endpoint, therefore should not be reported as an AE term. Instead, the 
signs, symptoms or clinical sequelae that result from disease progression should be reported as the 
AE term.   
For instance, a subject with pleural effusion presents with shortness of breath.  The cause of the 
shortness of breath is a pleural effusion resulting from disease progression.  The AE term should be 


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reported as “pleural effusion” instead of disease progression or metastasis to lungs.  If a subject has 
a seizure that is determined to be associated with a brain metastasis, the term “seizure” should be 
recorded as the AE instead of disease progression or brain metastasis.  If a subject experienced 
multi-organ failure due to disease progression, the term “multi-organ failure” should be reported as 
the AE instead of disease progression.   
Deaths that are assessed by the investigator as solely due to disease progression should be recorded 
on Study Completion or Early Discontinuation eCRF as efficacy data.  They should not be reported 
as an SAE. A patient death not solely due to disease progression, as assessed by the investigator, 
should be reported as an SAE immediately, regardless of relationship to the study drug. 
If there is any uncertainty regarding whether an AE is due to disease progression, it should be 
reported as an AE. 
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 should be reported as an event, e.g., “Death”, 
“Death of unknown cause”, or “Death unexplained.”  
9.2.2.6 
Serious Adverse Event Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests), even if it occurs 
during the post-treatment period, will be reported promptly to the sponsor (Section 9.2.2.2). 
9.2.2.7 
Expedited Reporting to Health Authorities, Investigator, Institutional Review 
Boards and Ethics Committees 
The sponsor will promptly assess all SAE against cumulative study drug experience to identify and 
expeditiously communicate new safety findings to health authorities, investigators, institutional 
review boards and ethics committees based on applicable legislation.  
To determine reporting requirements for individual adverse event cases, the sponsor will assess the 
expectedness of these events using the following reference documents: 
 Zanubrutinib (BGB-3111) Investigator’s Brochure 
 Local prescribing information for ibrutinib 
9.3 
Pregnancies 
A subject who has a positive pregnancy test result at any time after the study drug administration 
will be immediately withdrawn from participation in the study.  All post--study assessments will be 
collected at the time of discontinuation as described in Table 3. 
If a female subject or the partner of a male subject becomes pregnant while participating in this 
study, a pregnancy report form is required to be completed.  The investigator, or his/her designee, 
will record pregnancy information on the appropriate form and submit it to the sponsor within 2 


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weeks of learning of a subject’s or male subject’s female partner’s pregnancy.  The subject or male 
subject’s female partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to the sponsor.  Generally, 
follow-up- will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE, as 
described in Section 9.1 and Section 9.2 and will be followed as described in Section 9.1.1.3. 
An abortion, whether accidental, therapeutic or spontaneous, should always be reported as an SAE 
as described in Section 9.2.2.1.  Furthermore, any SAE occurring as a result of a post-study 
pregnancy and is considered reasonably related to the study drug by the investigator, will be 
reported to the sponsor as described in Section 9.2.2.2.  Similarly, any congenital anomaly/birth 
defect in a child born to a subject exposed to the study drug should be recorded and reported as an 
SAE.  
9.4 
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). 
9.5 
Data Monitoring Committee 
An independent DMC will monitor safety data periodically throughout the study.  An efficacy and 
safety interim analysis, which occurs approximately 6 months after the first 50 relapsed/refractory 
subjects randomized from Cohort 1, will be implemented in the study.  A stop in recruitment is not 
planned for this interim safety review. At regular safety reviews, data review will include but not be 
limited to deaths, SAEs, adverse events leading to dose reduction, dose interruption, or drug 
discontinuation. The DMC may recommend study modification, including termination of the study 
due to efficacy and/or safety concerns.  Subsequent safety data review is outlined in DMC charter.  
.  


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10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL 
PLAN 
All statistical analyses will be performed by the Sponsor or designee after the study is completed 
and the database is locked and released.   
Details of the statistical analyses will be included in a separate statistical analysis plan (SAP). 
10.1 Primary, Secondary and Exploratory Study Endpoints 
Please refer to Section 3 for a full listing of study endpoints. 
10.2 Statistical Analysis 
All inferential statistics described in this Section refer to the efficacy comparisons of Arms A and B 
in Cohort 1 which are the primary/secondary objectives of the study. Separate descriptive statistics 
in Cohort 2 will be used to report the efficacy of zanubrutinib in Arm C.   
10.2.1 
Analysis Sets   
The Intent to Treat analysis set (ITT) includes all enrolled subjects who are assigned to a treatment 
arm. The Relapsed/Refractory analysis set in Cohort 1 will be the primary analysis set used for 
efficacy analyses. 
The Relapsed/Refractory analysis set (a subset of the ITT analysis set) includes all randomized 
subjects with at least 1 prior line of therapy as determined by the IRT system. 
The Safety analysis set includes all subjects who received any dose of zanubrutinib or ibrutinib.  
Subjects will be assigned to the treatment arms as treated. The Safety analysis set will be used for 
all safety analyses. 
The Per-Protocol analysis set (PP) includes subjects who received any dose of study medication and 
had no major protocol deviations.  Criteria for exclusion from the PP analysis set will be determined 
and documented before the database lock for the primary analysis.  The PP analysis set will be the 
secondary analysis set for efficacy analyses. 
The PK analysis set includes all subjects who have at least one post-dose zanubrutinib 
concentration.  
10.2.2 
Subject Disposition 
The number of subjects enrolled, treated, prematurely discontinued from study drug (defined as 
those who discontinued study drug due to any reason except for progressive disease) and those with 
major protocol deviations will be counted by treatment arm.  The primary reason for study drug 
discontinued will be summarized according to the categories in the eCRF.  The end of study status 


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(alive, dead, withdrew consent or lost to follow-up) at the data cutoff date will be summarized using 
the data from the eCRF. 
Major protocol deviations will be summarized and listed by each category. 
10.2.3 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by treatment arm in ITT and 
Safety analysis sets using descriptive statistics.  Continuous variables include age, weight, vital 
signs, time since initial WM diagnosis; categorical variables include sex, age group (< 65 vs. ≥ 65 
years), race, disease stage, ECOG-PS, prior line of therapy for WM (0 vs. 1-3 vs. >3 prior 
therapies), geographic region, MYD88/CXCR4 gene mutation status, presence of extramedullary 
disease (yes vs. no), baseline bone marrow involvement (< 50% vs. ≥ 50%), WM IPSS (low, 
intermediate, high), and β2 microglobulin (≤3 mg/L, vs. >3 mg/L). 
10.2.4 
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 (ATC) code indicating therapeutic classification.  Prior and 
concomitant medications will be summarized and listed by drug and drug class in the CSR for this 
protocol.  Prior medications will be defined as medications that stopped before the first dose of 
study drug.  Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  A listing 
of prior and concomitant medications will be included in the CSR of this protocol. 
10.2.5 
Efficacy Analyses 
10.2.5.1 
Primary Efficacy Analysis 
Comparison of the primary endpoint CR/VGPR rate in Cohort 1 assessed by independent review 
committee will be tested using hierarchical fixed-sequence procedure under the null and alternative 
hypotheses as follows: 
H0: RRA=RRB 
Ha: RRA>RRB 
where RRA is the CR/VGPR rate in Arm A (zanubrutinib) and RRB is the CR/VGPR rate in Arm B 
(ibrutinib).   
Testing for above hypotheses will be performed in the Relapsed/Refractory analysis set first at 
1-sided alpha of 0.025.  If the result is in the Relapsed/Refractory analysis set is statistically 
significant, the primary objective has been met and further testing will be performed in the ITT 
analysis set at 1-sided alpha of 0.025. 


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A Cochran-Mantel-Haenszel (CMH) test of rate difference based on CXCR4 status (WHIM vs 
WT/missing) and prior line of therapy (1-3 vs. >3 for Relapsed/Refractory analysis set analysis and 
0 vs 1-2 vs >3 in ITT analysis) will be performed for hypothesis testing at the 0.025 level (1-sided) 
in the corresponding analysis set of Cohort 1.   
A CMH 95% stratified confidence interval (CI) of rate difference (RRA-RRB) with each rate 
weighted by number of subjects in each stratification factor combination will be constructed for the 
Relapsed/Refractory analysis set and the ITT analysis set, respectively. A Clopper-Pearson 95% CI 
of CR/VGPR rate within each arm will be constructed for the Relapsed/Refractory analysis set and 
the ITT analysis set, respectively. 
The primary efficacy analysis in Cohort 1 will be conducted approximately 12 months after the 
cohort assignment of the last subject.   
Sensitivity analysis of the primary endpoint will be performed using investigator assessment. An 
unstratified analysis using exact method will also be performed in the sensitivity analysis.  
10.2.5.2 
Secondary Efficacy Analysis 
If the primary efficacy analysis is statistically significant in Cohort 1, secondary endpoints will be 
tested in the analysis set where the null hypothesis for primary efficacy endpoint is rejected. 
MRR 
MRR will be tested for non-inferiority of Arm A vs Arm B.  The null and alternative hypotheses of 
MRR are set as follows: 
H0: MRRA-MRRB≤-8% 
Ha: MRRA- MRRB>-8% 
where MRRA is the major response rate in Arm A (zanubrutinib) and MRRB is the major response 
rate in Arm B (ibrutinib) based on respective analysis sets.   
MRR will be compared between Arms A and B.  It will be analyzed using the same methods as 
described in the primary endpoint.  A Cochran-Mantel-Haenszel (CMH) test of rate difference 
adjusting for stratification factors (CXCR4 status [WHIM vs WT/missing] and prior line of therapy 
[1-3 vs >3 for Relapsed/Refractory analysis set analysis and 0 vs 1-2 vs >3 in ITT analysis set 
analysis]) will be performed at the 0.025 level (1-sided).  Equivalently, the 2-sided 95% CI for the 
weighted rate difference (weighted by the number of subjects in each stratification factor 
combination) will be constructed to examine whether it excludes -8%.  Furthermore, superiority can 
be claimed if the lower limit excludes 0.    


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Justification of non-inferiority margin 
The same non-inferiority margin will be used for both ITT and Relapsed/Refractory analysis sets. 
Since no randomized trial has been conducted in WM, the ibrutinib treatment benefit over placebo 
can only be estimated from the single-arm ibrutinib Phase 2 trial in which the MRR is 0.73 with 
95% CI (0.60, 0.83).  As a ≥ 50% reduction of IgM is impossible without treatment, MRR can be 
considered 0% in the placebo treated subject.  Therefore, the lower bound of 95% CI (i.e., 60%) can 
be used as the treatment effect of ibrutinib over placebo (M1).  A NI margin of 8% (M2) is 
proposed assuming 86.7% of the ibrutinib benefit over a placebo is retained. With close to 90% of 
the ibrutinib effect preserved, the 8% NI margin in MRR is clinically justified.  The loss of the 
ibrutinib treatment benefit is well within the clinically acceptable range.  It is worth noting that the 
NI of MRR will only be performed after the superiority of zanubrutinib over ibrutinib in CR/VGPR 
rate, which is closely correlated with MRR, has been demonstrated.  Hence, a numerically higher 
MRR in zanubrutinib is certainly expected if the NI test of MRR is to be performed.  The inclusion 
of the NI test of MRR is mainly based on the sample size consideration in a rare disease setting 
where statistical significance might not be shown in a superiority test with a clinically meaningful 
MRR difference (e.g., 12% higher MRR in zanubrutinib over ibrutinib) in 150 randomized 
relapsed/refractory subjects. 
Best overall response (BOR) which is defined as the best response recorded from cohort assignment 
date until data cut or start of new antineoplastic treatment.  Subjects with no post-baseline response 
assessment (regardless of reason) will be considered non-responders for best overall response.  The 
proportion and its corresponding Clopper-Pearson 95% CI for each of the response categories (CR, 
VGPF, PR, Minor Response, SD, and PD) will be presented. 
Other secondary endpoint analyses: 
Progression-free survival (PFS) will be analyzed at the time of the primary analysis of VGPR/CR 
rate. In addition, subjects will continue to be followed for PFS events after the primary analysis of 
VGPR/CR tate, until the final analysis of PFS. During this period, the sponsor will keep maintaining 
trial integrity according to the Data Integrity Protection Plan (DIPP). Timing of the final analysis of 
PFS will be specified in the statistical analysis plan. 
Distribution of PFS will be estimated using the Kaplan-Meier (KM) method per treatment arm.  PFS 
censoring rule will follow FDA Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007). 
A stratified log-rank test with CXCR4 and prior line of therapy as strata (CXCR4 status [WHIM vs 
WT/missing] and prior line of therapy [1-3 vs. >3 for Relapsed/Refractory analysis set analysis and 
0 vs 1-2 vs >3 in ITT analysis set analysis]) will be used to test the PFS differences between Arms 
A and B.  The Cox regression will be used to estimate the hazard ratios (HR) of PFSA vs PFSB.  A 
95% CI of HR in PFS will be constructed.   


