Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies

Background: * Indolent B-cell malignancies are associated with frequent disease relapse * Standard frontline therapy includes a monoclonal anti-cluster of differentiation 20 (CD20) antibody with or without chemotherapy; novel targeted therapies have changed the treatment landscape and are preferred therapy for some patients with high-risk molecular features * Targeted therapies given indefinitely add to drug resistance, treatment-emergent toxicities, and non-compliance * Cluster of differentiation 47 (CD47) is a rational target for indolent B-cell malignancies; CD47 expression is higher in tumor cells than normal B-cells, and blocking CD47 results in phagocytosis of tumor cells * Magrolimab is an anti-CD47 monoclonal antibody with activity in refractory indolent lymphomas when combined with rituximab (a first generation anti-CD20 monoclonal antibody) * Obinutuzumab is a novel anti-CD20 monoclonal antibody with enhanced binding to the Fc receptor that may improve antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis, when combined with magrolimab * We aim to test the safety and efficacy of venetoclax when added to the backbone of magrolimab and obinutuzumab in patients with relapsed or refractory indolent B-cell malignancies * Treatment duration will be response-adapted and time-limited in all patients Objective: -To determine the safety of the triplet combination of venetoclax, magrolimab and obinutuzumab in relapsed and refractory indolent B-cell malignancies Eligibility: * Follicular lymphoma (FL) (grades 1-2, or 3a), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) with greater than or equal to 2 prior therapies, with at least one of those therapies containing an anti-CD20 monoclonal antibody * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Adequate bone marrow and organ function Design: * Phase 1 study with expansion cohorts of up to 76 patients with relapsed or refractory FL, MZL, MCL or CLL * The safety profile of magrolimab, venetoclax, and obinutuzumab will first be determined in a dose-finding phase of up to 24 patients (6-12 patients with FL and 6-12 patients with MZL, MCL or CLL). Patients without dose-limiting toxicity (DLT) will receive an additional 5 cycles (total 6 cycles) of the triplet combination. * After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for 2 cycles in a window for translational research. After the window, venetoclax will be added and patients will receive 6 cycles (total 8 cycles) of the triplet combination. * Patients who achieve a complete response (CR) (after a total of 6 cycles of the triplet combination) will stop treatment and initiate active monitoring with radiologic imaging and assays for circulating tumor DNA (ctDNA); if these patients relapse, they can be retreated with 6 additional cycles. Patients who achieve partial response (PR) after 6 cycles of the triplet will continue for an additional 6 cycles; then, will initiate active monitoring.