Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid in Combination With Polatuzumab (ViPOR-P) in Relapsed/Refractory B-cell Lymphoma

Background: * Combination chemotherapy with rituximab has been the mainstay of treatment for CD20-positive B-cell lymphomas. * Significant advances have been made in curing aggressive B-cell lymphomas with chemoimmunotherapy, but indolent lymphomas and relapsed/refractory aggressive lymphomas remain mostly incurable with chemotherapy alone. * Targeted therapies, aimed at disrupting key survival pathways in lymphoid malignancies, are emerging and showing significant activity in non-Hodgkin lymphoma (NHL) in both the relapsed and first-line settings. * Mechanistically based combinations of targeted agents are likely to benefit patients who cannot tolerate or who relapse after or are refractory to standard chemoimmunotherapy. * ViPOR-P targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis); BTK (B-cell receptor signaling and NF-kB); Cereblon (NF-kB) and CD20 with additional genotoxic stress from the anti-mitotic antibody-drug conjugate targeting CD79b, polatuzumab. Objectives: * To determine the maximum tolerated dose (MTD) and the safety and toxicity profile of polatuzumab and venetoclax in combination with ibrutinib, prednisone, obinutuzumab and Revlimid (lenalidomide) (ViPOR-P) in relapsed/refractory B-cell lymphomas * To determine the complete response (CR) rate of ViPOR-P in relapsed/refractory non-GCB DLBCL Eligibility: * Individuals \>= 18 years of age * ECOG performance status of \<= 2 * Histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma, excluding mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) * Adequate organ function unless dysfunction secondary to lymphoma Design: * Open-label, single-center, non-randomized phase 1 study * Standard 3 + 3 design will be used to determine the MTD of polatuzumab and venetoclax in combination with ibrutinib, prednisone, obinutuzumab and Revlimid (lenalidomide) (ViPOR-P) in relapsed/refractory B-cell lymphomas * A small expansion cohort will be treated at the MTD for a further analysis of safety and preliminary activity. * An expansion cohort of 32 patients (including 27 new patients + 5 patients already enrolled at DL3/MTD) with non-GCB DLBCL will be treated at the MTD to determine the CR rate to ViPOR-P of this aggressive lymphoma subtype. * Maximum 6 cycles of combination targeted therapy every 21 days. * To explore all dose levels in the phase 1 study and to assess the CR rate in non-GCB DLBCL patients in a dose expansion at the MTD as well as to allow for the possibility of a few screen failures and inevaluable subjects, the accrual ceiling will be set at 55 patients.