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Median PFS, if estimable, will be estimated using the KM method.  Its 2-sided 95% CIs, if 
estimable, will be constructed with a generalized Brookmeyer and Crowley method.  KM estimates 
of PFS will be plotted over time.  The PFS rate at selected timepoints such as, 12, 18 and 36 
months, defined as the percentages of subjects in the analysis set who remain alive and progression-
free at the specified time points, will be estimated using KM method along with the corresponding 
95% CI constructed using Greenwood’s formula.  
For responders with PR or above, the duration of CR/VGPR/PR within subjects who have achieved 
major response will be analyzed similarly as PFS. 
Indications for initiation of therapy (see Table 4) will be documented for all subjects at baseline 
visit.  Symptoms that triggered treatment will be followed at during and end of treatment visits until 
resolution. Percentages of subjects with resolution of each and all baseline symptom(s) will be 
summarized; and compared between Arms A and B using Fisher’s exact test. 
Maximum decrease in percentage of lymphoplasmacytoid lymphocytes in bone marrow will be 
compared using analysis of variance model with treatment arm (A vs. B) as group variable. 
Percentage of subjects with decreased percentage of lymphoplasmacytoid lymphocytes after the 
start of study medication will also be compared using Fisher’s exact test. Percentages of subjects 
with resolution and/or reduction of pretreatment lymphadenopathy and/or splenomegaly according 
to CT scan will be summarized separately; and compared using Fisher’s exact test. 
10.2.5.3 
Exploratory Efficacy Analysis 


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10.2.6 
Pharmacokinetic Analyses 
PK analysis set will be carried out to include plasma concentrations from this trial in an existing 
model.  PK parameters such as Cmin will be summarized, and additional PK parameters such as 
apparent clearance of the drug from plasma (CL/F) and area under the plasma concentration-time 
curve (AUC[0-24]) may be derived from the PK analysis set if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
The impact of plasmapheresis on zanubrutinib exposure will be estimated by comparing the AUC of 
zanubrutinib in subjects with or without the plasmapheresis procedure.   
10.2.7 
 
The mutational status of the MYD88 and CXCR4 genes has been shown to predict responsiveness of 
the BTK inhibitor ibrutinib in WM (Treon et al. 2015a).  All subjects will have sequencing of 
MYD88 and CXCR4 performed on bone marrow samples which will be sent to the central laboratory 
for analysis. 
10.3 Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (CBC, clinical chemistry, coagulation, and urinalysis), vital, physical exams and 
ECGs findings will also be used in determining the safety.  Descriptive statistics will be used to 
analyze all safety data by treatment arm, as well as by combining Arms A and C in the Safety 
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10.3.1 
Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the number of cycles received 
(number and percentage of subjects), duration of exposure (days), cumulative total dose received 
per subject (mg), dose intensity (mg/day) and relative dose intensity. 
The number (percentage) of subjects requiring dose reductions, dose interruption, and drug 
discontinuation due to AEs will be summarized.  The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics.  Frequency of 
reductions and dose interruptions will be summarized by categories.  
Subject data listings will be provided for all dosing records and for calculated summary statistics. 
10.3.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into standardized 
medical terminology using Medical Dictionary for Regulatory Activities (MedDRA®).  Adverse 
events will be coded to MedDRA® (Version 18.1 or higher) lower level term closest to the verbatim 
term.  The linked MedDRA® preferred term (PT) and primary system organ class (SOC) are also 
captured in the database. 
A TEAE is defined as an AE that had an onset date on or after the first dose of study drug up to 
30 days following study drug discontinuation or was worsening in severity from baseline 
(pretreatment) or initiation of new anticancer therapy, whichever comes first.  Only those AEs that 
were treatment emergent will be included in summary tables.  All AEs, treatment emergent or 
otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once by the highest severity grade according to 
NCI-CTCAE v4.03 within an SOC and PT, even if the subject experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by relationship to the study drug.  Treatment-related AEs include those events 
considered by the investigator to be related to study drug or with missing assessment of the causal 
relationship.  Serious adverse events, deaths, TEAE with grade 3 or above, related TEAE and 
TEAEs that led to treatment discontinuation, dose reduction or dose interruption will be 
summarized. 
10.3.3 
Laboratory Analyses 
Clinical laboratory (i.e., CBC, serum chemistry, and qualitative urinalysis) values will be evaluated 
for each laboratory parameter by treatment arm.  Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range.  Reference (normal) ranges for 
laboratory parameters will be included in the CSR for this protocol.  Descriptive summary statistics 
(e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 


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categorical variables) for laboratory parameters and their changes from baseline will be calculated.  
Laboratory values will be summarized by visit and by worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE 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 (e.g., calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
10.3.4 
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 visit and treatment arm for all 
visits.  Vital signs will be listed by subject and visit. 
10.3.5 
Electrocardiogram 
Descriptive statistics for baseline ECG parameters will be presented. 
10.4 Sample Size Consideration 
The sample size calculation is based on the comparison of the primary endpoint CR/VGPR rate in 
the Relapsed/Refractory analysis set in Cohort 1.  Assuming RRA=0.35 and RRB=0.15, seventy-five 
subjects per arm (150 total) provide a power of 0.814 in testing RRA versus RRB in the 
Relapsed/Refractory analysis set in Cohort 1 using a normal approximation to binomial test with a 
two-sided significance of 0.05.  Assuming MRRA=0.90 and MRRB=0.80, the power of 
demonstrating non-inferiority of zanubrutinib in the Relapsed/Refractory analysi set is 85.5% when 
a NI margin of 0.08 is used.   
In addition to 150 replased/refractory subjects, approximately 20% (38) treatment-naïve subjects 
with MYD88MUT will be enrolled in Cohort 1.  
Assuming MYD88MUT mutation is present in 90% of the enrolled subjects, a total of approximately 
210 subjects will be enrolled in Cohort 1 and Cohort 2 combined. 
10.5 Interim Analysis 
An interim analysis, which occurs approximately 6 months after the first 50 relapsed/refractory 
subjects are randomized from Cohort 1, will be implemented in the study.  This analysis is for 
futility only. No recruitment stop is planned for this interim analysis. If futility is demonstrated in 
the interim analysis, enrollment will be halted and safety and efficacy data will be further evaluated 
before making the decision of stopping the study permanently. Otherwise, the enrollment will be 
continued to 150 relapsed/ refractory subjects in Cohort 1.  Details of the interim analysis will be 
provided in the SAP. 


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10.6 Other Statistical Issues 
In the analyses described above and any other sensitivity analysis, subjects with missing data will be 
considered as non-responders and will be included in the denominator when calculating CR/VGPR 
rate, MRR and ORR.  Non-responders of the response categories will be excluded in the 
corresponding analysis of duration of response. A final analysis prior to study termination will be 
performed.  The time and scope of the final analysis will be included in the SAP.  
Any other statistical/ analytical issues will be discussed in the SAP. 


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11 
STUDY ADMINISTRATION AND INVESTIGATOR 
OBLIGATIONS 
11.1 Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2 Investigator Responsibilities 
11.2.1 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” ICH guidelines, and that the basic principles of “Good Clinical Practice,” 
as outlined in 21 Code of Federal Regulations (CFR) 312, Subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, Part 50, and 21 CFR, Part 56, are adhered to. 
Investigators and all sub-investigators must provide documentation of their financial interest or 
arrangements with BeiGene, or proprietary interests in the drug being studied.  This documentation 
must be provided before participation of the investigator and any sub-investigator.  The investigator 
and sub-investigator agree to notify BeiGene or its authorized representative of any change 
reportable interests during the study and for 1 year following completion of the study.  Study 
completion is defined as the date that the last subject has completed the protocol defined activities. 
11.2.2 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted by the principal investigator and the study center in accordance with 
GCP and all applicable regulatory requirements, including, where applicable, current version of the 
Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s informed consent form, and any other information that will be presented to potential 
subjects (e.g., advertisements or information that supports or supplements the informed consent) are 
reviewed and approved by the appropriate IEC/IRB.  The IEC/IRB must be constituted in 
accordance with all applicable regulatory requirements.  The sponsor will provide the investigator 
with relevant document(s)/data that are needed for IEC/IRB review and approval of the study.  
Before the study drug(s) can be shipped to the study center, the sponsor or its authorized 
representative must receive copies of the IEC/IRB approval, the approved informed consent form, 
and any other information that the IEC/IRB has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has approved 
for presentation to potential subjects is amended during the study, the investigator (or sponsor, 
where applicable) is responsible for ensuring the IEC/IRB reviews and approves, where applicable, 


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these amended documents.  The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form including obtaining IEC/IRB approval 
of the amended form before new subject consent to take part in the study using this version of the 
form.  Copies of the IEC/IRB approval of the amended informed consent form/other information 
and the approved amended informed consent form/other information must be forwarded to the 
sponsor promptly. 
11.2.3 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and before undertaking any study-related procedures.  The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent.  Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent. 
Informed consent will be obtained before the subject can participate in the study.  The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
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 patients’ clinical record. Informed consent may be obtained before 
the 35-day Screening period.  Consent must be obtained using the most current version of the form 
approved by the ethics committee. 
Repeating Screening procedures or tests are allowed if the patient did not previously meet the 
inclusion and exclusion criteria or if needed to have a documented result within the protocol-
specified Screening window.  The maximum number of repeats for a failed screening test is one 
within the screening window, and a patient may be re-screened no more than once. 
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. 
11.2.4 
Investigator Reporting Requirements 
As indicated in Section 9.1, 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. 


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11.2.5 
Confidentiality 
Information on maintaining subject confidentiality and privacy in accordance to individual local and 
national subject privacy regulations must be provided to each subject as part of the informed 
consent form process, either as part of the informed consent form (ICF) or as a separate signed 
document (for example, in the US, a site-specific HIPAA consent may be used). The investigator 
must assure that subjects’ anonymity will be strictly maintained and that their identities are 
protected from unauthorized parties.  Only subject initials (if allowed), date of birth (as permitted by 
local law), and an identification code (i.e., 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 subjects screened and for all subjects enrolled in the 
trial. 
The investigator agrees that all information received from BeiGene, including but not limited to the 
IB, this protocol, CRFs, the investigational new drug, and any other study information, remain the 
sole and exclusive property of BeiGene during the conduct of the study and thereafter.  This 
information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from BeiGene.  The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
11.2.6 
Case Report Forms 
For each subject enrolled, a CRF must be completed and signed by the principal investigator or sub-
investigator within a reasonable time period after data collection.  This also applies to records for 
those subjects who fail to complete the study (even during a pre-randomization Screening period if a 
CRF was initiated).  If a subject withdraws from the study, the reason must be noted on the CRF.  If 
a subject is withdrawn from the study because of a treatment limiting- AE, thorough efforts should 
be made to clearly document the outcome. 
The CRFs exist within an electronic data capture (EDC) system with controlled access managed by 
BeiGene or its authorized representative for this study. Study staff will be appropriately trained in 
the use of CRFs and applications of electronic signatures before the study start and before being 
given access to the EDC system. Original data and any changes of data will be recorded using the 
EDC system, with all changes tracked by the system and recorded in an electronic audit trail. The 
Investigator attests that the information contained in the CRFs is true by providing an electronic 
signature within the EDC system. After final database lock, the Investigator will receive a copy of 
the subject data from that site (e.g., paper, CD, or other appropriate media) for archiving the data at 
the study site.  


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11.2.7 
Drug Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability of 
all used and unused study drug.  This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition), subject dispensing records and returned or destroyed study 
product.  Dispensing records will document quantities received from BeiGene, quantities dispensed 
to subjects, including lot number, date dispensed, subject identifier number, subject initials (if 
allowed), the initials of the person dispensing the medication, and quantities destroyed or returned 
to BeiGene. At study initiation, the monitor will evaluate the site’s standard operating procedure for 
study drug disposal/destruction in order to ensure that it complies with BeiGene requirements.  At 
the end of the study, following final drug inventory reconciliation by the monitor, the study site will 
dispose of and/or destroy all unused study drug supplies, including empty containers, according to 
these procedures.  If the site cannot meet BeiGene’s requirements for disposal, arrangements will be 
made between the site and BeiGene or its representative for destruction or return of unused study 
drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
Study Monitor over the course of the study.  A patient diary will be provided to each subject to 
record the study drug dose taken each day. Any missed doses with explanation should be recorded 
in the diary. The diary should be returned to the site personnel for review, and will be reviewed by 
the Study Coordinator on a regular basis. 
11.2.8 
Inspections 
The investigator should understand that the facilities used for this trial and all source documents for 
this trial should be made available to appropriately qualified personnel from BeiGene or its 
representatives, to IRBs/IECs, or to regulatory authority or health authority inspectors. 
11.2.9 
Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators ascertain they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to BeiGene. 
11.3 Sponsor Responsibilities 
11.3.1 Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
initiated only by BeiGene. All protocol modifications must be submitted to competent authorities and 
to the IRB/IEC together with, if applicable, a revised model ICF in accordance with local 
requirements. Written documentation of competent authorities (as applicable according to local 
requirements), IRB/IEC and required site approval must be obtained by the sponsor before changes 
can be implemented. 


