Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) 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 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 targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis); BTK (B-cell receptor signaling and NFKB); Cereblon (NFKB) and CD20. Objectives: Phase 1b: To determine the maximum tolerated dose (MTD) and the safety and toxicity profile of the combination of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab and Revlimid(R) (ViPOR) in relapsed/refractory B-cell malignancies Phase 2: To determine the overall response rate (ORR) and complete response (CR) rate of ViPOR in relapsed/refractory B-cell malignancies Eligibility: Women and men greater than or equal 18 years of age ECOG performance status of less than or equal to 2 Histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma, excluding CLL/SLL. NOTE: untreated and relapsed and/or refractory MCL are included in the phase 2 MCL expansion. Adequate organ function unless dysfunction secondary to lymphoma effect Design: Open-label, single-center, non-randomized phase 1b/2 study Phase 1b: Standard 3 + 3 design will be used to determine the MTD of dose-escalated venetoclax with fixed dose ibrutinib, prednisone, obinutuzumab and Revlimid(R) (ViPOR) in relapsed/refractory B-cell malignancies Phase 2: Expansion cohorts of aggressive and indolent non-MCL patients and MCL patients will be treated at the MTD to determine the ORR and CR rate in these subtypes. Maximum 6 cycles of combination targeted therapy every 21 days To explore all dose levels in both non-MCL and MCL patient cohorts in the phase 1b study, and to assess the ORR and CR rate in aggressive and indolent non-MCL and MCL patient cohorts in a phase 2 dose expansion at the MTD, the accrual ceiling will be set at 155 patients.