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 Meeting Abstract

Authors: Horwitz, S. M.; Kim, Y. H.; Foss, F. M.; Zain, J. M.; Myskowski, P.; Lechowicz, M. J.; Fisher, D. C.; Shustov, A.; Bartlett, N. L.; Delioukina, M. L.; Koutsoukos, T.; Fruchtman, S. M.; O'Connor, O. A.; Duvic, M.
Abstract Title: 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
Meeting Title: 52nd Annual Meeting of the American Society of Hematology (ASH)
Abstract: Background: Pralatrexate (FOLOTYN(R)) 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/m(2) 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/m(2) demonstrated activity in patients with aggressive lymphoma. A dose de-escalation strategy was used in PDX-010 to identify an optimal,dose for CTCL.Methods: Eligibility included CTCL histology of mycosis fungoides, Sezary 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/m(2)) and/or schedules (weekly for 3/4 or 2/3, weeks). All patients received supplementation with vitamin B-12 1 mg inramuscularly every 8 to 10 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.Results: 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/m(2) 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 a 15 mg/m2 weekly for 3/4 weeks 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 I 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/m(2) 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/m(2) 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.,Conclusions: 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.
Journal Title: Blood
Volume: 116
Issue: 21
Meeting Dates: 2010 Dec 4-7
Meeting Location: Orlando, FL
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-11-19
Start Page: 1154
End Page: 1155
Language: English
PROVIDER: biosis
PUBMED: 22276300
Notes: --- - Meeting Abstract: 2800 - 52nd Annual Meeting of the American-Society-of-Hematology (ASH) - Orlando, FL, USA - December 04 -07, 2010 - Amer Soc Hematol - "Source: Biosis"