Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results.

Pralatrexate is a new anti-folate with increased affinity for the reduced folate carrier 1 (RFC-1) and longer intracellular retention in tumor cells due to efficient polyglutamation by folylpolyglutamyl synthetase (FPGS). Pralatrexate and gemcitabine each have activity as monotherapy in patients with relapsed or refractory lymphoma. Preclinical data reported synergy for the combination in NHL cell lines and xenografts that was schedule dependent (pralatrexate followed by gemcitabine) (Clin Cancer Res 2006;12:924-932). We initiated a multi-center Phase 1/2a study (PDX-009; NCT00481871) to evaluate this treatment combination. The primary objective of the Phase 1 portion was to determine the maximum tolerated dose (MTD) and optimal Phase 2 dose and schedule for the combination of pralatrexate and gemcitabine in patients with relapsed or refractory lymphoma.

Eligibility criteria included histologically confirmed lymphoma, progressive disease after ≥1 prior treatment and ECOG performance score 0-2. Patients in group A (n=7) received pralatrexate on day 1 and gemcitabine on day 2, once weekly for 3/4 wks. Patients in group B (n=10) also received pralatrexate and gemcitabine on sequential days, but were treated only every 2 wks (q2w). Patients in group C (n=17) received pralatrexate followed 1h later by gemcitabine on the same day q2w. All patients received vitamin B₁₂ and folic acid supplementation. Prior gemcitabine exposure was permitted.

As of May 2009, 34 patients were treated in Phase 1, including 24 men (71%), and median age was 63 years (range, 19-81). Histology included 13 patients with B-cell lymphoma, 11 with T/NK-cell lymphoma, 7 with Hodgkin's lymphoma, and 3 with “other” lymphoma. Patients had received a median of 3.5 prior regimens (range 1-11). All patients with once-weekly sequential-day dosing (pralatrexate 10-15 mg/m² and gemcitabine 300-400 mg/m²) in Group A had dose-limiting toxicities (DLTs) of thrombocytopenia and/or neutropenia; therefore accrual to this schedule was halted and subsequent cohorts received pralatrexate with gemcitabine on the q2w schedule (groups B and C). The MTD with the q2w dosing schedule was pralatrexate/gemcitabine 10/400 mg/m² when given on sequential days (group B) and 15/600 mg/m² when given on the same day (group C). The DLTs for group B were cellulitis, pulmonary embolus, thrombocytopenia, and febrile neutropenia and the DLTs for Group C were fatigue, hypoxia, mucositis, and thrombocytopenia. Across all groups, the most frequently reported Gr 3-4 pralatrexate-related adverse events were neutropenia (41%), thrombocytopenia (35%), anemia (29%), and leukopenia (12%). Of 33 patients who were evaluable for response, 7 (21%) showed partial response, including patients with Hodgkin's lymphoma (4), diffuse large B-cell lymphoma (1), angioimmunoblastic T-cell lymphoma (1), and composite diffuse large B-cell lymphoma and T-cell lymphoma (1). Responses were seen in patients treated on the same day as well as the sequential day schedules.

Treatment with pralatrexate and gemcitabine is feasible, with acceptable toxicity, when administered on a q2w schedule. However, the MTD of each drug is 50% greater when given on the same day as compared to treating on sequential days. Preliminary results show activity of the combination of pralatrexate and gemcitabine in lymphoid malignancies with a 21% response rate in this heavily pretreated population. Phase 2 expansions at the MTD will explore both sequential-day dosing (10/400 mg/m²) and same-day dosing (15/600 mg/m²) in a q2w schedule.

Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Advani:Allos Therapeutics, Inc: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.