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)

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
a. 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 3)
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
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 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.
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
- Combined (estrogen and progestogen containing) hormonal contraception
associated with the inhibition of ovulation
o Oral, intravaginal or transdermal
- Progestogen-only hormonal contraception associated with the inhibition of
ovulation
o Oral, injectable, implantable
- An intrauterine device (IUD)
- 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 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

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
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. Active CNS involvement by WM. Patients with a previous history of CNS
involvement must undergo MRI and 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 BGB-3111 or ibrutinib