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A Randomized Phase 3 Trial of Continuous vs. Intermittent Maintenance Therapy With Zanubrutinib as Upfront Treatment in Older Patients With Mantle Cell Lymphoma


Description

This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a complete remission (CR) with rituximab works in older adult patients with mantle cell lymphoma (MCL) who have not received treatment in the past (previously untreated). Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to continue administering the drug indefinitely until disease progression. This continuous treatment comes with clinical as well as financial toxicity, which could be especially detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus rituximab therapy, it may be safe and equally effective to stop treatment and restart zanubrutinib upon disease progression rather than continuing indefinitely in previously untreated older

Trial Eligibility

Inclusion Criteria: * • Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH) as confirmed by the enrolling center * Any stage allowed (stage I-IV) * 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 * Steroids for management of mantle cell lymphoma are allowed up to a dose of prednisone 100mg/day (or equivalent) for up to 7 days * No prior systemic treatment for mantle cell lymphoma * No prior radiation treatment for stage I MCL * No prior exposure to a BTK inhibitor or anti-CD20 monoclonal antibody * No prior stem cell transplant * Age \>= 70 years OR age \>= 60 to \< 70 years with comorbidities precluding autologous stem cell transplantation (autoSCT) including at least one of the following: a) cardiac ejection fraction (EF) \< 45%, b) diffusing capacity for carbon monoxide \< 60% predicted; c) creatinine clearance \< 70 but \> 30ml/minute (min); 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; or e) Cumulative Illness Rating Scales (CIRS) total score \> 6 * ECOG Performance Status 0-2 * Absolute neutrophil count (ANC) \>= 750/mm\^3 (without growth factor support within 7 days) * Platelet count \>= 75,000/mm\^3 (or \>= 50,000/mm\^3 for patients with bone marrow involvement of lymphoma) without growth factor support or transfusion within 7 days * Creatinine clearance \>= 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 * Total bilirubin =\< 1.5 x upper limit of normal (ULN) (unless documented Gilbert's syndrome) * Aspartate transferase (AST) / alanine transaminase (ALT) =\< 3 x ULN * Patients should not be considered candidates for stem cell transplant or must have declined a stem cell transplant strategy * No clinically significant cardiovascular disease including the following * Unstable angina within 3 months before registration * New York Heart Association class III or IV congestive heart failure * History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) * QT correction formula (QTcF) \> 480 msecs based on Fredericia's formula * History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * No active Hepatitis B or Hepatitis C infection. Patients with prior hepatitis B virus (HBV) exposure (positive HBV core antibody and/or surface antigen) are eligible if they have no detectable viral load, and are taking appropriate prophylactic antiviral therapy to prevent reactivation. Patients with history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * No 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 * No history of stroke or intracranial hemorrhage within 6 months prior to registration * No 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. Patient must be able to swallow pills * Potential trial participants should have recovered from major surgery * No vaccination with a live vaccine within 35 days prior to registration * No hypersensitivity to zanubrutinib or rituximab or any of the other ingredients of the study drugs * Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. * Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment * Avoid use of moderate CYP3A4 inhibitors, PGP inhibitors, and moderate CYP3A4 inducers * Archival tissue must be available for submission in all patients for histopathology review, though participation in correlative substudies is optional

Study Info

Organization

Alliance for Clinical Trials in Oncology


Primary Outcome

Progression-free survival (PFS) 1 (Arm A)


Outcome Timeframe Time from randomization until the earlier of first progression or death from any cause, assessed up to 10 years

NCTID NCT05976763

Phases PHASE3

Primary Purpose TREATMENT

Start Date 2023-09-08

Completion Date 2038-08-31

Enrollment Target 421

Interventions

DRUG Zanubrutinib

BIOLOGICAL Rituximab

OTHER Patient Observation

PROCEDURE Bone Marrow Biopsy

OTHER Fludeoxyglucose F-18

PROCEDURE Positron Emission Tomography

PROCEDURE Computed Tomography

PROCEDURE Magnetic Resonance Imaging

PROCEDURE Esophagogastroduodenoscopy

PROCEDURE Colonoscopy

PROCEDURE Biospecimen Collection

OTHER Questionnaire Administration

Locations Recruiting

City of Hope Comprehensive Cancer Center

United States, California, Duarte


City of Hope at Irvine Lennar

United States, California, Irvine


Cedars Sinai Medical Center

United States, California, Los Angeles


Smilow Cancer Hospital-Derby Care Center

United States, Connecticut, Derby


Smilow Cancer Hospital Care Center-Fairfield

United States, Connecticut, Fairfield


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