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Information on any change in risk and /or change in scope must be provided to subjects already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming willingness to remain in the trial. 
11.3.2 
Study Report and Publications 
A CSR will be prepared and provided to the regulatory agency(ies).  BeiGene will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study 
Reports (ICH E3).  Note that an abbreviated report may be prepared in certain cases. 
As this is a multi-center study, the first publication or disclosure of study results shall be a complete, 
joint multi-center publication or disclosure coordinated by the sponsor.  Thereafter, any secondary 
publications will reference the original publication(s). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications and presentations 
(both oral and written) to the sponsor for review before submission or presentation in accordance 
with the clinical study agreement. This allows the sponsor to protect proprietary information, 
provide comments based on information from other studies that may not yet be available to the 
investigator, and ensure scientific and clinical accuracy. 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.  
If a written contract for the conduct of the study, which includes publication provisions inconsistent 
with this statement is executed, that contract’s publication provisions shall apply rather than this 
statement.  
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. 
 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 temporarily suspend or prematurely discontinue this 
study either at a single study center or at all study centers at any time for reasons including, but not 
limited to, safety or ethical issues or severe non-compliance with this protocol, GCP, the clinical 
study agreement or applicable laws and regulations.  If the sponsor determines such action is 


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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 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 
11.5.1 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified.  These documents should be 
classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB/IEC, 
and governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Subject clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs) would include (although not be limited to) the 
following: subject hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, Screening ECHO/MUGA, 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 (e.g., 
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 (e.g., 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 


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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 subject, 
appropriate copies should be made for storage outside of the site. 
Provision of Study Results and Information to Investigators 
When the CSR 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 subject(s). 
The sponsor will not routinely inform the investigator or subject the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will be undetermined at such an early stage of research.   
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 subject’s medical records) is the sole property of the sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial property 
rights which are conceived or reduced to practice by the study center personnel during the course of 
or as a result of the study are the sole property of the sponsor, and are hereby assigned to the 
sponsor. 
If a written contract for the conduct of the study which includes ownership provisions inconsistent 
with this statement is executed between the sponsor and the study center, that contract’s ownership 
provisions shall apply rather than this statement. 


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All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a subject’s medical records) will be kept by the investigator and 
other study center personnel.  This information and data will not be used by the investigator or other 
study center personnel for any purpose other than conducting the study.   
These restrictions do not apply to: 
 Information which becomes publicly available through no fault of the investigator or study 
center personnel. 
 Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study. 
 Information which is necessary to disclose in order to provide appropriate medical care to a 
subject. 
 Study results which may be published as described in Section 11.3.2. 
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 ICH GCP guidelines, the Study Monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the CRFs for 
consistency. 
The monitor is responsible for routine review of the CRFs at regular intervals throughout the study 
to verify adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them.  The monitor should have access to any subject records needed to verify the 
entries on the CRFs.  The investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
11.7.2 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any time 
during or after completion of this clinical study.   If the investigator is notified of an inspection by a 
regulatory authority the investigator agrees to notify the sponsor or its designee immediately.  The 
investigator agrees to provide to representatives of a regulatory agency or BeiGene access to 
records, facilities, and personnel for the effective conduct of any inspection or audit. 
 


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12 
REFERENCES 
BeiGene Investigator’s Brochure, BGB-3111. Edition 3, document number BGB-3111‑012016, 
January 2016. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time.  Biometrics.  1982; 
38(1): 29-41. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  Nephron.  
1976;16(1):31-41. 
Dimopoulos, MA, Kastritis E, Owen RG, Kyle RA, Landgren O, Morra E, et al.  Treatment 
recommendations for patients with Waldenström’s macroglobulinemia (WM) and related disorders: 
IWWM-7 consensus.  Blood. 2014; 124: 1404-1411. 
Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI.  New York Heart Association.   Criteria 
Committee.  Nomenclature and criteria for diagnosis of diseases of the heart and great vessels.  9th ed. 
Boston, MA:  Lippincott Williams and Wilkins; March 1, 1994. 
European Medicines Agency Committee for Medicinal Products for Human Use (CHMP).  
Scientific Conclusions and grounds for the variation to the terms of the marketing authorization(s).  
Active substance(s): ibrutinib.  EMA/CHMP/644858/2017; 22 June 2017. 
European Medicines Agency guidance on evaluating PK of investigational drugs in patients with 
impaired renal function:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162133.pdf; 
20 February 2014. 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine.  http://medicine.iupui.edu/flockhart/table.htm 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research (2007). FDA Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics (2007).  
Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers. 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm
093664.htm 
Food and Drug Administration Guidance for Industry:  E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073153.pdf 
Food and Drug Administration Guidance on Evaluating PK of investigational drugs in patients with 
impaired renal function:  http://www.fda.gov/downloads/Drugs/.../Guidances/UCM204959.pdf; March 
2010. 
Gertz MA, Fonseca R, Rajkumar SV. Waldenström’s Macroglobulinemia. Oncologist. 
2000;5:63-67. 
Gertz MA. Waldenström macroglobulinemia: 2015 update on diagnosis, risk stratification, and 
management.  Am. J. Hematol.  2015;90:347–354. 


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Jacobson CA, Freedman AS. First-line treatment of indolent lymphoma: axing CHOP?   Lancet. 
2013;381:1163.  http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)62016-4.pdf 
Imbruvica® (Ibrutinib) Prescribing Information, August 2018.  
https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-information.pdf  
Metabolism and Transport Drug Interaction Database, University of Washington, Department of 
Pharmaceutics https://www.druginteractioninfo.org/  
Morel P, Duhamel A, Gobbi P, Dimopoulos MA, Dhodapkar MV, McCoy J, et al. International 
prognostic scoring system for Waldenström macroglobulinemia.  Blood.  2009;113(18):4163-70. 
National Cancer Institute Common Toxicity Criteria Version 4.03. Cancer Therapy Evaluation 
Program. 14 June 2010. 
National Comprehensive Cancer Network (NCCN) Guidance Insights, JNCCN. 2012; 
10:1211-1218. 
NCCN Guidelines, Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia 2015: v2. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655. 
Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al.  Response assessment in 
Waldenström macroglobulinaemia: update from the VIth International Workshop.  Br J of 
Haematol.  2013;160:171-176. 
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al.  
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with 
indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-
inferiority trial.  Lancet.  2013;381:1203–10. 
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 (14th International Conference on Malignant Lymphoma presentation, Abstract #237). 
Hematol Oncol. 2017;35(S2):234-5. 
Szende A, Oppe M, Devlin N. (Eds.)  EQ-5D Value Sets: Inventory, Comparative Review and User 
Guide. Springer 2007. 
Tam CS, Trotman J, Simplson D, et al. Pooled analysis of safety data from zanubrutinib (BGB 
3111) monotherapy studies in hematologic malignancies. European Hematology Association 
Learning Center. June 15, 2018; 214907, Abstract PF445. 
Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al.  Ibrutinib in Previously Treated 
Waldenström’s Macroglobulinemia.  N Engl J Med.  2015a;372:1430-40. 
Treon SP, Xu L, Hunter Z.  MYD88 Mutations and Response to Ibrutinib in Waldenström’s 
Macroglobulinemia. N Engl J Med.  2015b; 373:584-85. 
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y,et al.  MYD88 L265P somatic mutation in 
Waldenström’s Macroglobulinemia.  N Engl J Med.  2012; 367:826-33. 
 


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13 
APPENDICES 
 
 


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Appendix 1: 
Signature of Investigator 
 
PROTOCOL TITLE: 
A Phase 3, Randomized, Open-Label, Multicenter Study Comparing 
the Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) 
Inhibitors BGB-3111 and Ibrutinib in Subjects with Waldenström’s 
Macroglobulinemia (WM)  
PROTOCOL NO: 
 
BGB-3111-302 
This protocol is a 
 communication of BeiGene USA, Inc.  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 USA, Inc. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and the 
name of the center in which the study will be conducted.  Return the signed copy to PAREXEL International 
(IRL), Limited. 
 
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: 
WM Response Assessment  
Categorical Response Definitions  
IWWM-6 “IgM-based” without consideration of EMDa (Modified Owen 2013) 
Response category 
Definition 
Complete response (CR) 
Normal serum IgM values  
Note: An IgM/ SPEP M protein level obtained within 4 weeks 
post-plasmapheresis cannot be used to determine a response of 
CR 
 
• Disappearance of monoclonal protein by immunofixation  
Note: If immunofixation status is not reported/not interpretable 
for any available timepoints, the best possible response is 
VGPR. One negative immunofixation is sufficient to be called 
CR for a particular visit. Once a negative immunofixation has 
been reported for a visit, any subsequent visits with 
immunofixation status not reported or not interpretable can be 
CR as long as all remaining data supports a continued CR 
status 
Negative cryoglobulinemia if cryoglobulinemia was Positive at 
baseline. Otherwise, if cryoglobulinemia was negative or not 
available at baseline, a negative cryoglobulinemia assessment at 
post-baseline is not required for an overall timepoint assessment 
of CR. 
Very good partial response (VGPR) 
≥90% reduction in serum IgM level from baseline or normal 
serum IgM values 
Partial response (PR) 
≥50% reduction of serum IgM from baseline  
Minor response (MR) 
At least 25% but <50% reduction of serum IgM from baseline  
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR, MR, or progressive 
disease 
Progressive disease (PD) 
Confirmed ≥25% increase in serum IgM and total increase of 
≥500 mg/dL from nadir (on treatment)b,c 
a IgM assessment should be made incorporating only IgM-related clinical data including IgM, M protein 
(SPEP/paraprotein), serum immunofixation, plasmapheresis, cryoglobulinemia and drug hold, as applicable.  If the 
patient has developed new symptomatic disease attributable to WM, the overall response will be assessed as disease 
progression. 
b Sequential changes (separated by at least 4 weeks) in IgM levels should be determined by the IgM value from the 
quantitative serum immunoglobulin assay, unless for assay limitations this is not possible, in which case the M-protein 
level by densitometry (SPEP) will be used 
c If there is a rapid rise in serum IgM level or an increase in known extramedullary disease leading to an “apparent” 
response of PD (e.g. there is an increase in IgM level of at least 25% and 500 mg/dL from nadir) after the study drug has 
been held for at least 7 consecutive days, an assessment of IgM flare will be assigned instead of PD. The period to 
which this is applicable begins on the day of the first missed dose and ends when the subject has IgM levels or 
extramedullary disease that no longer qualify as “apparent” PD or the subject has a confirmed response of PD*, 
whichever comes first.  Please see Guidelines for specific clinical or laboratory circumstances and timing below. 
 


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Categorical Response Definitions  
IWWM-6 Including EMD (Modified Owen 2013) 
Response category 
Definition 
Complete response (CR) 
Normal serum IgM values  
• Disappearance of monoclonal protein by immunofixation  
• No histological evidence of bone marrow involvement  
• Complete resolution of lymphadenopathy/splenomegaly (if 
present at baseline)a,d  
Very good partial response (VGPR) 
Monoclonal IgM protein is detectable 
≥90% reduction in serum IgM level from baselinea or normal 
serum IgM values 
Improvement in extramedullary disease, 
lymphadenopathy/splenomegaly if present at baseline a,d 
No new signs or symptoms of active disease 
Partial response (PR) 
• ≥50% reduction of serum IgM from baseline 
• Reduction in lymphadenopathy/splenomegaly (if present at 
baseline) a,d  
Minor response (MR) 
At least 25% but <50% reduction of serum IgM from baseline  
Stable disease (SD) 
• Not meeting criteria for CR, VGPR, PR, MR, or progressive 
disease 
Progressive disease (PD) 
At least one of the following:  
• Confirmed ≥25% increase in serum IgM and total increase of 
≥500 mg/dL from nadir (on treatment)b,c 
• New lymph nodes >1.5 cm, or ≥50% increase from nadir in 
sum product of diameter (SPD) of >1 node, or ≥50% increase in 
longest diameter of a previously identified node 
• New splenomegaly or ≥50% increase from nadir in 
enlargement  
• New extranodal disease 
• New or recurrent involvement in bone marrow 
• New symptomatic disease 
a For response assessments that occur during cycles where a CT scan is not required then results from prior scans (up to 
12 weeks during the first 48 weeks and up to 24 weeks thereafter) can be carried forward in those subjects with 
extramedullary disease at baseline 
b Sequential changes (separated by at least 4 weeks) in IgM levels should be determined by the IgM value from the 
quantitative serum immunoglobulin assay, unless for assay limitations this is not possible, in which case the M-protein 
level by densitometry (SPEP) will be used 
c If there is a rapid rise in serum IgM level or an increase in known extramedullary disease leading to an “apparent” 
response of PD (e.g. there is an increase in IgM level of at least 25% and 500 mg/dL from nadir) after the study drug has 
been held for at least 7 consecutive days, an assessment of IgM flare will be assigned instead of PD. The period to 
which this is applicable begins on the day of the first missed dose and ends when the subject has IgM levels or 
extramedullary disease that no longer qualify as “apparent” PD or the subject has a confirmed response of PD*, 
whichever comes first.  Please see Guidelines for specific clinical or laboratory circumstances and timing below. 
dIf only physical exam (PE)is available and the clinical assessment is indicative of an unequivocal improvement from 
baseline (enlarged spleen have regressed, abnormal lymph nodes have reduction in measurements), then the reduction in 
extramedullary disease can be assessed by PE alone. 


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Guidelines for specific clinical or laboratory circumstances: 
 
1. Baseline serum total IgM value above the central laboratory limit of quantitation 
 
If the baseline central laboratory serum total IgM value exceeds the upper limit of 
quantitation, the M-protein value, by central assessment, will be used for response 
determination throughout the study. 
 
2. Baseline serum total IgM value, by central assessment, is not interpretable due to technical 
reasons 
 
If the baseline central laboratory serum total IgM value is not interpretable due to technical 
reasons, the central laboratory serum M-protein value will be used of response determination 
throughout the study. In cases where both the central laboratory total serum IgM and M-
protein values are not interpretable due to technical reasons, the local serum total IgM (or 
local M-protein value, in cases where the local serum total IgM value exceeds the upper 
level of quantitation) will be used for response assessment throughout the study.  
 
