Non-covalent BTK Inhibitor Nemtabrutinib in Combination With the CD20 Monoclonal Antibody Rituximab for the Treatment of Marginal Zone Lymphoma

PRIMARY OBJECTIVES: I. To evaluate safety and tolerability of nemtabrutinib administered in combination with rituximab (NR) in patients with marginal zone lymphoma (MZL). (Safety lead-in) II. To evaluate efficacy of nemtabrutinib administered in combination with rituximab (NR) in patients with MZL based on complete response rate. (Phase 2) SECONDARY OBJECTIVE: I. To evaluate efficacy of nemtabrutinib administered in combination with rituximab in patients with MZL based on overall response rate (ORR), progression free survival, duration of response, and overall survival. EXPLORATORY OBJECTIVE: I. To evaluate B cell receptor pathway resistance mechanisms in non-responders and patients that relapse. OUTLINE: Patients receive nemtabrutinib orally (PO) once daily (QD) on days 1-28 of each cycle and rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1 and 3 and on day 1 of cycles 5-12. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After 12 cycles, patients with a complete response (CR) or partial response (PR) may optionally continue to receive nemtabrutinib PO QD for up to an additional 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and positron emission tomography (PET)/computed tomography (CT), CT, or magnetic resonance imaging (MRI) throughout the study. Additionally, patients may optionally undergo bone marrow biopsy and tissue biopsy on study. After completion of study treatment, patients are followed up at 30 days. Patients with CR after 24 cycles or with progressive disease (PD) after 12 cycles are followed every 3 months for up to 1 year. Patients with CR after 12 cycles may optionally follow up every 3 months for up to 2 years.