The Pralatrexate Romidepsin Doublet: A Well Tolerated and Highly Effective Combination for Patients with Relapsed or Refractory Peripheral T Cell Lymphoma

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphomas in which only ~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) and sought to evaluate biological mechanisms of synergy. 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. Twenty six patients were enrolled and were evaluable for toxicity. Median age was 52 yrs (23 73) and 58% were male. The median number of prior therapies was 3 (range 1 16) Histologies included HL (N=3) B cell (N=10 of which FL=4) and T cell (N=13) The median number of cycles completed was 4 (range 1 12) 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 mucositis at all dose levels. Patients dosed at the MTD (P 25 mg/m2 R 12mg/m2 QOW) did not experience any toxicities. The grade 3/4 toxicities reported in >5% of patients were: neutropenia (31% thrombocytopenia (31% anemia (23% oral mucositis (15% hyponatremia (8% pneumonia (8% and sepsis (8% Twenty two patients were evaluable for response, 1 patient is currently on therapy. The ORR in the total, non PTCL and PTCL populations was 59% 33% (no CR) and 77% respectively. Of the PTCL patients 4/13 (31% achieved a CR, 6/13 (46% achieved a PR, and 1 patient had stable disease. The mean duration of response (DOR) for all patients on the study (N=13) was 6.1 months (1.1 26.5) for the non PTCL population (N=3) was 4.8 m (1.1 11) and for the PTCL population (N=10) was 6.55 months (range 1.6 26.5 +ongoing) The mean progression free survival (PFS) for all patients on study (N=26) was 4.8 m .3 30.2) for the non PTCL population (N=13) was 2.8 m (0.3 14.5) and for the PTCL population was 6.13 months (range 1.5 30.2 +ongoing) Pharmacokinetic studies were performed for P and R and data for the first 15 patients is presently available for reporting. PK analyses were performed using WinNonLin(r) to determine Cmax and AUC.  Cmax results for P 10 mg/m2 and P 15 mg/m2 are 1810+ 1063 ng/mL and 2748+ 995 ng/mL, respectively.  Cmax results for R 12 mg/m2 and R 14 mg/m2 are 420+ 198 ng/mL and 552+ 346 ng/mL, respectively. After infusion with P 10 mg/m2 or 15 mg/m2 PK analysis indicate AUC0 24.08h of 3616+ 1543 h*ng/mL and 4104+ 2124 h*ng/mL, respectively. AUC0 28h after treatment with R 12 mg/m2or 14 mg/m2 was 1503+ 1286 h*ng/ml and 2535+ 2560 h*ng/mL. These values are consistent with that observed for both of these drugs in previous studies. Results from the phase I study conclude that the combination of P R given on the QOW schedule is safe and very well tolerated. These data support the lineage specific activity of the P+R combination, which is currently being expanded to a multicenter Phase II for PTCL. Disclosures Amengual:Bristol  Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Sawas:Seattle Genetics: Honoraria; Gilead Sciences: Speakers Bureau.  Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity9s Board of Directors or advisory committees;  Research Funding;  Research Funding; Bristol  Research Funding; Bristol  Research  Research