Identification of An Active, Well-Tolerated Dose of Pralatrexate In Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL): Final Results of a Multicenter Dose-Finding Study.

Pralatrexate (FOLOTYN^®) is an antifolate designed for preferential tumor uptake and accumulation. Pralatrexate was granted accelerated approval by the US Food and Drug Administration at a dose of 30 mg/m² weekly for 6/7 weeks for relapsed or refractory peripheral T-cell lymphoma. Given that cutaneous T-cell lymphoma (CTCL) is often an indolent disease treated in a maintenance fashion, the goal of this trial was to identify a dose with clinical activity and minimal toxicity to allow continuous or maintenance treatment. In the present study, designated PDX-010, the initial dose of pralatrexate for relapsed or refractory CTCL was based on data showing that 30 mg/m² demonstrated activity in patients with aggressive lymphoma. A dose de-escalation strategy was used in PDX-010 to identify an optimal dose for CTCL.

Eligibility included CTCL histology of mycosis fungoides, Sézary syndrome, or primary cutaneous anaplastic large-cell lymphoma, with disease progression after at least 1 prior systemic therapy, and written informed consent. The starting dose and schedule was 30 mg/m² of pralatrexate by intravenous (IV) push weekly for 3/4 weeks. If toxicity as defined per the protocol was observed, subsequent cohorts received reduced doses (20, 15, 10 mg/m²) and/or schedules (weekly for 3/4 or 2/3 weeks). All patients received supplementation with vitamin B₁₂ 1 mg intramuscularly every 8 to10 weeks, and folic acid 1 mg orally once daily (QD). Response was evaluated by the modified severity weighted adjustment tool (mSWAT) every 2 cycles for 6 months, and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first.

Fifty-four patients were treated across 2 stages of this study. In the dose-finding phase, 31 patients were sequentially enrolled into 6 cohorts and treated at varying doses and schedules. The optimal dose and schedule, as defined in the protocol, was identified as 15 mg/m² weekly for 3/4 weeks, based on the tolerability and efficacy (overall response rate [ORR] of 50%) observed in the initial 6 patients in that cohort. Among the 31 patients in the dose-finding stage, the ORR for patients treated at a dose intensity ≥15 mg/m² weekly for 3/4 weeks was 61% (11/18), and the ORR for those patients treated in lower-dose cohorts was 8% (1/13). The second stage of the study included 23 additional patients treated at 15 mg/m² weekly for 3/4 weeks, for a total of n = 29 patients treated at this optimal dose. Among these 29 patients, the median number of prior systemic therapies was 4.5 (range 1 to 11), and patients received pralatrexate for a median of 4 cycles (range 1 to 23). Patients enrolled in this cohort could be dose-escalated at investigator discretion if there was an absence of toxicity and a response < CR. At this time 53/54 patients treated in this study are evaluable for efficacy, including 28/29 patients treated at 15 mg/m² for 3/4 weeks. At the optimal dose, the ORR was 43% (12/28) and 50% (20/40) in patients treated at a dose intensity ≥15 mg/m² weekly for 3/4 weeks.

At the optimal dose/schedule, grade 1–2 adverse events (AEs) occurring in >10% were fatigue (34%), mucositis (28%), nausea (24%), edema (24%), epistaxis (21%), pyrexia (17%), constipation (14%), and vomiting (14%). The only grade 3 AE in >10% was mucositis (17%). Hematologic toxicities were limited to grade 3 neutropenia (3%), grade 1–2 anemia (14%), grade 3 anemia (3%), grade 1–2 thrombocytopenia (7%), grade 3 thrombocytopenia (3%), grade 1–2 leukopenia (3%), and grade 4 leukopenia (3%). No grade 4 nonhematological toxicities were observed.

Pralatrexate shows high activity with acceptable toxicity in patients with relapsed or refractory CTCL at the identified optimal dose and schedule of 15 mg/m² weekly for 3/4 weeks. The lack of significant hematologic toxicity or cumulative toxicity seen in this study suggests that pralatrexate should be further evaluated as continuous or maintenance therapy for patients with CTCL. Final efficacy and tolerability data will be reported.

Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Lechowicz:Allos Therapeutics, Inc.: Consultancy; Celgene Corporation : Consultancy. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding.