Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies

Background: * Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and lymphomas accounting for 5 to 10% of all lymphomas in the US * Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimens, that produce long-term progression-free survival in about 30% of these cases * Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall survival of less than 1 year. Treatment options for R/R TCM are very few and of limited efficacy, thus novel treatment strategies are urgently needed. * Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical activity with single agent the overall response (ORR) around 25% * Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in preclinical models, and has demonstrated high clinical activity with an ORR of 79% * Many TCMs rely on The Ikaros-dependent nuclear factor κB (NF-κB)/interferon regulatory factor 4 (IRF4) signaling pathway to maintain proliferation, which is why lenalidomide, which induces degradation of Ikaros and downregulates IRF4, has single agent activity in R/R TCM with overall response rate (ORR) of 26% to 42%, depending on the subtype. * Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines, predicting that the addition of lenalidomide to the established romidepsin/ CC-486 (5-azacitidine) combination will further improve efficacy. Objectives: -To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the four-drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and dexamethasone in patients with TCM Eligibility: * Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows: * Patients with systemic disease * Have received at least one line of prior therapy * Must have received brentuximab vedotin if the disease is anaplastic large cell lymphoma or cluster of differentiation 30 (CD30)-positive cutaneous T-cell lymphoma * Age \>= 18 years of age * Eastern Cooperative Oncology Group performance status of \<= 2 (or \<= 3 if decrease is due to the disease) * Histologically or cytologically confirmed relapsed and/or refractory mature TCM * Adequate organ and marrow function Design: * Open-label, single-center, uncontrolled Phase 1 study * 3 + 3 design will be used to determine the maximum tolerated dose (MTD) of dose-escalated lenalidomide with fixed dose of romidepsin and CC-486 (5-azacitidine) * An expansion cohort of 9 patients will be evaluated at the MTD * Maximum 6 cycles (28-day cycle) of combination therapy * To explore all dose levels, including further evaluation in a dose expansion cohort, the accrual ceiling will be set at 30 patients