Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas in which only 20-25% of patients experience long-term survival with CHOP chemotherapy. Recently several drugs have been approved for this entity including pralatrexate (P), romidepsin (R), and belinostat which have response rates ranging from 26%-29% as single agents. Based on our demonstration of synergy of P+R in preclinical models of TCL, we initiated a study on the safety and efficacy of P+R in a phase I-II study for relapsed or refractory lymphomas (NCT01947140). Methods: A 3+3 dose-escalation study started at P 10mg/m² and R 12mg/m² with escalation to P 25 mg/m² and R 14 mg/m². Patients were treated on 1 of 3 dosing schedules (weekly x 3 Q28D; weekly x 2 Q21D and QOW Q28D). The primary objective was to determine MTD and DLT; the secondary objective included describing ORR (CR+PR). Patients were required to have relapsed lymphoma of any subtype, ECOG PS < 2, and adequate organ and marrow function. There was no upper limit to the number of prior therapies or transplantation. Results: Twenty-five patients were enrolled and were evaluable for toxicity. Median age was 52 yrs (23-73) and 60% were male. The median number of prior therapies was 3 (range 1-16). Histologies included HL (N = 3), B-cell (N = 7 of which FL = 4) and T-cell (N = 15). The median number of cycles completed was 4 (range 1-8+ ongoing). There were 3 DLTs in cohort 4 (P 20mg/m²& R 12mg/m²given weekly x 2 Q21D) consisting of 2 Grade 3 oral mucositis and 1 Grade 4 sepsis. The QOW Q28D schedule had no DLTs at equivalent and higher doses. The grade 3/4 toxicities reported in > 5% of patients were: neutropenia (32%), thrombocytopenia (32%), anemia (24%), oral mucositis (16%), hyponatremia (8%), pneumonia (8%) and sepsis (8%). Twenty-one patients were evaluable for response, 2 patients are currently on therapy. The ORR in the total, non-PTCL and PTCL populations was 52%; 33% (no CR) and 77% (38% CR) respectively. Presently 1 patient is awaiting safety and response analysis. Conclusions: These data support the lineage specific activity of the P+R combination, which is being expanded to a multicenter Phase II for PTCL. Clinical trial information: NCT01947140