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

Summary

Objectives

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 cycles 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 (EFLI) 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 (EDG) 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.

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