A Phase 3 Randomized, Open-Label, Multicenter 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

JRCT ID: jRCT2041210121

Registered date:26/12/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Mantle Cell Lymphoma
• Date of first enrollment: 11/06/2021
• Target sample size: 25
• Countries of recruitment: Australia,Japan,Austria,Japan,Belgium,Japan,China,Japan,France,Japan,Germany,Japan,Ireland,Japan,Italy,Japan,New Zealand,Japan,Poland,Japan,Spain,Japan,Taiwan,Japan,Ukraine,Japan,United Kingdom,Japan,United States,Japan,Canada,Japan,Netherlands,Japan,Portugal,Japan,Russia,Japan,Turkey,Japan,Romania,Japan
• Study type: Interventional
• Intervention(s): Two 80mg capsules of BGB-3111 are administrated orally twice daily (160mg twice daily)

Outcome(s)

• Primary Outcome: The primary endpoint is PFS as determined by independent central review using the Lugano Classification for NHL and defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first.

Key inclusion & exclusion criteria

• Age minimum: >= 60age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. >= 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)
2. 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)
3. No prior systemic treatments for MCL
4. 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
5. Availability of archival tissue confirming diagnosis of MCL, or willing to undergo fresh tumor biopsy
6. ECOG performance status of 0, 1, or 2
7. Life expectancy of >= 3 months
8. Adequate organ function defined as:
a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor support within 7 days)
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 x upper limit of normal (ULN)
d. Serum total bilirubin <= 1.5 x ULN (unless documented Gilberts syndrome)
9. 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.
10. 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.
11. Ability to provide written informed consent and ability to understand and comply with the requirements of the study
12. 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

Exclude criteria

1. Known central nervous system involvement by lymphoma
2. Prior hematopoietic stem cell transplantation
3. Prior exposure to a BTK inhibitor, rituximab, or bendamustine
4. Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
5. 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
6. 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 Fridericias 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
7. 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
8. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
9. 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
10. Active fungal, bacterial and/or viral infection requiring systemic therapy
11. Underlying medical conditions that, in the investigators opinion, will render the administration of study drug hazardous or obscure the interpretation of safety or efficacy results
12. 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.
13. Major surgery within 4 weeks of the first dose of study drug
14. Pregnant or lactating women
15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
16. Ongoing alcohol or drug addiction
17. Hypersensitivity to zanubrutinib, bendamustine, or rituximab or any of the other ingredients of the study drugs
18. Requires ongoing treatment with a strong CYP3A inhibitor or inducer (see Appendix 3)
19. Concurrent participation in another therapeutic clinical trial.

Related Information

• Primary Sponsor: Tsuji Hitoshi
• Secondary ID(s): NCT04002297