3. Subjects with documented cryoglobulinemia 
 
For subjects with abnormal cryoglobulin result at Screening and confirmed by the central 
test, the local laboratory will retest for the presence of cryoglobulins prior to C1D1. The 
C1D1 sample will serve as the baseline. In addition, serum quantitative immunoglobulins 
should be retested using the residual cryoglobulin blood sample at the local laboratory, 
which should be collected and processed under warm conditions. Only when serum 
immunoglobulin cannot be quantified, serum immunoelectrophoresis sample will need to be 
re-collected, processed, and analyzed at local laboratory under warm conditions. The blood 
samples (for cryoglobulin and serum immunoglobulins) should be collected and processed 
under warm conditions at the local laboratory throughout the study to ensure that the same 
methodology is used throughout the study. The results for cryoglobulin and serum 
immunoglobulins would need to be recorded in the eCRF at all required visits. It is 
recommended that the blood samples (cyroglobulins/serumIgM/SPEP/serum 
immunofixation) should be sent to central lab for analysis in addition to the local lab and 
collected and processed under warm conditions throughout the study.  
  
4. Plasmapheresis 
 
Subjects may undergo plasmapheresis, when clinically indicated, during the first two cycles 
of study treatment. A pre-plasmapheresis serum total IgM and M-protein must be obtained 
during the screening period, or the highest predose value (least confounded by 
plasmapheresis) will serve as the baseline value for response assessment throughout the 
study. IgM response and nadir determination should be at least 4 weeks following the last 
plasmapheresis procedure). Subjects requiring plasmapheresis after Cycle 2 will be adjudged 
to have progressive disease. 
 


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5. Assigning IgM Flare due to study drug hold 
 
An assessment of IgM flare will be assigned instead of PD after study drug has been held at 
least 7 consecutive days and there is a rapid rise in serum IgM level (or an increase in known 
extramedullary disease for resonse that includes extramedullary disease assessment) leading 
to an “apparent” response of PD. The period that this is applicable begins on the day of the 
first missed dose and ends when the subject has IgM levels or extramedullary disease that no 
longer qualify as “apparent” PD* (e.g. there is a drop in IgM level below 25% and 500 
mg/dL from nadir) or the subject has a confirmed response of PD*, whichever comes first. 
When assigning response for IgM flare after drug is restarted, the following conditions must 
be met: 
 If IgM levels and/or known extramedullary disease continues to decrease from peak IgM 
level (off study drug) or peak (highest SPD) in extramedullary disease, when drug was 
held, PD will not be recorded. If, however, while on study drug the IgM level or SPD 
increases above the peak level that occurred when drug was held, and IgM level or SPD 
increase is confirmed with a repeat assessment 4 weeks later, the subject will be 
considered to have PD and IgM will not be assessed. 
 If, after 10 weeks of study drug re-initiation (to allow for fluctuation), the next assessed 
IgM level shows either a continued rise at each timepoint from the initiation of the drug 
hold or no decrease from the previous visit, then a serum IgM level obtained 4 weeks 
later must be used to confirm PD. PD will be confirmed if the subsequent IgM 
measurement is greater than or equal to the previous IgM assessment (first IgM 
assessment post 10 weeks study drug initiation). The response assessment of PD* will be 
recorded at the first visit 10 weeks after study drug re-initiation. 
 Similarly, if apparent PD was due to an increase in extramedullary disease and after 
10 weeks of study drug re-initiation the evaluation of extramedullary shows either a 
continued rise from the initiation of the drug hold or no decrease from the previous visit, 
then PD is confirmed and the response assessment of PD will be recorded at the first 
visit 10 weeks after study drug re-initiation. 
 If during drug re-inititation the IgM level decreases and then rises at any timepoint 
thereafter: 
o If at the time of the IgM rise, the IgM level still qualifies as PD* then a 
confirmatory serum IgM level obtained 4 weeks later must be used to confirm 
PD*. PD will be confirmed if the subsequent IgM measurement is greater than or 
equal to the previous IgM assessment (IgM at the time of the initial IgM rise 
following IgM decrease). The response of PD will be recorded at the time of the 
initial IgM rise following the IgM decrease.   
o If at the time of the IgM rise, the IgM level does not qualify as PD* then continue 
response assessments as described above. 
Of note, in the setting of multiple drug holds the nadir continues to be the lowest achieved 
serum IgM level on study for purposes of response assessment.  
 
PD* is defined per protocol as an increase in serum IgM level of at least 25 percent and 
500 mg/dL from lowest nadir 
 


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6. Missing CT scans 
 
If a required CT scan timepoint is missed, it should be performed as soon as possible.  In cases where a single 
CT scan timepoint is missed and the subsequent CT scan findings remain the same or improved from the 
prior scan, response can be assessed for the intervening cycles using the CT scan obtained prior to the missed 
CT scan.  If 2 consecutive CT scan timepoints are missed, then the best response that can be assessed during 
those cycles is an MR (minor response). 
 
 
 


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Appendix 3: 
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: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers.  
Abbreviation: CYP: cytochrome P450. 
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. 
 
 
 


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Appendix 4: 
Sensitive CYP2C8, CYP2C19 Substrates or CYP2C8, 
and CYP2C19 Substrates with a Narrow Therapeutic Index 
 
CYP2C8 Substrates 
CYP2C19 Substrates 
repaglinide1 
Anti-epileptics: 
paclitaxel 
S-mephenytoin1,2  
 
Proton Pump Inhibitors  
 
lansoprazole1 
omeprazole1 
1 Sensitive substrates:  Drugs that exhibit an area under the plasma concentration-time curve (AUC) ratio (AUCi/AUC) 
of 5-fold or more when co-administered with a known potent inhibitor. 
2 Substrates with narrow therapeutic index (NTI):  Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de 
Pointes). 
Source:  Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers.  
Abbreviations: AUC: area under the plasma concentration time curve; CYP: cytochrome P450; NTI: narrow therapeutic 
index. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of concomitant 
medication to check for drug interaction information or contact the medical monitor of the protocol. 
 
 
 


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


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Appendix 6: 
List of Country Specific Amendments 
 
Amendment 1.1-UK: 
17 January 2017 
Amendment 1.3-Germany: 
30 January 2017 
Amendment 1.4-Sweden: 
24 February 2017 
Amendment 2.1-France: 
02 November 2017 
 
 


Signature Page for VV-CLIN-016390 v1.0
Signature Page for VV-CLIN-016390 v1.0
Approval
Clinical Pharmacology
26-Aug-2019 19:57:40 GMT+0000
Approval
Clinical Development
26-Aug-2019 20:08:25 GMT+0000
Approval
CMO
26-Aug-2019 20:33:07 GMT+0000
Approval
China Development
27-Aug-2019 01:36:27 GMT+0000
Approval
Drug Safety
27-Aug-2019 17:23:06 GMT+0000
Approval
Biometrics
28-Aug-2019 04:58:13 GMT+0000
Approval
Regulatory Affairs
28-Aug-2019 06:19:26 GMT+0000
Approval
Drug Safety
28-Aug-2019 22:36:41 GMT+0000



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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-302 
Study Protocol 
Title: 
A Phase 3, Randomized, Open-Label, Multicenter Study 
Comparing the Efficacy and Safety of the Bruton s Tyrosine 
Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects with 
Waldenström s Macroglobulinemia (WM) 
Date: 
Oct 18, 2019  
Version: 
1.0 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
10 
2 
STUDY OVERVIEW 
10 
3 
STUDY OBJECTIVES 
14 
3.1 
Primary Objective (Cohort 1) 
14 
3.2 
Secondary Objectives (Cohort 1) 
14 
3.3 
Exploratory Objectives 
14 
4 
STUDY ENDPOINTS 
15 
4.1 
Primary Endpoint 
15 
4.2 
Secondary Endpoints 
15 
4.3 
Exploratory Endpoints 
16 
5 
SAMPLE SIZE CONSIDERATIONS 
17 
6 
STATISTICAL METHODS 
17 
6.1 
Analysis Sets 
17 
6.2 
Data Analysis General Considerations 
19 
6.2.1 
Definitions and Computations 
19 
6.2.2 
Handling of Missing Data 
20 
6.2.3 
Adjustment for Covariates 
20 
6.2.4 
Multiplicity Adjustment 
20 
6.2.5 
Data Integrity 
22 
6.3 
Subject Characteristics 
22 
6.3.1 
Subject Disposition 
22 
6.3.2 
Protocol Deviations 
23 
6.3.3 
Randomization Stratification Factors 
23 
6.3.4 
Demographics and Other Baseline Characteristics 
23 
6.3.5 
Disease History and Baseline Disease Characteristics 
24 
6.3.6 
Medical History 
25 
6.3.7 
Prior Systemic Anti-Cancer Therapies 
25 
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6.3.8 
Prior and Concomitant Medications 
25 
6.4 
Efficacy Analyses 
26 
6.4.1 
Primary Efficacy Analyses 
26 
6.4.2 
Secondary Efficacy Analyses 
27 
6.4.2.1 
Key secondary endpoint: Major Response Rate 
28 
6.4.2.2 
Other secondary endpoints 
29 
6.4.3 
Sensitivity Analyses 
34 
6.4.4 
Subgroup Analyses 
34 
6.4.5 
Exploratory Efficacy Analyses 
35 
6.5 
Safety Analyses 
37 
6.5.1 
Extent of Exposure 
37 
6.5.2 
Adverse Events 
38 
6.5.3 
Laboratory Values 
40 
6.5.4 
Vital Signs 
41 
6.5.5 
Electrocardiograms (ECG) 
41 
6.5.6 
ECOG 
42 
6.6 
Pharmacokinetic Analyses 
42 
7 
INTERIM ANALYSIS 
42 
8 
CHANGES IN THE PLANNED ANALYSIS 
43 
8.1 
Timing of the primary efficacy analysis 
43 
8.2 
Testing Strategy for the primary endpoint family and the key secondary 
endpoint family 
43 
8.3 
Age group as covariate in stratified analysis of the primary and secondary 
endpoints 
43 
8.4 
Timing of the final analysis of PFS 
44 
9 
REFERENCES 
45 
10 
APPENDIX 
47 
10.1 
Appendix A: Imputation of Missing or Partially Missing Dates 
47 
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10.2 
Appendix B: WM International Prognostic Scoring System (IPSS) 
49 
 
 LIST OF TABLES  
Table 1.  Date of Progression or Censoring for Progression-free Survival 
30 
Table 2.  Treatment Precipitating Symptoms 
33 
Table 3.  Laboratory Parameters of Interest 
40 
 
 LIST OF FIGURES  
Figure 1.  Schema for Study BGB-3111-302 
13 
Figure 2.  Flowchart for the Multiplicity Adjustment 
21 
 
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eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
EDC 
Electronic data capture 
INR 
International normalized ratio 
IPSS 
International prognostic scoring system 
IRC 
Independent review charter 
LDT 
Lab developed test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal residual disease 
MRR 
Major response rate 
NGS 
Next generation sequencing 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PD 
Disease progression 
PFS 
Progression-free survival 
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WM 
 
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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-3111-302.  This document is based on the protocol Version 4 dated 
21-SEP-2018.  The analysis plan for the pharmacogenomics and exploratory 
analyses 
are not included in this SAP.   
 
