Pralatrexate Injection Combined with CHOP for Treatment of PTCL-Results from the Fol-CHOP Dose-Finding Phase 1 Trial.

Pralatrexate is a folate antagonist which selectively enters cells expressing reduced folate carrier type 1 (RFC-1), and competitively inhibits dihydrofolate reductase (DHFR), leading to interruption of RNA synthesis, DNA replication, and apoptosis. This Phase 1 study was conducted to evaluate the Maximum Tolerated Dose (MTD) of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (Part 1) and the response and pharmacokinetics of six cycles of this combination (Fol-CHOP) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL). In Part 1, on Days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, or 30 mg/m2 of pralatrexate in combination with CHOP, per dose escalation, in five sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4 and 5 respectively. The pralatrexate dose of 30 mg/m2 was selected to be combined with CHOP for Part 2 and was administered to 33 additional patients in the expansion cohort. At the MTD, the Fol-CHOP regimen was generally well tolerated in patients with PTCL, with an ORR of 83.9% (20 CRs, 6 PRs) as assessed by treating Investigators. Thirty-five patients (67.3%) experienced Grade 3/4 treatment-emergent adverse events (TEAE), the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea and vomiting (7.7% each). In conclusion, Fol-CHOP (CHOP+Folotyn 30 mg/m2) was found to be a safe and effective treatment for newly diagnosed PTCL and deemed worthy of further investigation. (ClinicalTrials.gov: #NCT02594267.).