Testing the Combination of Anti-cancer Drugs Mosunetuzumab, Polatuzumab Vedotin, and Lenalidomide for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVE: I. To determine the safety and tolerability of mosunetuzumab + polatuzumab vedotin + lenalidomide in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). SECONDARY OBJECTIVE: I. To observe and record anti-tumor activity of the combination of mosunetuzumab, polatuzumab vedotin, and lenalidomide in R/R DLBCL. EXPLORATORY OBJECTIVES: I. To assess the efficacy in patients that have failed prior polatuzumab vedotin containing regimens (i.e., patients who progressed/relapsed after prior polatuzumab). II. To assess anti-tumor activity in patients that a) have ≥ Deauville score of 3 within the first 90 days after standard of care chimeric antigen receptor (CAR) T-cell therapy; b) other patients who have failed prior treatment (e.g. relapse after Day 90 from CAR-T, or relapsed after other therapies and were not considered candidates for CAR-T). III. To identify biomarkers that can predict the response to mosunetuzumab + polatuzumab vedotin + lenalidomide. IV. To describe anti-tumor activity in patients whose tumors have previously failed to respond to polatuzumab (i.e., patients who progressed/relapsed after prior polatuzumab). OUTLINE: This is a dose-escalation study of mosunetuzumab, followed by a dose-expansion study. Patients receive mosunetuzumab intravenously (IV) over 2-4 hours on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Cycles repeat every 28 days for 8 cycles in patients who achieve a complete response (CR) or up to 17 cycles for patients with a partial response (PR) or stable disease (SD) in the absence of disease progression or unacceptable toxicity. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 of each cycle and lenalidomide orally (PO) on days 1-21 of each cycle. Cycles of polatuzumab vedotin repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Cycles of lenalidomide repeat every 28 days for 8 cycles in patients who achieve CR, or up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo positron emission tomography (PET)/ computed tomography (CT) and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3-6 months for 2 years.