FDA Approval for Clofarabine
- Approved for pediatric acute lymphoblastic leukemia
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.On December 28, 2004, the U.S. Food and Drug Administration granted accelerated approval for clofarabine (Clolar™, made by Genzyme Corporation), a purine nucleoside antimetabolite given by intravenous infusion for treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.
The approval of this indication is based on the induction of complete responses. Clinical studies demonstrating increased survival or other clinical benefit have not been conducted. Approval was granted under accelerated approval regulations that require the applicant to conduct and complete additional clinical studies to confirm clinical benefit.
Efficacy and safety were demonstrated in a single multicenter trial that enrolled 49 patients. Most patients had received two to four prior regimens and 15/49 (31 percent) had undergone at least one transplant. The median age was 12 years.
Clofarabine was given at a dose of 52 mg/m2, intravenously, over two hours daily for five days, repeated every two to six weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow, and recovery of peripheral platelet and absolute neutrophil counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an Independent Response Review Panel (IRRP).
Six patients (12 percent) achieved a CR and four patients (8 percent) achieved a CRp, and five patients (10 percent) achieved a PR. Of the 15 responding patients, six had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days.
The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections, and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity was characterized as left ventricular systolic dysfunction; tachycardia may also occur.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.