Doxorubicin, CC-(486) (5-azacitidine), Romidepsin, and Duvelisib (hARD) for T-cell Lymphoma

Background: T-cell lymphomas (TCLs) are a heterogeneous group of lymphoid malignancies defined by clonal proliferation of post-thymic T lymphocytes. Patients with newly diagnosed TCLs are most commonly treated with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen, with less than 30% having durable complete responses (CRs). Of the chemotherapy agents used, doxorubicin is the one which was consistently associated with prolonged progression-free survival (PFS) and overall survival (OS) in retrospective studies. Treatment options for the 70% of patients with TCL who relapse are limited and of minimal efficacy; novel treatment strategies are urgently needed. Many TCL have mutations in epigenetic modifier genes, and histone deacetylase inhibitors such as romidepsin are approved for treatment of peripheral T-cell lymphoma (PTCL); however, the overall response rate (ORR) with single-agent treatment is only 20-30%, and improvement in OS was not shown. Romidepsin and the hypomethylating agent CC-486 (5-azacitidine) acted synergistically in vitro, and showed high clinical activity, with an ORR of up to 79% in some types of TCL. Many TCLs rely on the PI3K pathway, whether through activation of CD28 through fusions or gain-of-function mutations or by interruptions of the CD28-inhibiting PD-1/PD-L1 immune checkpoint. Duvelisib is an inhibitor of the PI3K gamma and delta isoforms; in phase I trials it has shown both single-agent activity and synergy with romidepsin for patients with TCL. As combinations of both CC-486 (5-azacitidine)/romidepsin and duvelisib/romidepsin have demonstrated both adequate safety and clinical efficacy, safety and efficacy of the triplet combination should be explored. Objectives: To determine the safety and toxicity profile, maximum tolerated dose (MTD), and the recommended phase II dose (RP2D) of the four-drug combination of CC-486 (5-azacitidine), romidepsin and duvelisib, and doxorubicin, in patients with TCL. Eligibility: Patients with histologically or cytologically confirmed newly diagnosed or relapsed/refractory T-cell lymphoma (TCL) defined as follows: Cohort 2: Untreated patients with any peripheral TCL, not including anaplastic large cell lymphoma (ALCL), but including acute and lymphoma subtypes of adult T-cell leukemia/lymphoma (ATLL). Cohorts 1 and 3: Any relapsed/refractory peripheral T-cell lymphoma including ATLL and ALCL who have disease after receiving at least one line of systemic therapy, which must include brentuximab vedotin if the disease is ALCL. Age \>= 18 years of age ECOG performance status of \<= 2 Adequate organ and marrow function Design: Open-label, single-center, non-randomized Phase 1 study "3 + 3" design will be used to determine the RP2D of dose-escalated duvelisib with fixed dose romidepsin CC-486 (5-azacitidine) and doxorubicin with two expansion cohorts at the RP2D Maximum 8 cycles (21-day cycles) of combination therapy To explore all dose levels, including further evaluation in two dose expansion cohorts, the accrual ceiling will be set at 60 patients