MULTI‐CENTER PHASE II STUDY OF ORAL AZACITIDINE (CC‐486) PLUS CHOP AS INITIAL TREATMENT FOR PERIPHERAL T‐CELL LYMPHOMA (2019)

Introduction: Peripheral T-cell lymphomas (PTCL) are an uncommon and heterogeneous group of non-Hodgkin lymphomas with divergent cells of origin and mechanisms of lymphomagenesis. Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, the most commonly prescribed initial treatment for systemic PTCL, provides suboptimal complete remission rates and response duration in the majority of non-ALCL patients. Emerging genetic studies have shown recurrent mutations affecting TET2, DNMT3A, IDH2 and RHOA in PTCL subtypes, particularly in nodal peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) such as angioimmunoblastic T-cell lymphoma. The association of aberrant DNA methylation with PTCL lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine is an epigenetic modifier of DNA methylation by inhibition of DNA methyltransferase at low doses. In human PTCL patients, treatment with 5-azacitidine produced sustained responses (ORR 75%, CR/Cru 50%) in R/R AITL in a retrospective cohort study (Lemonnier et al. Blood 2018;132:2305). The feasibility of combining CHOP chemotherapy with azacitidine has been evaluated in 2 phase 1 studies in B-cell lymphoma, one with injectable 5-azaticidine (Clozel et al. Cancer Discov 2013;3:1002), the other with oral azacitidine (CC-486) (Martin et al. Blood 2017;130:192). We initiated a multi-center phase 2 study in 5/2018 to evaluate the efficacy and safety of chemo-sensitization with oral azacitidine (CC-486) in combination with CHOP for initial treatment of PTCL (ClinicalTrials.gov - NCT03542266). Methods: This exploratory phase 2 study prioritizes enrollment of nodal TCL with TFH phenotype (PTCL-TFH). Additional eligible subtypes include PTCL/NOS and ATLL. Subjects receive standard dose CHOP on day 1 of each cycle for a total of 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily is administered for 7 days prior to CHOP cycle 1 initiation, and for 14 days (days 8-21) before CHOP cycles 2-6. Supportive care includes mandatory G-CSF and recommended prophylaxis against PCP and VZV. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. The study has a sample size of 20, and follows two-stage minimax design for primary efficacy analysis. Correlative biomarker studies are prospectively planned to assess changes in genome-wide methylation, gene expression and immune profile in response to DNMT inhibitor. The study is actively enrolling patients at Weill Cornell Medicine, with additional 3 US sites due to open in the 2nd quarter of 2019. Keywords: angioimmunoblastic T-cell lymphoma (AITL); epigenetics; peripheral T-cell lymphomas (PTCL). Disclosures: Ruan, J: Consultant Advisory Role: Celgene, Seattle Genetics, AstraZeneca; Research Funding: Celgene, Pharmacyclics, Seattle Genetics, Janssen. Leonard, J: Consultant Advisory Role: Gilead, AstraZeneca, Novartis, Celgene; Research Funding: Celgene. Van Besien, K: Research Funding: Celgene. Mehta-Shah, N: Consultant Advisory Role: Kyowa Hakka Kirin; Research Funding: Verastem, Celgene, AstraZeneca, Roche/Genentech, Bristol Myers Squibb. Sokol, L: Consultant Advisory Role: Celgene, Seattle Genetics and Spectrum Pharmaceuticals. Martin, P: Consultant Advisory Role: Celgene, Janssen, AstraZeneca, Gilead; Research Funding: Celgene.