Klein, Sandra E.

Abstract Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL, and has confirmed this data in early phase clinical studies. We showed that the combination of romidepsin and hypomethylating agents, decitabine or azacytidine, uniquely induces the expression of genes, including cancer testis antigens, gamma interferon and endogenous retrovirus. We are conducting a phase 1 study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. In addition, we are conducting a Phase 1/2A study of durvalumab combined with oral 5-azacitidine + romidepsin (Arm A), pralatrexate + romidepsin (Arm B), romidepsin (Arm C), or oral 5-azacitidine (Arm D) in patients with PTCL. Patient characteristics are listed in Table 1. We have treated a total of 12 patients across the 2 trials and 4 different Arms including pralatrexate plus pembrolizumab (3 patients), pralatrexate, decitabine and pembrolizumab (3 patients), decitabine and pembrolizumab (3 patients) and azacytidine, romidepsin and durvalumab (3 patients). Twelve patients out of 12 received at least one dose of drug and were evaluable for toxicity. There was a dose limiting toxicity (DLT) for each arm including prolonged grade 3 thrombocytopenia, febrile neutropenia, grade 3 hyponatremia and rash, and cytokine release syndrome, respectively. There were no treatment-related deaths. Eight patients out of 12 are evaluable for response at the time of this analysis. Three out of 8 patients achieved a complete remission, 3 out of 8 patients had a partial remission, and 2 out of 8 patients experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, pembrolizumab and azacytidine, romidepsin and durvalumab. These preliminary clinical data suggest that the addition of immune-checkpoint inhibitors on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. These trials are registered at www.clinicaltrials.gov (NCT03240211, NCT03161223). Patient characteristics (n=12)Median age (range)68 (26-77)Sex, n (%) Male Female6 (50) 6 (50)Race, n (%)White/Non-Hispanic White/Hispanic Black Asian Unknown5 (42) 1 (8) 3 (25) 1 (8) 2 (17)Histology, n (%) PTCL, NOS AITL Mycosis Fungoides PTCL, NOS TFH ATLL Sezary Syndrome ALCL, ALK+2 (17) 2 (17) 2 (17) 1 (8) 1 (8) 1 (8) 1 (8)Stage at diagnosis IB II III IV Unknown1 (8) 2 (17) 3 (25) 4 (33) 2 (17)Median number of prior therapies (range) **2 unknown3 (0-5) Citation Format: Enrica Marchi, Helen Ma, Francesca Montanari, Ahmed Sawas, Jennifer K. Lue, Changchun Deng, Kareema T. Whitfield, Sandra Klein, Matthew V. Matthew, Freedy J. Loffredo, Luigi Scotto, Hyejung Lee, Hye A. Kim, Alice T. Jacobs, Aishling M. Rada, Karen A. Khan, Salvia Salvia, John Lister, Nora N. Benanni, Mark A. Francescone, Pier Luigi Zinzani, Wonseog Kim, Owen A. O'Connor. The integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT160.

8049 Background: Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL and induce the expression of cancer testis antigen, suggesting a role in the addition of the immune-checkpoint inhibitor, pembrolizumab. Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with relapsed and refractory PTCL and CTCL. A standard 3+3 dose-escalation is applied in the triplet Arm (Arm B) while in the doublet Arms (A and C) de-escalation is applied in case of toxicity. Pharmacokinetic and pharmacodynamic studies are ongoing. Results: We treated a total of 12 patients with 4 patients in each Arm. All patients that received at least one dose of drug were evaluable for toxicity. There was a dose limiting toxicity (DLT) in each arm including prolonged grade 3 thrombocytopenia (Arm A), febrile neutropenia (Arm B), grade 3 hyponatremia, and rash (Arm C). There were no treatment-related deaths. Six patients out of 12 were evaluable for response at the time of this analysis. One patient achieved a complete remission, 2 had partial remission, 1 had stable disease, and 2 experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, and pembrolizumab. Table summarizes the patient characteristics, toxicities, and response rates. Conclusions: These preliminary clinical data suggest that the integration of pembrolizumab on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. Clinical trial information: 03240211 . [Table: see text]