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

Background: Aggressive B-cell lymphomas can be cured but people with disease that resists treatment or that returns after treatment have poor outcomes with standard therapies. Indolent B-cell lymphomas are generally incurable with standard therapy and treatment is aimed at controlling symptoms and achieving a durable remissions. Researchers want to see if a combination of drugs can help patients with both aggressive and indolent B-cell lymphomas. Objective: To learn if it is safe and effective to give polatuzumab along with venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide to people with certain B-cell lymphomas. Eligibility: Adults ages 18 and older with relapsed and/or refractory B-cell lymphoma who have had at least one prior cancer treatment. Design: Participants will be screened with: Medical history Physical exam Assessment of how they do their daily activities Blood and urine tests Heart function test Tissue biopsy (if needed) Body imaging scans (may get a contrast agent through an intravenous (IV) catheter) Participants will have a bone marrow aspiration and/or biopsy. A needle will be put into the hipbone. Bone marrow will be removed. Participants may give blood, tissue, saliva, or cheek swab samples. They may have optional biopsies. Screening tests will be repeated during the study. Treatment will be given for up to 6 cycles. Each cycle lasts 21 days. Participants will take venetoclax and prednisone tablets by mouth. They will take ibrutinib and lenalidomide capsules by mouth. They will get obinutuzumab and polatuzumab by IV infusion. They will keep a medicine diary. Participants will visit the clinic 30 days after treatment ends. They will have follow-up visits for 5 years. If needed, they can visit their local doctor instead. They may be contacted by phone, mail, etc., for the rest of their life....

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.