Study Comparing Zanubrutinib (BGB-3111) plus Rituximab Versus Bendamustine plus Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma Who Are Ineligible for Stem Cell Transplantation

Prior treatment

• Major surgery within 4 weeks of the first dose of study drug
• Vaccination with a live vaccine within 35 days prior to the first dose of study drug
• Ongoing alcohol or drug addiction
• Requires ongoing treatment with a strong CYP3A inhibitor or inducer (see Appendix 3)
• Concurrent participation in another therapeutic clinical trial.
• Prior hematopoietic stem cell transplantation
• Prior exposure to a BTK inhibitor, rituximab, or bendamustine
• Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
• Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before Screening b. Unstable angina within 3 months before Screening c. New York Heart Association class III or IV congestive heart failure (see Appendix 6) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) e. QTcF > 480 msecs based on Fridericia’s formula f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at Screening
• History of stroke or intracranial hemorrhage within 6 months before first dose of study drug

Other illness

• Active fungal, bacterial and/or viral infection requiring systemic therapy
• Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of safety or efficacy results
• Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
• Hypersensitivity to zanubrutinib, bendamustine, or rituximab or any of the other ingredients of the study drugs
• Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer
• History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

Other

• Known central nervous system involvement by lymphoma
• Pregnant or lactating women
• Patients enrolled in Germany only, who are severely immunocompromised.

• ≥ 70 years of age at the time of informed consent, OR ≥ 60 and < 70 years of age with comorbidities precluding autologous stem cell transplantation including at least one of the following: a. Cardiac ejection fraction (LVEF) ≤ 45% b. Diffusing capacity for carbon monoxide (DLCO) ≤ 60% predicted c. Creatinine clearance < 70 but ≥ 30 mL/min (if estimated by the Cockcroft-Gault equation, must be confirmed by nuclear medicine scan or 24-hour urine collection) d. Eastern Cooperative Oncology Group (ECOG) performance status of 2, which poses an unacceptable risk of toxicity for high-dose therapy and stem cell transplantation e. Cumulative Illness Rating Scale (CIRS) total score > 6 (Appendix 9)
• Male patients are eligible if abstinent, vasectomized or if they agree to the use of barrier contraception in combination with other methods described in Section 5.3 during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
• Ability to provide written informed consent and ability to understand and comply with the requirements of the study
• For all patients irrespective of their age, creatinine clearance of ≥ 30 mL/min determined by either: a. Estimation using the Cockcroft-Gault equation or b. Measurement by nuclear medicine scan or 24 hour urine collection
• Histologically confirmed diagnosis of MCL based on the World Health Organization 2016 classification of tumors of hematopoietic and lymphoid tissue (Swerdlow et al, 2016), including demonstration of positive cyclin D1 and/or t(11;14) a. For patients enrolled in France only, MCL disease must be classified as Ann Arbor Stage II, III, or IV
• No prior systemic treatments for MCL
• Presence of measurable disease, defined as ≥ 1 nodal lesion that is > 1.5 cm in longest diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter
• Availability of archival tissue confirming diagnosis of MCL, or willing to undergo fresh tumor biopsy
• ECOG performance status of 0, 1, or 2
• Life expectancy of ≥ 3 months
• Adequate organ function defined as: a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor support within 7 days) For patients enrolled in the United Kingdom (UK) and Germany only, ANC must be > 1000/mm3 b. Platelets > 75,000/mm3 (or ≥ 50,000/mm3 for patients with bone marrow involvement of lymphoma); without growth factor support or transfusion within 7 days c. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 × upper limit of normal (ULN) d. Serum total bilirubin ≤ 1.5 × ULN (unless documented Gilbert’s syndrome) For patients with Gilbert’s syndrome enrolled in the UK only, direct bilirubin must be ≤ 1 x ULN e. For patients enrolled in the UK only, international normalized ratio (INR) < 1.5 for patients not receiving therapeutic anticoagulation; INR 2.0 to 3.0 for patients receiving therapeutic anticoagulation
• Female patients of childbearing potential must practice highly effective methods of contraception (Section 5.3) initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib or bendamustine, or 12 months after the last dose of rituximab, whichever is longer.