2 
STUDY OVERVIEW 
This is a Phase 3, randomized, open-label, multicenter study comparing the efficacy and safety 
of 
linemia 
(Dimopoulos et al 2014).  Subjects may be treatment-naïve (TN) or have relapsed or been 
refractory to prior therapy.  Relapsed means a subject previously achieved a CR or VGPR/PR but 
after a period of 6 months or more showed progressive disease.  Refractory means a subject 
experienced prior treatment failure or disease progression within 6 months of therapy initiation.  
Subjects with no prior therapy (TN) will comprise no more than 20% of the study population in 
Cohort 1.  The study is composed of an initial Screening Phase (up to 35 days), a Treatment 
Phase, and a Follow-up Phase.  The study schema is presented in Figure 1.   
Approximately 210 subjects will be enrolled on the study.  All subjects enrolled on the study will 
have the MYD88 gene sequenced by a central laboratory using a LDT assay using the baseline 
bone marrow.  Approximately one hundred and eighty-eight WM subjects (150 
relapsed/refractory subjects and approximately 38 treatment-naïve subjects) who have the 
MYD88MUT mutation, which is characteristic of WM and present in approximately 90% of cases, 
will be enrolled on to Cohort 1 and randomized to one of two treatment arms (Cohort 1; 
zanubrutinib treatment [Arm A] or ibrutinib treatment [Arm B]) in a 1:1 ratio using CXCR4 
mutational status (CXCR4WHIM vs.  CXCR4WT vs missing) and number of prior lines of therapy for 
WM (0 vs.  1-3 vs.  >3 prior therapies) as stratification factors.  Subjects found to have 
MYD88WT by gene sequencing, which is estimated to be present in approximately 10% of 
enrolled subjects, will be enrolled to Cohort 2 and will receive zanubrutinib treatment on a third, 
non-randomized study arm (Arm C).  This non-randomized arm is aimed to evaluate the efficacy 
of zanubrutinib in MYD88WT WM subjects, among whom suboptimal efficacy has been observed 
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(i.e., shorter median survival and lower MRR and CR/VGPR rates versus MYD88MUT) when 
treated with ibrutinib.  In addition, those subjects whose MYD88 mutational status is missing or 
inconclusive will be assigned to Cohort 2, Arm C.  Arm C will enroll approximately 22 subjects.   
The primary efficacy analysis will be conducted at least 15 months after 90% enrollment in the 
RR Analysis Set was completed.  At the time, 90% of subjects enrolled in Cohort 1 are expected 
to have at least 19 months of study follow up.  Tumor response will be assessed every cycle 
(every 4 weeks) for the first 48 weeks and then every 3 cycles thereafter by an independent 
review committee (IRC) according to an adaptation of the response criteria updated at the Sixth 
IWWM (Owen et al 2013; 
Macroglobulinemia 2015: v2).  Serum IgM and M-protein levels will be measured at Screening, 
on Day 1 of every cycle for the first 48 weeks (12 cycles) then every 3 cycles thereafter.  For 
subjects with evidence of extramedullary disease (lymphadenopathy and/or splenomegaly) by 
computed tomography (CT) scan at baseline, assessment by CT scan will occur every 12 weeks 
(starting from C4D1) during the first 48 weeks (until C13D1), then every 24 weeks until PD or 
complete resolution of extramedullary disease.  A CT scan is also required at the safety follow-
up visit.  Bone marrow will be assessed by aspirate and biopsy at Screening, after 12 cycles 
(C13D1), at time of suspected CR, and as clinically indicated. 
Response assessments will occur in all subjects at the beginning of every cycle (every 4 weeks) 
starting from C2D1 during the first 12 cycles (48 weeks), and then every 3 cycles (every 12 
weeks) thereafter e.g., C2D1, C3D1, etc.  For those with extramedullary disease at baseline 
response assessments must occur in conjunction with CT scans until resolution of extramedullary 
disease.  For response assessments that occur during cycles where a CT scan is not required then 
results from prior scans (up to 12 weeks/3 cycles during the first 48 weeks/12 cycles and up to 24 
weeks/6 cycles thereafter) can be carried forward in those subjects with extramedullary disease 
at baseline.  Quality of life (QOL) will be measured every 12 weeks during the first 48 weeks, 
and then every 24 weeks thereafter by the EORTC QLQ-C30 and EQ-5D in MYD88MUT WM 
subjects (Cohort 1). 
All subjects will be followed for AEs for 30 additional days after the last dose of study drug.  All 
treatment-related AEs and serious AEs (SAEs) will be followed until resolution or stabilization.  
Efficacy evaluations will continue until documented PD for subjects who discontinued for 
reasons other than PD.   
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Screening Phase: Screening evaluations will be performed within 35 days prior to the 
randomization, with the exception of a fresh bone marrow biopsy, which may be performed up to 
42 days prior to randomization, as long as no intervening therapy has been administered.  A fresh 
bone marrow aspirate is required for flow cytometry and the MYD88 and CXCR4 mutational 
analyses at Screening.  If subject enrolls based on a bone marrow biopsy that was obtained 
within the 42 days of randomization, then a fresh bone marrow aspirate will still be required 
during the Screening period.  Subjects who agree to participate will sign the informed consent 
form prior to any screening evaluations.  Screening procedures are outlined in the Study 
Assessments and Procedures Schedule in the protocol.  Screening evaluations can be repeated 
within the screening period.   
Treatment Phase:  Subjects will be assigned to either Cohort 1 (MYD88MUT) or Cohort 2 
(MYD88WT/missing) based on the mutational status of the MYD88 gene.  Cohort 1 subjects will be 
randomized using an Interactive Response Technology (IRT) system by the status of 
stratification factors to receive the first dose of zanubrutinib or ibrutinib at Cycle 1 Day 1.  
Cohort 2 subjects (MYD88WT/missing) will be assigned by the IRT to receive zanubrutinib.  
Subjects randomized to Arm A will take 160 mg (80 mg x 2 capsules) of zanubrutinib PO BID.  
Subjects randomized to Arm B will take 420 mg (140 mg x 3 capsules) of ibrutinib PO QD.  
Subjects assigned to Cohort 2 (Arm C) will take zanubrutinib 160 mg (80 mg x 2 capsules) PO 
BID.  All subjects will continue to be treated and followed by the defined schedules in the 
protocol for IgM, radiologic assessments and bone marrow, etc.  until PD, unacceptable toxicity, 
death, withdrawal of consent, lost to follow-up, end of treatment duration or the study is 
terminated by the sponsor, whichever comes first.  A treatment cycle consists of 28 days.   
Follow-up Phase:  In all study arms, subjects will return approximately 30 days after the last 
dose of study drug for Safety Follow-up Visit(s) for the collection of AEs and SAEs that may 
have occurred after the subject discontinued from the study.  For subjects that had 
extramedullary disease at baseline, a CT scan is also required at the Safety Follow-up Visit.  All 
treatment-related SAEs will be followed until resolution or stabilization.  The investigator or 
his/her designee will also continue to collect information on new anticancer therapy given after 
the last dose of study drug.  Efficacy evaluations will continue until documented PD.  If study 
drug is discontinued due to reasons other than PD, serum IgM and M-protein levels will continue 
to be followed every 12 weeks (±14 days)  while other efficacy evaluations will be followed as 
n.  Efficacy assessments will be continued, as per protocol, until PD, 
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withdrawal of consent, death, lost to follow-up, end of study or study termination by sponsor, 
whichever occurs first.  Follow-up will continue to occur even though a subject may have started 
a new anticancer therapy after the last dose of study drug.  For full efficacy assessment 
schedules, please refer to Section 7.3 and Table 2 of the protocol.  Subjects will be followed for 
survival and further anticancer therapy information after progression of disease via phone contact 
 (±14 days)  until study end.   
Post Study: Subjects assigned to Arms A and C (zanubrutinib) who, in the opinion of the 
investigator, continue to benefit from zanubrutinib or ibrutinib at study closure may continue 
treatment with zanubrutinib by enrolling on the zanubrutinib Long Term Extension Study.  This 
study is a rollover study for subjects who wish to continue receiving zanubrutinib. 
Figure 1.  Schema for Study BGB-3111-302  
 
 
 
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3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE (COHORT 1) 
To compare the efficacy in terms of VGPR/CR rate of zanubrutinib vs ibrutinib in 
subjects with MYD88MUT WM 
3.2 
SECONDARY OBJECTIVES (COHORT 1) 
To compare the efficacy in terms of major response rate (MRR) of zanubrutinib vs 
ibrutinib in subjects with MYD88MUT WM 
To evaluate the efficacy in terms of duration of response and progression-free survival of 
zanubrutinib vs ibrutinib in subjects with MYD88MUT WM 
To further evaluate clinical benefit, and anti-lymphoma effects of zanubrutinib vs 
ibrutinib in subjects with MYD88MUT WM  
To evaluate safety and tolerability of zanubrutinib versus ibrutinib in subjects with 
MYD88MUT WM, as measured by the incidence and severity of adverse events according 
to the National Cancer Institute (NCI) Common Terminology for Adverse Events 
(CTCAE) v4.03. 
3.3 
EXPLORATORY OBJECTIVES 
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4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINT 
The primary endpoint is the proportion of subjects in each arm of Cohort 1 achieving either CR 
or VGPR, as determined by independent review committee (IRC) using an adaptation of the 
response criteria updated at the Sixth IWWM (Owen et al.  2013 and NCCN Guidelines, 
). 
4.2 
SECONDARY ENDPOINTS 
Efficacy (Cohort 1): 
Major response rate (MRR) as assessed by the IRC, defined as the proportion of subjects 
achieving CR, VGPR, or partial response (PR). MRR by IRC is the key secondary 
endpoint. 
Duration of response (DOR) as assessed by the IRC, defined as the time from first 
determination of response (CR, VGPR or PR) (per modified IWWM criteria) until first 
documentation of progression (per modified IWWM criteria) or death, whichever comes 
first 
Rate of CR or VGPR as assessed by the Investigator 
DOR as assessed by the Investigator, defined as the time from first determination of 
response (CR, VGPR or of PR) (per modified IWWM criteria) until first documentation 
of progression (per modified IWWM criteria) or death, whichever comes first 
Progression-free survival (PFS) as assessed by the IRC, defined as time from 
randomization to the first documentation of progression (per modified IWWM criteria) or 
death, whichever occurs first 
PFS as assessed by the Investigator, defined as time from randomization to the first 
documentation of progression (per modified IWWM criteria) or death, whichever occurs 
first 
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Resolution of treatment-precipitating symptoms, defined as the absence of the symptoms 
that triggered initiation of study treatment (per the IWWM treatment guidelines) at any 
point during study treatment  
Anti-lymphoma effect, defined as any reduction in bone marrow involvement by 
lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly 
by CT scan, at any time during the course of study treatment  
Safety (Cohort 1) 
The incidence, timing, and severity of treatment-emergent AEs (TEAE) according to 
NCI-CTCAE v.03 
4.3 
EXPLORATORY ENDPOINTS 
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MYD88MUT WM  
(Cohort 1) 
Change in QOL as assessed by EORTC QLQ-C30 and EQ-5D in subjects with 
MYD88MUT WM (Cohort 1) 
Medical resource utilization as assessed by the number of hospitalizations, length of 
hospital stay, and supportive care in subjects with MYD88MUT WM (Cohort 1) 
 
 
 
 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the comparison of the primary endpoint of CR or VGPR 
rate in the Relapsed/Refractory analysis set in Cohort 1.  Assuming RRA=0.35 and RRB=0.15, 
where RRA and RRB denote the CR or VGPR rate in arm A and arm B, seventy-five subjects per 
arm (150 total) provides a power of 0.814 in testing RRA versus RRB in the Relapsed/Refractory 
analysis set in Cohort 1 using a normal approximation to binomial test with a two-sided 
significance of 0.05.  Assuming MRRA=0.90 and MRRB=0.80, the power of demonstrating non-
inferiority of zanubrutinib in the Relapsed/Refractory analysis set is 85.5% when a NI margin of 
8% is used.   
In addition to the 150 relapsed/refractory subjects, approximately 20% (38) treatment-naïve 
subjects with MYD88MUT will be enrolled in Cohort 1.   
Assuming MYD88MUT mutation is present in 90% of the enrolled subjects, a total of 
approximately 210 subjects will be enrolled in Cohort 1 and Cohort 2 combined. 
 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
Analysis Sets for Cohort 1: 
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The Intent to Treat (ITT) Analysis Set includes all randomized subjects who are assigned to a 
treatment arm in Cohort 1.   
The Relapsed/Refractory (RR) Analysis Set (a subset of the ITT analysis set) includes all 
randomized subjects with at least 1 prior line of therapy as determined by the IRT system.  The 
Relapsed/Refractory Analysis Set will be the primary analysis set used for efficacy analyses. 
The Per-Protocol (PP) Analysis Set includes subjects in the ITT Analysis Set meeting following 
criteria (ICH E9):  
Received any dose of randomized treatment regimen 
Had a valid post-baseline measurement for either IgM (central or local) or M-protein by 
SPEP (central or local) 
 
Categories of important protocol deviation are defined in Section 6.3.2.  Similarly, The Per-
Protocol Relapsed/Refractory Analysis Set includes subjects in the Relapsed/Refractory Analysis 
Set who met the above criteria.   
Criteria for exclusion from the PP Analysis Set will be determined and documented before the 
database lock for the primary analysis.   Non-inferiority test for the secondary endpoint of MRR 
by IRC will be also tested in the Per-Protocol Relapsed/Refractory Analysis set and in the Per-
Protocol Analysis set.   .  
Analysis Set for Cohort 2: 
The efficacy analysis set in Cohort 2 includes all subjects who received any dose of zanubrutinib 
and are centrally confirmed to have MYD88WT. 
Analysis Set for Cohort 1 and Cohort 2: 
The Safety Analysis Set includes all subjects who received any dose of zanubrutinib or ibrutinib.  
The Safety Analysis set will be used for all safety analyses. 
The PK Analysis Set includes all subjects who have at least one post-dose zanubrutinib 
concentration.   
The number and percentage of subjects in each analysis set will be summarized.   
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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.  
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 treatment 
(study day 1).  For subjects not dosed, the enrollment (Arm C) or randomization date (Arm A/B) 
will be used instead of the first dose date.  For assessments conducted on or after study day 1, 
study day will be calculated as (assessment date  date of study day 1 + 1).  For assessments 
conducted before the date of study day 1, study day is calculated as (assessment date  date of 
study day 1).  There is no study day 0.   
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings; Study day and any corresponding durations will be presented based on the 
imputations specified in Analysis Details Specification document. 
Treatment duration: The treatment duration will be calculated as (date of last dose of study 
treatment  date of first dose of study treatment + 1). 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the first dose of study treatment.   
The last serum IgM value (or SPEP M-protein) on/before cycle 1 day 1 (C1D1) will serve as the 
baseline (last value prior to drug administration) for all assessments throughout the study except 
for subjects who have undergone plasmapheresis before cycle 1 day 1.  For subjects who have 
undergone plasmapheresis, the last pre-plasmapheresis serum IgM/SPEP M-protein value (if 
available at screening) should be used.  In the case of multiple prior consecutive plasmapheresis 
procedures during screening, the highest pre-dose value (least confounded by plasmapheresis) 
should be used as the baseline. 
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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. 
When summarizing categorical variables, subjects with missing data are generally included in 
the denominator to calculate percentages unless otherwise specified.  When needed, the category 
subjects with missing data is presented.   
When summarizing continuous variables, subjects with missing data are not included in 
calculations unless otherwise specified. 
No imputation of AE grades will be performed.  TEAEs with missing CTCAE grade will only be 
summarized in the all-grades column. 
If the assessment of the relationship of an AE to study treatments is missing, then the AE is 
assumed to be related to the study treatment in the safety analysis summary.  No imputation will 
be done in the AE listings. 
6.2.3 Adjustment for Covariates 
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 
Multiplicity for study-wide type-I error will be adjusted for the tests of primary VGPR/CR rate 
endpoint and key secondary MRR endpoint in R/R analysis set and ITT analysis set. A flowchart 
of the multiplicity adjustment is shown in Figure 2.  
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Figure 2.  Flowchart for the Multiplicity Adjustment 
 
