Testing Continuous Versus Intermittent Treatment With the Study Drug Zanubrutinib for Older Patients With Previously Untreated Mantle Cell Lymphoma

PRIMARY OBJECTIVE:

I. To compare time to first progression or death (progression free survival [PFS]1) with continuous treatment (Arm A) and time to second progression or death (PFS2) with intermittent treatment that is restarted at first progression (Arm B).

KEY SECONDARY OBJECTIVE:

I. To compare overall survival between patients who achieve a complete remission (CR) with induction therapy subsequently treated with continuous treatment versus (vs.) intermittent treatment as part of maintenance therapy.

SECONDARY OBJECTIVES:

I. To determine overall response rate (ORR) and CR rate to induction therapy with zanubrutinib and rituximab in previously untreated MCL.

II. To determine adverse events during induction and post-induction in each study arm (Arm A and B) by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

III. To determine PFS1, event free survival (EFS) and overall survival (OS) in each study arm (A and B).

IV. To determine the overall response rate (ORR) and complete response rate (CR) after restarting zanubrutinib, following the first progression, in the intermittent treatment arm (Arm B).

V. To compare burden of symptomatic adverse events (AEs) as assessed by Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients randomized to Arm A versus Arm B.

QUALITY OF LIFE PRIMARY OBJECTIVE:

I. To compare health-related quality of life (QOL) at 12 months post-randomization as assessed by the Functional Assessment of Cancer Therapy (FACT) Lymphoma Symptom Index-18 (FLYMSI-18) total score between patients randomized to Arm A versus Arm B.

QUALITY OF LIFE SECONDARY OBJECTIVES:

I. To compare health-related QOL at other time points as assessed by the FLYMSI-18 total score between patients randomized to Arm A versus Arm B.

II. To compare burden of symptomatic AEs as assessed by PRO-CTCAE between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment.

QUALITY OF LIFE EXPLORATORY OBJECTIVES:

I. To compare the geriatric functional and cognitive PRO as assessed by Elderly Functional Index (ELFI) and Neurology (Neuro) QOL in Arm A versus Arm B.

II. To compare cognitive function at various time points as assessed by the Neuro-QOL between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment.

EXPLORATORY OBJECTIVES:

I. To evaluate the completion rate of a lymphoma-specific patient assessment of life survey (PALS) with patient directed questions on life, health, and social determinants of health (SDH) and assess the impact of the survey collected data on outcomes for all enrolled patients (study arms A and B).

II. To evaluate minimal residual disease (MRD) in those patients who achieve a CR after induction therapy (arms A and B) and how detectable MRD status changes after continued therapy vs. discontinuation of therapy (i.e. arms A vs. B).

OUTLINE:

INDUCTION THERAPY: Patients receive zanubrutinib orally (PO) twice daily (BID) on days 1-28 of each cycle and rituximab intravenously (IV) on day 1 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. . Patients undergo bone marrow biopsy and fluciclovine F18 (FDG) positron emission tomography (PET)/ computed tomography (CT) or CT throughout the trial. Patients may also undergo esophagogastroduodenoscopy (EGD) and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial.

MAINTENANCE THERAPY: Patients achieving a CR after induction therapy are randomized to 1 of 2 arms.

ARM A: Patients receive zanubrutinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days until first disease progression on study. Patients undergo CT or magnetic resonance imaging (MRI) or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial.

ARM B: Patients undergo observation until first disease progression and then receive zanubrutinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days until second disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial and may undergo bone marrow biopsy on study.

After completion of study treatment, patients are followed within 30 days and every 6 months for 10 years.

Inclusion criteria

• • Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by immunohistochemical stains and/or evidence of CCND1 rearrangement or t(11;14)(q13;q32) as confirmed by the enrolling center (such as by fluorescence in situ hybridization [FISH], polymerase chain reaction [PCR]/sequencing, karyotype). Patients with cyclin D1 and/or t(11;14) negative mantle cell lymphoma with an expression profile suggesting a diagnosis of mantle cell lymphoma [MCL] such as SOX11 expression are also eligible

• Any stage allowed (stage I-IV)

• Patient must have at least one objective measurable disease parameter by PET or CT. Measurable disease in the liver is required if the liver is the only site of lymphoma OR bone marrow involvement by MCL
• Steroids for management of mantle cell lymphoma are allowed up to a dose of prednisone 100mg/day (or equivalent) for up to 7 days prior to registration
• 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 if thrombocytopenia is due to 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)
• Known QT correction formula (QTcF) > 480 msecs based on Fredericia's formula (unless pacemaker in place)
• 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
• Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study.
• Patients on strong CYP3A4 inducers must discontinue the drug 14 days prior to registration.