Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies
Owen A O'Connor, Steven Horwitz, Paul Hamlin, Carol Portlock, Craig H Moskowitz, Debra Sarasohn, Ellen Neylon, Jill Mastrella, Rachel Hamelers, Barbara Macgregor-Cortelli, Molly Patterson, Venkatraman E Seshan, Frank Sirotnak, Martin Fleisher, Diane R Mould, Mike Saunders, Andrew D Zelenetz, Owen A O'Connor, Steven Horwitz, Paul Hamlin, Carol Portlock, Craig H Moskowitz, Debra Sarasohn, Ellen Neylon, Jill Mastrella, Rachel Hamelers, Barbara Macgregor-Cortelli, Molly Patterson, Venkatraman E Seshan, Frank Sirotnak, Martin Fleisher, Diane R Mould, Mike Saunders, Andrew D Zelenetz
Abstract
Purpose: To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.
Patients and methods: Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle.
Results: The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months.
Conclusion: Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Trial registration: ClinicalTrials.gov NCT00052442.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Source: PubMed