There are 2 primary hypotheses with respect to the primary endpoint of CR or VGPR rate, which 
will be tested by the hierarchical fixed-sequence procedure in the order of : superiority in the RR 
Analysis Set; and superiority in the ITT Analysis Set. These 2 hypotheses form the family of the 
primary hypotheses. Since each hypothesis within the family of the primary hypotheses is tested 
at a 1-sided 0.025 level, based on the closed test principal, the family-wise error rate (FWER) 
within the primary hypotheses family is controlled at a 0.025 level (1-sided). 
The secondary endpoints will only be tested if the first primary hypothesis (superiority of the CR 
or VGPR rate in the RR Analysis Set) is significant.  For the secondary endpoints, only the key 
secondary endpoint of MRR will be considered in controlling the study-wide FWER.  The 
testing in the other secondary endpoints will be descriptive only.  The key secondary endpoint of 
MRR will be tested for noninferiority in the RR Analysis Set and the ITT Analysis Set.  These 2 
hypotheses form the family of the secondary hypotheses and can be considered as the descents of 
the superiority testing of the CR or VGPR rate in the corresponding analysis sets (Bretz et al, 
2009).  The noninferiority in MRR in the RR Analysis Set will be tested at a 1-sided 0.025 level 
if the superiority of the CR or VGPR rate is demonstrated in the RR Analysis Set under this 
approach. If the superiority of the CR or VGPR rate can be demonstrated in both of the RR and 
the ITT Analysis Sets, the noninferiority of MMR will be tested in the RR and the ITT Analysis 
Sets respectively at a 1-sided level of 0.025.   
Based on Bretz (2009), the testing strategy described above is a consistent procedure that avoids 
illogical dependencies.  Under the above testing strategy, the family-wide error rate in both of 
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the primary and the secondary families of hypotheses is strongly controlled at a 1-sided level of 
0.05 while the family-wide error in the primary family of hypotheses is strongly controlled at 1-
sided level of 0.025 (Bretz 2009).  
6.2.5 Data Integrity 
Before pre-specified statistical analysis begins, the integrity of the data should be reviewed to 
assure fit-for-purpose.  The data set for analysis should be an accurate and complete 
representation of the subjects  relevant outcomes from the clinical database.   All essential data 
should be complete and reviewed up to a pre-specified cutoff date.  Critical consistency checks 
and appropriate source data verification should be completed according to the final data 
extraction plan. 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The following subject disposition information will be summarized by arm: 
Number of subjects randomized (or number of subjects enrolled for Arm C) 
Number (%) of subjects treated 
Number (%) of subjects randomized, but not treated 
o
Reason for not treated 
Number (%) of treated subjects who discontinued treatment 
o
Reason for treatment discontinuation 
Number (%) of treated subjects who discontinued study 
o
Reason for study discontinuation 
The number of subjects randomized or enrolled will be summarized by country/site. 
The number and percentage of subjects still receiving treatment and still in the study at data 
cutoff will also be summarized.   
Study follow-up time is defined as the time from the randomization (or enrollment date for Arm 
C) to the death date or the end of study date for the subjects who discontinued from study 
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(whichever occurs first), or the data cutoff date for the ongoing subjects.  Study follow-up time 
will be summarized descriptively (e.g. median, min, max, etc.). 
6.3.2 Protocol Deviations 
Important protocol deviation criteria will be established before the database lock. The following 
categories will be considered when evaluating a deviation as an important protocol deviation: 
Enrollment of a patient into the study even though that patient did not meet all eligibility 
criteria according to the current protocol at the time of the enrollment  
Failure to withdraw a patient from study treatment when that patient met protocol criteria 
requiring withdrawal from study treatment 
Administration of the incorrect study treatment to a study patient 
Administration of a medication considered prohibited according to the current protocol at 
the time of the medication administration  
Assignment of patient to the incorrect study cohort based on the study selection assay  
Prior to obtaining informed consent, performance of a study-specific procedure that is not 
considered a standard or typical procedure for the disease under study. 
Important protocol deviations will be summarized by deviation category and by arm.  A listing 
will also be provided.   
6.3.3 Randomization Stratification Factors 
In Cohort 1, the number of subjects with each of the IRT randomization stratification factors will 
be summarized by arm.  The randomization stratification factors include the CXCR4 mutation 
status and the prior lines of therapy. In addition, stratification errors (defined as IRT-based strata 
vs data-driven strata inconsistencies) will be summarized.  All the stratified analysis will be based 
on the strata used for randomization. 
6.3.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics including the following will be summarized by arm 
using descriptive statistics:  
Age (years);  
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Age group (<=65 vs.  >65 years); 
Gender; 
Race and ethnicity;  
Geographic region; 
Height (cm), weight (kg), and body mass index (BMI, kg/m2); 
Vital signs; 
Eastern Cooperative Oncology Group (ECOG) performance status; 
ECG parameters (PR internal, QT interval, QTcF interval). 
6.3.5 Disease History and Baseline Disease Characteristics 
Baseline disease characteristics including the following will be summarized by arm using 
descriptive statistics: 
Time since initial WM diagnosis; 
Prognostic group at WM diagnosis and at study entry; 
Prior line of therapy for WM (0 vs.  1-3 vs.  >3); 
Time since the most recent progression; 
Serum immunoglobulin (IgM, IgA and IgG); 
Serum IgM (>=40 g/L vs <40 g/L) 
SPEP M-protein; 
Serum immunofixation (positive vs.  negative); 
quantitative and qualitative: 
L vs.  >3 mg/L); 
Genotype by LDT/Sanger method: (MYD88-MUT/CXCR4-WT vs MYD88-
MUT/CXCR4-WHIM vs MYD88-WT/CXCR4-WT vs missing); 
Presence of extramedullary disease per investigator (yes: 
splenomegaly/lymphadenopathy vs.  no); 
Presence of extramedullary disease per IRC (yes: splenomegaly/lymphadenopathy vs.  
no);  
Baseline bone marrow involvement %; 
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WM IPSS (as derived by sponsor based on  Appendix B: low, intermediate, high); 
Hemoglobin (quantitative and qualitative: 110 g/L vs.  >110 g/L); 
Platelet (quantitative and qualitative: 100 109/L vs.  >100 109/L); 
ANC (quantitative and qualitative: 1.5 109/L vs.  >1.5 109/L); 
Any cytopenia (yes: hemoglobin 
 or platelet count 
9/L or ANC 
109/L vs. no); 
Hematocrit (%); 
Prior radiotherapy and prior transplants (yes vs. no);  
WM signs and symptoms. 
Cryoglobulinemia based on central lab (positive vs negative) 
Categories of baseline characteristics can be modified depending the availability of data and/or 
percentage of categories. 
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 subjects reporting a history of any 
medical condition, as recorded on the CRF, will be summarized by system organ class (SOC) 
preferred term (PT), and arm.  A listing of medical history will be provided.   
6.3.7 Prior Systemic Anti-Cancer Therapies  
Number of prior 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 arm using descriptive 
statistics.  A listing will be provided as well. 
The therapies with the same sequence/regimen number are counted as one prior therapy. 
6.3.8 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes version March 2017 or later and will be further classified to 
the appropriate Anatomical Therapeutic Chemical (ATC) code.   
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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 
treatment and were continuing at the time of the first dose of the study treatment, or (2) started 
on or after the first dose date of the study treatment up to 30 days after the last dose date or the 
initiation of a new anti-cancer therapy. 
The number and percentage of subjects reporting prior medications and concomitant medications 
will be summarized by ATC medication class Level 2, WHO DD preferred name, and arm, 
respectively.  A listing of the prior and concomitant medications will be provided. 
6.4 
EFFICACY ANALYSES 
Statistical testing will be performed to compare the efficacy of zanubrutinib (Arm A) and 
ibrutinib (Arm B) in Cohort 1. For all efficacy analyses, subjects will be analyzed according to 
the treatment arm to which they were randomized. Descriptive statistics will be used to report the 
efficacy of zanubrutinib in Cohort 2 (Arm C).  Subjects with missing response assessments will 
be considered as non-responders and will be included in the denominator when calculating the 
CR or VGPR rate, MRR, and ORR.  The non-responders will be excluded in the corresponding 
duration of response analyses. 
Statistical analyses will be performed after the database is locked. 
6.4.1 Primary Efficacy Analyses 
The primary endpoint is the CR or VGPR rate in Cohort 1 assessed by IRC.   
The following two hypotheses of zanubrutinib compared to ibrutinib in CR or VGPR rate will be 
tested in the analyses of the primary endpoint:  
Superiority of zanubrutinib compared to ibrutinib in the RR Analysis Set; 
Superiority of zanubrutinib compared to ibrutinib in the ITT Analysis Set. 
The 2 hypotheses listed above will be tested each at a 1-sided level of 0.025 using the 
hierarchical fixed-sequence procedure in the following order to adjust for multiplicity: 1) 
superiority in the RR Analysis Set;  and 2) superiority in the ITT Analysis Set.  The study is 
positive if the superiority of zanubrutinib compared to ibrutinib in the CR or VGPR rate is 
demonstrated in the RR Analysis Set. 
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The superiority of the primary endpoint of VGPR/CR rate will be tested using the Cochran-
Mantel-Haenszel (CMH) test stratified by the CXCR4 status (WHIM vs WT/missing), the prior 
line of therapy (1-3 vs.  >3 for analyses in the Relapsed/Refractory Analysis Set; 0 vs 1-3 vs >3 
for analyses in the ITT Analysis Set) and age group (<=65 vs >65) at a 1-sided significance level 
of 0.025.  If the 1-sided p-value is less than 0.025, it will be concluded that the VGPR/CR rate in 
zanubrutinib is greater than the VGPR/CR rate in ibrutinib and that the primary objective is met.   
The 95% confidence interval (CI) for the Mantel-Haenszel common risk difference (Mantel-
Haenszel, 1959) will be constructed using a normal approximation and 
standard error 
(Sato 1989) stratified by the CXCR4 status (WHIM vs WT/missing), the prior line of therapy (1-
3 vs.  >3 for analyses in the Relapsed/Refractory Analysis Set; 0 vs 1-3 vs >3 for analyses in the 
ITT Analysis Set) and age group (<=65 vs >65).   
The primary analysis of superiority in the primary endpoint will be performed in the RR 
Analysis Set first at least 15 months after 90% enrollment in the RR Analysis Set was completed. 
At the time, 90% of Cohort 1 subjects are expected to have at least 19 months of study follow up.  
If the superiority of the CR or VGPR rate is demonstrated in the RR analysis set, the superiority 
of the CR or VGPR rate will be further tested in the ITT Analysis Set. 
Analyses of the best overall response (BOR) will be performed as well.  BOR is defined as the 
best response recorded from the randomization or enrollment date to the data cutoff date or the 
start of new anti-cancer therapies, whichever comes first.  Subjects without any post-baseline 
response assessment (regardless of the reason) will be considered as non-responders.   
6.4.2 Secondary Efficacy Analyses  
 The key secondary endpoint of major response rate (MRR) by IRC will be tested only if any of 
the superiority tests for the primary endpoint is significant.  If the primary endpoint of CR or 
VGPR rate is superior in the RR Analysis Set only, the key secondary endpoint of MRR will be 
tested for noninferiority in the RR Analysis Set at a 1-sided significance level of 0.025. If the 
primary endpoint of CR or VGPR rate is superior in both the RR and the ITT Analysis Sets, the 
key secondary endpoint of MRR will be tested for noninferiority in the RR and the ITT Analysis 
Set respectively at a 1-sided significance level of 0.025. The study-wide type I error will be 
controlled at a 1-sided 0.05 level under this testing scheme (Bretz 2009). 
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For the other secondary endpoints including PFS, the tests will be descriptive without 
multiplicity adjustment.  
6.4.2.1
Key secondary endpoint: Major Response Rate 
The major response rate (MRR) by IRC, defined as the proportion of subjects achieving CR, 
VGPR, and PR, will be tested for noninferiority of zanubrutinib compared to ibrutinib.  The null 
and alternative hypotheses of MRR are set as follows: 
H0: MRRA-MRRB  -8% 
Ha: MRRA- MRRB > -8%, 
where MRRA is the major response rate in zanubrutinib and MRRB is the major response rate in 
ibrutinib.   
The 95% confidence interval (CI) for the Mantel-Haenszel common risk difference (Mantel-
Haenszel, 1959) will be constructed with normal approximation and standard error based on Sato 
(1989) with strata CXCR4 status (WHIM vs WT/missing), prior line of therapy (1-3 vs.  >3 for 
Relapsed/Refractory analysis set analysis and 0 vs 1-3 vs >3 in ITT analysis) and age group 
(<=65 vs >65).  If the lower bound of the CI is greater than the non-inferiority margin of -8%, 
the null hypothesis will be rejected, and it can be concluded that the MRR in zanubrutinib is non-
inferior to the MRR in ibrutinib.  In addition, as a sensitivity analysis, the Mantel-Haenszel 
common risk difference will also be estimated using the null variance estimator (Klingenberg, 
2013). 
If the lower bound of the CI is greater than 0, superiority is significant at the nominal level of 
0.025 (1-sided). The superiority test of MRR is not included in the multiplicity adjustment for 
the study-wide type-I error (Figure 2).    
As a sensitivity analysis, non-inferiority for MRR will be also tested in the per-protocol analysis 
set corresponding to the analysis set for which non-inferiority is significant. 
MRR and the Clopper-Pearson 95% confidence interval (CI) will be reported for each arm.   
Justification of the non-inferiority margin for MRR 
The same non-inferiority margin will be used for both ITT and Relapsed/Refractory analysis 
sets. 
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Since no randomized trial has been conducted in WM, the ibrutinib treatment benefit over 
placebo can only be estimated from the single-arm ibrutinib phase 2 trial in which the MRR is 
0.73 with 95% CI (0.60, 0.83).  
M is impossible without treatment, 
MRR can be considered 0% in the placebo treated subject.  Therefore, the lower bound of 95% 
CI (i.e., 60%) can be used as the treatment effect of ibrutinib over placebo (M1).  A NI margin of 
8% (M2) is proposed assuming 86.7% of the ibrutinib benefit over a placebo is retained.  With 
close to 90% of the ibrutinib effect preserved, the 8% NI margin in MRR is clinically 
justified.  The loss of the ibrutinib treatment benefit is well within the clinically acceptable 
range.  It is worth noting that the NI of MRR will only be performed after the superiority of 
zanubrutinib over ibrutinib in CR/VGPR rate, which is closely correlated with MRR, has been 
demonstrated.  Hence, a numerically higher MRR in zanubrutinib is certainly expected if the NI 
test of MRR is to be performed.  The inclusion of the NI test of MRR is mainly based on the 
sample size consideration in a rare disease setting where statistical significance might not be 
shown in a superiority test with a clinically meaningful MRR difference (e.g., 12% higher MRR 
in zanubrutinib over ibrutinib) in 150 randomized relapsed/refractory subjects. 
6.4.2.2
Other secondary endpoints  
6.4.2.2.1 
Progression-free survival (PFS) will be analyzed at the time of the primary analysis of VGPR/CR 
rate. In addition, after the primary analysis subjects will continue to be followed for PFS events 
until the final analysis of PFS which is scheduled at approximately 4 years after study start. 
During this period, the sponsor will continue to maintain trial integrity according to the Data 
Integrity Protection Plan (DIPP).   
PFS is defined as the time (in months) from the randomization or enrollment date to the date of 
the earliest occurrence of disease progression (PD) or death (due to any cause), whichever occurs 
first. PFS will be analyzed twice: at the time of the primary analysis and approximately 4 years 
after the first subject was randomized.  
PFS will be right-censored for subjects who meet one of the following conditions: 1) no baseline 
disease assessments; 2) starting a new anti-cancer therapy before PD or death; 3) PD or death 
immediately after more than 6 months since the last disease assessment (more than 12 months if 
a subject is on the response assessment schedule of every 24 weeks); and 4) alive without 
documentation of PD.  The censoring convention generally follows the FDA Guidance for 
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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).   
The HR (Arm A/Arm B) for PFS by IRC and its 2-sided 95% confidence interval (CI) will be 
estimated from a stratified Cox regression model stratified by the CXCR4 status (WHIM vs 
WT/missing), the prior lines of therapy (1-3 vs. >3 for the Relapsed/Refractory Analysis Set 
analysis and 0 vs 1-3 vs >3 in the ITT Analysis Set) and age group (<=65 vs >65) will be 
performed only at the final analysis of PFS.  An unstratified Cox regression model will be also 
used to estimate the hazard ratio (HR) of the PFS in zanubrutinib compared to ibrutinib and the 
corresponding 95% CI at the final analysis of PFS.   
The Kaplan-Meier curves for PFS will be presented for each arm.  A listing of the PFS related 
information, e.g. the date of the progression or censoring and the corresponding reasons, will 
also be provided.In addition to the analysis at the time of the primary analyses of the primary 
endpoint, the final analysis of PFS will be performed approximately 48 months after study start.  
In the iNNOVATE monotherapy arm (Dimopoulos 2017), the 18-month PFS rate is estimated as 
0.86.  Assuming an exponential distribution for PFS and a hazard ratio of 0.8, approximately 33 
events are expected to be accumulated for Cohort 1 relapsed/refractory subjects at the time of the 
final PFS analysis.  The landmark PFS rates at 36-month for Arm A and Arm B based on the 
above assumptions are 0.79 and 0.74, respectively.  
After the initial  analysis of PFS at the time of primary analysis of the primary endpoint, the 
number of PFS events at the final analysis will be re-assessed based on Bagiella and Heitjan 
(2001). Exponential distribution will be assumed for event rate for each arm. The data observed 
at initial analysis will be used to determine the posterior predictive distribution. The range of 
projected number of PFS events will be calculated based on Bayesian prediction interval. At the 
final analysis of PFS, the hazard ratio will also be estimated using a Bayesian Cox regression 
model based on the partial likelihood and a non-informative prior. The posterior probability of 
hazard ratio < 1 will calculated based on the posterior distribution of log hazard ratio. 
6.4.2.2.2
Duration of major response is defined as the time (in months) from the date of the earliest PR or 
better to the date of PD or death for any cause (whichever occurs earlier) for the subjects who 
achieved PR or better. The censoring convention and the analyses of duration of major response 
will be the same as those of PFS.  
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In addition, duration of VGPR or better and duration of overall response (defined as the time 
from date of the earliest minor response or better to PD or death due to any cause, whichever 
occurs earlier) will be analysed similarly as with duration of major response. Duration of 
responses (major response, VGPR or better, overall response) will not be compared between two 
arms. 
6.4.2.2.3 
Analyses of the VGPR/CR rate will be repeated based on the investigator assessment with the 
same method as described in Sec 6.4.1. The concordance between the IRC and Investigator 
assessments in terms of VGPR/CR status and BOR will be summarized. 
6.4.2.2.4 MRR
Analyses of MRR will be repeated based on the investigator assessment with the same method as 
described in Sec 6.4.2.1. 
6.4.2.2.5 
Analyses of PFS will be repeated based on the investigator assessment with the same method as 
described in Sec 6.4.2.2.1. 
6.4.2.2.6 
Analyses of DOR will be repeated based on the investigator assessment with the same method as 
described in Sec 6.4.2.2.2. 
6.4.2.2.7 
Treatment-P
Symptoms
Resolution of the treatment-precipitating symptoms is defined as the absence of the symptoms 
that triggered the initiation of the study treatment (per the IWWM treatment guidelines, Table 2) 
at any point during study treatment.   
The difference in the resolution of any treatment-precipitating symptoms and in the resolution of 
all treatment precipitating symptoms between zanubrutinib and ibrutinib will be tested using chi-
square test.  The number and percentage of subjects with the resolution of each and all symptoms 
will be summarized.   
 
