A Study of Zanubrutinib, Obinutuzumab, and Sonrotoclax in People With Mantle Cell Lymphoma

A Phase II Study of MRD-guided Zanubrutinib, Obinutuzumab, and Sonrotoclax (BOSon) for Previously Untreated Transplant-ineligible Patients With Mantle Cell Lymphoma

The researchers are doing this study to find out whether the combination of zanubrutinib, obinutuzumab, and sonrotoclax (BOSon) is an effective treatment approach for people with mantle cell lymphoma (MCL).

Inclusion Criteria:

• Documentation of disease: Patients must have pathologically confirmed MCL at the treating institution

• Evaluable disease, stage II-IV

  o Patients with non-nodal leukemic MCL may enroll even without FDG PET/CT measurable disease; an end-of-treatment BMBx to confirm response is required in such cases

• Age ≥ 65 years at screening

• If Age <65, then required to fulfill one of the following criteria disqualifying for autologous transplant (autoHCT):

  • Comorbid disease(s) such as CAD, heart failure, pulmonary dysfunction, liver, or kidney dysfunction that precludes autoHCT based on expected increased morbidity
  • ECOG ≥ 2 (Appendix 1) due to comorbidities
  • Ejection fraction ≥ 35% and <45%
  • Impaired pulmonary function test with DLCO <50% of expected
  • Medical conditions that in the opinion of the treating physician in consultation with the MSK PI or Co-PI preclude autoHCT

• Not pregnant and not nursing

• Required organ function:

  o Adequate hematologic function, defined as:

• Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 or >= 500 cells/mm3 if cytopenia is related to MCL (bone marrow involvement)

• Platelets ≥ 75,000 cells/mm3 or 25,000 if related to MCL

• Hemoglobin ≥ 9 g/dL or 8 g/dL if related to MCL

Adequate renal function defined as follows:

• Creatinine clearance (CrCL) of ≥ 30 mL/min by the Cockcroft-Gault formula

  o Adequate hepatic function defined as follows:

• Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN; patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may enroll)

• AST and ALT ≤ 2 x institutional ULN

Adequate cardiac function defined as follows:

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
• To be eligible for this trial, patients should be class 2B or better (see Appendix 2: New York Heart Association (NYHA) Functional Classification).
• No myocardial infarction within 6 months of screening
• No unstable angina within 3 months of screening
• No history of life-threatening arrhythmias
• No CVA within 6 months from C1D1 Patient or healthcare proxy must be able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
• HIV infection: Patients with a history of HIV infection that is well controlled on antiretroviral therapy are eligible if all of the following criteria are met: (1) undetectable HIV viral load by standard clinical assay AND (2) CD4+ T cell count of ≥200 cells/microliter. NOTE: Many HIV treatment regimens have the potential for drug-drug interactions; concomitant antiretroviral therapy should be cleared by a clinical pharmacist and approved by the site PI.
• Hepatitis B: Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing per SOP
• Hepatitis C: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA

Exclusion Criteria:

• Active infection requiring parenteral antibiotic(s)

• 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

• Patients unable to swallow capsules or those with disease(s) or conditions significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic/active inflammatory bowel disease, or partial or complete bowel obstruction

• Patients undergoing major surgery within 4 weeks of the first dose of study drug

• Patients with ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures

• Patients receiving treatment with any moderate or strong CYP3A4 inhibitor or moderate or strong CYP3A4 inducer ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer are ineligible

• Concurrent participation in another therapeutic clinical trial

• Patients with a prior or concurrent malignancy except for those whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen

• Concomitant Medications: Concomitant medications use should only exclude patients from trial participation when clinically relevant known or predicted drug-drug interactions (see Section 5, Appendix 8) or potential overlapping toxicities will impact safety or efficacy.

  o The following are exclusionary: receiving treatment with any moderate or strong CYP3A4 inhibitor or moderate or strong CYP3A4 inducer ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer.

• History of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent (s) (or any of its excipients).

• Prior treatment:

  • Previous systemic therapy is prohibited
  • Systemic steroids are allowed for urgent disease control, improvement of performance status, or non-cancer indications

• Must be <14 days' duration and ≤ 100 mg/day prednisone equivalent

• Steroids must be discontinued prior to C1D1 study treatment

• Inhaled, topical, and replacement/stress steroids are permitted