Folotyn
Generic Name: pralatrexate injection
Date of Approval: September 24, 2009
Company: Allos Therapeutics, Inc.
Treatment for: Peripheral T-cell Lymphoma
FDA Approves Folotyn
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The U.S. Food and Drug Administration (FDA) has approved Folotyn (pralatrexate injection) for use as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Folotyn is the first and only drug approved by the FDA for this indication and represents a new treatment option for patients with relapsed or refractory PTCL. This indication is based on overall response rate. Clinical benefit such as improvement in progression free survival or overall survival has not been demonstrated.
Clinical Studies
The Folotyn approval was based on the results from PROPEL, an open-label, single-arm, multi-center, international clinical trial that enrolled 115 patients with relapsed or refractory PTCL, 109 of whom were considered evaluable for efficacy according to the trial protocol. Patients were considered evaluable if they received at least one dose of Folotyn, their diagnosis of PTCL was confirmed by independent pathology review, and they had relapsed or refractory disease after at least one prior treatment. Patients were treated with 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. In addition, patients received 1mg of vitamin B12 intramuscularly every 8-10 weeks and 1.0-1.25 mg of folic acid orally on a daily basis.
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). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.
The results of the trial demonstrated that 29 of 109 evaluable patients, or 27%, responded to Folotyn. The median duration of response was 287 days, or 9.4 months (range 1-503 days). Thirteen of 109 evaluable patients had a duration of response ≥ 14 weeks (range 98-503 days). The most common grade 3/4 adverse events were thrombocytopenia, which was observed in 33% of patients; mucositis in 21% of patients; neutropenia in 20% of patients; and anemia in 17% of patients. See below for Important Safety Information.
The median number of prior systemic therapies was 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 70) did not have evidence of response to their most recent prior therapy before entering the trial. The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).
Important Safety Information
Warnings and Precautions:
Folotyn may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit or modify dose for hematologic toxicities.
Mucositis may occur. If ≥ Grade 2 mucositis is observed, omit or modify dose.
Patients should be instructed to take folic acid (1.0 -1.25 mg orally on a daily basis) and receive vitamin B12 (1 mg intramuscularly every 8-10 weeks) to potentially reduce treatment-related hematological toxicity and mucositis.
Folotyn can cause fetal harm. Women should avoid becoming pregnant while being treated with Folotyn, and pregnant women should be informed of the potential harm to the fetus.
Use caution and monitor patients when administering Folotyn to patients with moderate to severe renal function impairment.
Elevated liver function test abnormalities may occur and require monitoring. If liver function test abnormalities are ≥ Grade 3, omit or modify dose.
Folotyn Side Effects
The most common adverse reactions observed in PROPEL were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events (>3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea and thrombocytopenia. Forty-four percent of patients experienced a serious adverse event while on study or within 30 days after their last dose of Folotyn. Twenty-three percent of patients discontinued treatment due to adverse reactions.
Drug Interactions:
Co-administration of drugs subject to renal clearance (e.g., probenecid, NSAIDs, and trimethoprim/sulfamethaxazole) may result in delayed renal clearance.
Use in Specific Patient Populations:
Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother.
Patient Counseling Information
Need for Folic Acid and Vitamin B12 Patients treated with Folotyn must be instructed to take folic acid and Vitamin B12 as a prophylactic measure to potentially reduce possible side effects.
Mucositis Physicians should discuss with patients the signs and symptoms of mucositis. Patients should be instructed on ways to reduce the risk of its development, and/or ways to maintain nutrition and control discomfort from mucositis if it occurs.
Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any signs of infection develop including fever. Patients should also be instructed to contact their physician if bleeding or symptoms of anemia occur.
Concomitant Medications Patients should be instructed to inform their physician if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs).
Pregnancy/Nursing Patients should be instructed to tell their physician if they are pregnant or plan to become pregnant due to the risk of fetal harm. Patients should be instructed to tell their physician if they are nursing.
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