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Table 2.  Treatment Precipitating Symptoms 
Clinical indications for initiation of therapy  
 Recurrent fever, night sweats, weight loss, fatigue  
 Hyperviscosity  
 
 
 Symptomatic hepatomegaly and/or splenomegaly  
 Symptomatic organomegaly and/or organ or tissue infiltration  
 Peripheral neuropathy due to WM 
Laboratory indications for initiation of therapy  
 Symptomatic cryoglobulinemia  
 Cold agglutinin anemia  
 Immune hemolytic anemia and/or thrombocytopenia  
 Nephropathy related to WM  
 Amyloidosis related to WM  
 
 
 Platelet count <100 × 109/L  
 
6.4.2.2.8 Anti-L
Anti-lymphoma effect is defined as any reduction in bone marrow involvement by 
lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT 
scan, at any point during study treatment.  
The maximum percentage of decrease in bone marrow lymphoplasmacytoid lymphocytes will be 
compared using the ANOVA (analysis of variance) model with the treatment arms (arm A and 
B) as the group variable.  The number and percentage of subjects with a decreased percentage of 
lymphoplasmacytoid lymphocytes after the start of the study drug will be summarized within 
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each treatment arm.  The difference in the proportions between zanubrutinib and ibrutinib will be 
tested using chi-seq test. 
The number and percentage of subjects with a reduction in the size of the pre-treatment 
lymphadenopathy and/or splenomegaly according to CT scan will be summarized within each 
treatment arm.  The difference in the proportions between zanubrutinib and ibrutinib will be 
tested using chi-seq test. 
6.4.3 Sensitivity Analyses  
For the primary endpoint of VGPR/CR rate, an unstratified analysis will also be performed. 
6.4.4 Subgroup Analyses 
The primary and selected secondary endpoints will be summarized, as appropriate, in the 
following subgroups: 
Age group (<=65 vs. >65); 
Gender; 
Geographic region (Asia vs. Australia/New Zealand vs. Europe vs. North America); 
Prior line of therapy (0 vs. 1-3 vs. >3 and RR vs. TN); 
Baseline ECOG-PS (0 vs. 
; 
Baseline CXCR4 mutation status by Sanger method (WHIM vs. WT/missing); 
Baseline IgM ( 40 g/L vs >40 g/L);  
Baseline 
; 
Baseline H
; 
Baseline P
9/L vs. >100 109/L); 
Baseline presence of extramedullary disease (yes vs. no); 
WM IPSS (low vs. intermediate vs. high) 
When the sample size of a subgroup is too small, the subgroup may be omitted from the analyses 
or be combined with other subgroups.  Forest plots for the subgroup analyses will be provided with 
unstratified rate difference and its 95% confidence interval. 
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6.4.5 Exploratory Efficacy Analyses 
EORTC QLQ-C30 
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The scores at each assessment timepoint and changes from baseline in the global health 
status/QoL scale and the five functional scales (Physical Functioning, Role Function, 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) will be summarized descriptively. The 
, or 
 
In addition to descriptive analysis, the QLQ-C30 global health status/QOL scale scores will be 
compared between treatment groups in Cohort 1 using a linear mixed model for repeated 
measures (MMRM). The model will include the repeated measurement (including baseline) of 
QLQ-C30 global health status/QOL scale as dependent variable and treatment arm and 
randomization stratification factors, and intercept and slope of time on as fixed effects 
(Mallinckrodt 2018). The random subject effects will include subject random intercept and 
subject random slope of time. The 2 random subject effects are assumed to follow a bivariate 
normal distribution (with mean 0). The difference between treatment arms as well as its 95% 
confidence interval will be estimated, and the corresponding p-value will be presented.   
EQ-5D-5L 
The EQ-5D-5L comprises a descriptive system and an EQ Visual Analogue scale (EQ VAS) 
with following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
-
rated health on a 0 to 100 scale, with 100 labelled 
 
EQ VAS will be summarized descriptively. Descriptive statistics will also be performed 
including the number and percentage of subjects reporting each level of problem on each 
dimension of the EQ-5D 
Medical resource utilization, including the number of hospitalizations, the length of hospital stay, 
and supportive care (e.g., transfusions, growth factor support, intravenous antibiotics), will be 
summarized at each cycle (including Screening and C1D1) for each study arm in Cohort 1.  
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Correlation between the trough plasma zanubrutinib concentration and the efficacy endpoints 
may be explored in the PK analysis set. 
 
