General Information

Folotyn contains pralatrexate, a small molecule chemotherapeutic agent that inhibits dihdrofolate reductase (DHFR). DHFR is a folate dependent enzyme involved in the building of DNA and other processes. Folotyn is transported into tumor cells via the reduced folate carrier (RFC-1). This injectable, small molecule, cytotoxic agent has been designed for improved transport into tumor cells and greater intracellular drug retention.

Folotyn is specifically indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

Folotyn is supplied as a solution designed for intravenous administration. The recommended dose is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7 week cycles until progressive disease or unacceptable toxicity.

Vitamin Supplementation
Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of Folotyn, and dosing should continue during the full course of therapy and for 30 days after the last dose of Folotyn. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the first dose of Folotyn and every 8-10 weeks thereafter.

Clinical Results

FDA Approval
The FDA approval of Folotyn was based on the results of an open-label, single-arm, multicenter, international trial. The trial enrolled 111 subjects with relapsed of refractory PTCL. The subjects received Folotyn at 30 mg/m2 once weekly by IV push over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 subjects treated, 109 were evaluable for efficacy. The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). The overall response rate was 27% and the median duration of response was 287 days (9.4 months). Of the responders, 66% responded within cycle 1. The median time to first response was 45 days.

Mechanism of Action

Folotyn contains pralatrexate, an antineoplastic folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

Literature References

O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, Sarasohn D, Neylon E, Mastrella J, Hamelers R, Macgregor-Cortelli B, Patterson M, Seshan VE, Sirotnak F, Fleisher M, Mould DR, Saunders M, Zelenetz AD 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. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 2009 Sep 10;27(26):4357-64