.  
Additional analyses may be performed by combining the data from Arms A and C to assess the 
efficacy of zanubrutinib, regardless of the MYD88 mutation status. 
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, 
coagulation, and urinalysis), vital signs, physical exams, and ECGs findings will also be used in 
determining the safety.  Descriptive statistics will be used to summarize the safety data by 
treatment arm.  For all safety analyses, subjects will be analyzed according to the treatment arm 
corresponding to the actual treatment received. The safety data will be summarized by study 
drug (combining Arm A and Arm C for zanubrutinib) as well. 
6.5.1 Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received (number and percentage of subjects), duration of exposure (days), cumulative total dose 
received per subject (mg), actual dose intensity (mg/day) and relative dose intensity (%). 
The number and percentage of subjects with dose reductions, dose interruption, and drug 
discontinuation due to AEs will be summarized.  The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics.  The frequency 
of dose reductions and dose interruptions will be summarized by categories.  
The actual dose intensity is defined as the actual cumulative dose (mg) taken based on the total 
dose per day divided by the duration of treatment (days).The relative dose intensity (RDI) is 
defined as the ratio of the actual dose intensity to the planned dose intensity in percentage. 
Subject data listings will be provided for all dosing records and for the calculated summary 
statistics. 
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In addition, time to treatment failure will calculated as time from randomization to 
discontinuation of study treatment due to any reason. Time to treatment failure will be censored 
at the data cutoff for the subjects who did not discontinue study treatment. The hazard ratio for 
time to treatment failure and its 95% CI will be estimated from a stratified Cox regression using 
the randomization stratification factors and age group. The Kaplan-Meier method will be used to 
estimate the distribution of time to treatment failure for each treatment group. 
6.5.2 Adverse Events  
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA®).  Adverse events will be coded to MedDRA® (Version 18.1 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA® preferred term (PT) and primary 
system organ class (SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset time or increase 
in severity level on or after the first dose of study drug and within 30 days after the last dose of 
study drug or prior to the initiation of a new anti-cancer therapy, whichever occurs first.  A 
treatment-related adverse event is an AE that is assessed by the investigator as related to the 
study drug or with missing assessment of the causal relationship. 
TEAEs will be summarized based on the number and percentage of subjects experiencing AEs 
by MedDRA SOC and PT.  A subject reporting the same AE more than once will be counted 
only once when calculating the incidence 1) within a given SOC, and 2) within a given SOC and 
PT combination.  The maximum CTCAE toxicity grade and strongest causal relationship to the 
study drug for such events will be used.   
An overall summary of TEAEs will include the number and percentage of subjects with at least 
one: 
TEAE; 
treatment-related TEAE; 
grade 3 or higher TEAE;  
treatment-related grade 3 or higher TEAE; 
fatal TEAE; 
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treatment-related fatal TEAE; 
serious TEAE; 
treatment-related serious TEAE; 
TEAE leading to treatment discontinuation; 
treatment-related TEAE leading to treatment discontinuation; 
TEAE leading to dose reduced; 
treatment-related TEAE leading to dose reduced; 
TEAE leading to dose interruption; 
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.   
The adverse events of special interest (AESIs) will be defined and summarized by AESI category 
and PT for the following: 
all AESIs; 
grade 3 or higher AESIs; 
serious AESIs; 
AESIs by maximum severity.  
Time to first AESI along with cumulative event rates at milestone timepoints as well as subject 
incidence in 3-month intervals over time may be presented for selective AESIs. 
The following AEs of hepatic events will be summarized by PT: 
All AEs of hepatic events; 
AEs of hepatic events grade 3 or higher; 
Serious AEs of hepatic events; 
AEs of hepatic events by maximum severity.  
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.   
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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. 
6.5.3 Laboratory Values 
The actual value and change from baseline for selected hematology, serum chemistry, 
coagulation, and urinanalysis parameters will be summarized at each scheduled visit.  A list of 
parameters of interest is provided in Table 3.  Laboratory parameters that are graded in NCI-
CTCAE v4.03 will be summarized by the CTCAE grade.   
A summary of the number and percentage of subjects with grade 3 or higher toxicity will be 
provided for selected laboratory parameter of interest.  In the summary of laboratory parameters 
by CTCAE grade, parameters with CTCAE grading in both high and low directions (e.g., 
calcium, glucose, magnesium, potassium, sodium) will be summarized separately.  Shift tables 
assessing the toxicity grade at baseline versus the worst post-baseline toxicity grade recorded 
will be presented.   
Table 3.  Laboratory Parameters of Interest 
Hematology 
Serum Chemistry 
Coagulation 
Hemoglobin 
(decrease) 
Alanine 
transaminase (ALT) 
(increase) 
Albumin 
(decrease) 
Activated partial 
thromboplastin time 
(aPTT) (increase) 
Platelets (decrease) 
Aspartate 
transaminase (AST) 
(increase) 
Uric Acid 
(increase) 
International Normalized 
Ratio (INR) (increase) 
WBC (increase, 
decrease) 
Alkaline 
Phosphatase 
(increase) 
Sodium 
(increase, 
decrease) 
 
Absolute Neutrophil 
Count (ANC, 
decrease) 
Total Bilirubin 
(increase) 
Phosphorus 
(decrease) 
 
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Absolute Lymphocyte 
Count (increase, 
decrease) 
Creatinine (increase) Potassium 
(increase, 
decrease) 
 
 
Calcium (increase, 
decrease) 
Magnesium 
(increase, 
decrease) 
 
 
Glucose (increase, 
decrease) 
 
 
For hypocalcemia and hypercalcemia, serum calcium will be corrected using the following 
formula: 
Corrected calcium = Serum calcium + 0.8 * (4  serum albumin) where serum calcium is 
recorded in mg/dL and serum albumin is recorded in g/dL. 
Box-whisker plots will be generated for parameters of interest. 
Hematology, serum chemistry, coagulation, and urinalysis results for each subject will be 
presented in data listings.  A listing of all grade 3 or higher laboratory values will also be 
provided.   
Incidence of subjects who met one or more of the 
 
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 visit.  A listing by subject 
and visit will be provided as well. 
6.5.5 Electrocardiograms (ECG) 
Actual value and change from baseline for the PR, QT, and QTc-Fridericia intervals will be 
summarized.  If triplicate readings are recorded (e.g.  Screening), the average of the readings for 
the visit will be used for the summary. 
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The number and percentage of subjects satisfying the following QT and QTcF conditions at any 
time post-baseline will be summarized: 
> 450, > 480, or > 500 msec; 
msec increase from baseline.  
A listing of abnormal ECG by subject and visit will be provided. 
6.5.6 ECOG 
ECOG performance status will be summarized at each visit.  Shift tables assessing the ECOG 
performance status at baseline versus the worst post-baseline performance status will be 
presented.   
6.6 
PHARMACOKINETIC ANALYSES 
Population PK analysis will be carried out to include plasma concentrations from this trial in an 
existing model.  PK parameters such as Cmin will be summarized, and additional PK parameters 
such as apparent clearance of the drug from plasma (CL/F) and area under the plasma 
concentration-time curve (AUC[0-24]) may be derived from the population PK analysis if supported 
by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
The impact of plasmapheresis on zanubrutinib exposure will be estimated by comparing the AUC 
of zanubrutinib in subjects with or without the plasmapheresis procedure.   
Further PK analyses will be described in a separate analysis plan. 
 
7 
INTERIM ANALYSIS 
An interim analysis, which occurs approximately 6 months after the first 50 relapsed/refractory 
subjects are randomized from Cohort 1, will be implemented in the study.  This analysis is for 
futility only. Early stopping for efficacy will not be considered for this interim analysis. 
Therefore, only nominal alpha spending 0.00001 will be performed due to the interim analysis. 
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No recruitment stop is planned for this interim analysis. If futility is demonstrated in the interim 
analysis, enrollment will be halted and safety and efficacy data will be further evaluated before 
making the decision of stopping the study permanently. Otherwise, the enrollment will be 
continued to 150 relapsed/ refractory subjects in Cohort 1.   
Details of the interim analysis is provided in an interim analysis SAP. 
 
8 
 CHANGES IN THE PLANNED ANALYSIS 
8.1 
TIMING OF THE PRIMARY EFFICACY ANALYSIS 
In the protocol amendment 4.0, it is specified that the primary efficacy analysis will be 
conducted approximately 12 months after the last relapsed/refractory subject is randomized. In 
this version of SAP, the primary efficacy analysis is planned to occur at least 15 months after 
90% enrollment in the RR Analysis Set was completed. At the time, 90% of subjects in Cohort 1 
are expected to have at least 19 months of median study follow-up. This is considered sufficient 
to demonstrate an improvement of clinical benefit of zanubrutinib over ibrutinib.     
8.2 
TESTING STRATEGY FOR THE PRIMARY ENDPOINT FAMILY AND THE KEY SECONDARY 
ENDPOINT FAMILY  
Testing strategy and multiplicity adjustment for the primary and key secondary endpoint 
hypotheses are added to Section 6.2.4 to provide a formal and rigorous testing framework based 
on Bretz (2009). As a result, the family-wise error rate (FWER) within the primary hypotheses 
family is controlled at a 0.025 level (1-sided) and the FWER within both primary and secondary 
hypotheses (i.e. the study-wise error rate) is controlled at a 0.05 level (1-sided).  
8.3 
AGE GROUP AS COVARIATE IN STRATIFIED ANALYSIS OF THE PRIMARY AND SECONDARY 
ENDPOINTS 
Age group (<=65 vs >65) is added as additional covariate in the stratified analysis of the primary 
and secondary endpoints because it is considered as an important prognostic factor and one of 
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five variables included in the final predictive model in IPSS-WM (Morel, 2009). The cutoff of 
age group is based on IPSS age variable cutoff for low risk and intermediate/high risk subjects. 
8.4 
TIMING OF THE FINAL ANALYSIS OF PFS 
In this version of SAP, it is added that the final analysis of PFS will be performed approximately 
48 months after study start as described in Sec 6.4.2.2. Assuming an exponential distribution for 
PFS, the control arm median PFS of 84 months, a hazard ratio of 0.8, approximately 33 events 
are expected to be accumulated for Cohort 1 relapsed and refractory subjects at the time of the 
final PFS analysis. The estimated landmark PFS rates at 36-month for Arm A and Arm B are 
0.79 and 0.74, respectively based on the above assumptions.    
 
 
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9 
REFERENCES 
Bretz, F., Maurer, W., and Paul Gallo, P. 
-J. Wang, Journal of 
Biopharmaceutical Statistics, 19:1, 25-34. 
Brookmeyer, R.  and Crowley, J.  (1982) A confidence interval for the median survival time.  
Biometrics, 38, 29-41.   
Dimopoulos MA, et al. Treatment recommendations for patients with Wanldenstrom 
macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014. 
124(9):1404-1411. 
Dimopoulos MA, et al. Ibrutinib for patients with rituximab-refractory Waldenström's 
macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, 
phase 3 trial. Lancet Oncology. 2017.18 (2):241-250. 
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) 
Greenwood, M.  (1926) The natural duration of cancer.  Public health and medical subjects, 33: 
1-26.   
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. 
J. P. (2008). 
Recommendations for the Primary Analysis of Continuous Endpoints in Longitudinal Clinical 
Trials. Drug Information Journal, 42(4), 303 319.  
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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. 
Morel, P., Duhamel, A., Gobbi, P., Dimopoulos, M. A., Dhodapkar, M. V., McCoy, J., Crowley, 
J., Ocio, E. M., Garcia-Sanz, R., Treon, S. P., Leblond, V., Kyle, R. A., Barlogie, B., & Merlini, 
G. (2009). International prognostic scoring system for Waldenström macroglobulinemia. Blood, 
113(18), 4163-4170. 
NCI-CTCAE v4.03 
http://www.oncology.tv/SymptomManagement/NationalCancerInstituteUpdatesCTCAEtov403.a
spx. Accessed 23 May 2019. 
Owen et al. Response assessment in Waldenström macroglobulinaemia: update from the VIth 
International Workshop. Br J Haematol. 2013 Jan;160(2):171-6. 
Macroglobulinemia. IWWM. 2015: v2 
Sato, T. (1989). On the Variance Estimator of the Mantel-Haenszel Risk Difference. Biometrics. 
45, 1323 1324, letter to the editor. 
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.  
2015 Apr 9;372(15):1430-40. 
 
 
 
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10 APPENDIX 
10.1 APPENDIX A: IMPUTATION OF MISSING OR PARTIALLY MISSING DATES 
In general, missing or partial dates will not be imputed as data level.  The following rules will 
apply for the specific analysis and summary purposes mentioned below only.   
A.1 Prior/Concomitant Medications/Procedures 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant.  The following rules will be applied to 
impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
If both month and day are missing, then set to January 01 
If only day is missing, then set to the first of the month 
If end date of a medication is partially missing, impute as follows: 
If both month and day are missing, then set to December 31 
If only day is missing, then set to last day of the month 
If start date or end date of a medication is completely missing, do not impute. 
A.2 Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates.  
When the start date or end date of an AE is partially missing, the date will be imputed to 
determine whether the AE is treatment-emergent.  When in doubt, the AE will be considered 
treatment emergent by default.  The following rules will be applied to impute partial dates for 
AEs: 
If start date of an AE is partially missing, impute as follows: 
If both month and day are missing, then the imputed day and month will be January 01 or 
the first dosing date if they have the same year, whichever is later.   
If only day is missing, then the imputed day will be the first day of the month or the first 
dosing date if they have the same month and year, whichever is later  
If start date is completely missing, the imputed day will be the first dosing date as long as 
AE end date is not before the first dosing date.   
If end date of an AE is partially missing, impute as follows: 
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If both month and day are missing, then set to December 31 
If only day is missing, then set to last day of the month 
If end date is completely missing, do not impute. 
A.3 Deaths 
In case complete death dates are not recorded, impute as follows: 
If both month and day are missing, then the imputed month and day will be 01Jan or the 
last date of the last date of subject known to be alive + 1, whichever is later. 
If only day is missing, the death will be assumed to be on the first day of the month or the 
last date of subject known to be alive +1, whichever is later.   
A.4 New Anti-cancer therapy 
If the start day of a subsequent anti-cancer therapy is incomplete or missing, impute as follows:  
If both month and day are missing, then the imputed month and day will be 01Jan or the 
last day of the month for the last adequate disease assessment if they have the same year. 
If only day is missing, then the imputed day will be the first day of the month. 
A.5 Diagnosis 
If a diagnosis date is partially missing, impute as follows: 
If both month and day are missing, then set to January 01 
If only day is missing, then set to the first of the month 
If a diagnosis date is completely missing, do not impute. 
A.6 Prior Therapy/Response to Prior Therapy 
If a prior therapy or response to prior therapy date is partially missing, impute as follows: 
If only day is missing, then set to the 15th of the month 
 
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10.2 APPENDIX B: WM INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS) 
Score: 
Age > 65 yr 
Hemoglobin  11.5 g/dL 
Platelet count  100 x 109/L 
2-microglobulin > 3 mg/L 
Monoclonal IgM concentration (M-protein by SPEP)> 7.0 g/dL 
IPSS: 
Low 
 
 
0 or 1 (except age) score 
Intermediate  
age or 2 scores 
High  
 
 3 scores 
Source: Morel (2009) 
 
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