FDA Approval for NelarabineBrand name(s): Arranon® Injection
On October 28, 2005, the U.S. Food and Drug Administration (FDA) granted accelerated approval for nelarabine (Arranon® Injection, GlaxoSmithKline), a purine nucleoside
antimetabolite, for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.
This use is based on the induction of complete responses. Clinical studies demonstrating increased survival or other clinical benefit have not been conducted.
The nelarabine FDA submission consisted of two multicenter, open-label, single-arm trials, the first in pediatric patients (21 years of age or less at the time of initial diagnosis) conducted by the Children’s Oncology Group (COG), the second in adult patients conducted by the Cancer and Leukemia Group B (CALGB) and the Southwest Oncology Group.
Study eligible patients had a Karnofsky Performance Status (KPS) > 50 and had adequate renal (kidney) and liver function. Subjects must have recovered from toxicity of all previous chemotherapy. At least six weeks must have elapsed since administration of nitrosoureas or craniospinal or hemipelvic radiation therapy. Pregnant or lactating women and patients with baseline ≥ grade 2 neurotoxicity were excluded. The primary study endpoint included in the submission was the rate of complete response (CR) and the rate of complete response with incomplete hematologic recovery (CR*).
Pediatric study patients received nelarabine 650 mg/m² administered intravenously over one hour daily for five consecutive days repeated every 21 days. Adult patients received nelarabine 1,500 mg/m² administered intravenously over two hours on days 1, 3, and 5 repeated every 21 days. Doses were reduced for non-hematologic or hematologic toxicities in both groups. Depending upon the availability of a donor and other considerations patients could be removed from study to receive a hematologic stem cell transplant (HSCT).
The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. A supporting efficacy population consisted of 31 patients who had relapsed or had been refractory to one prior induction regimen.
The mean age of both study populations was approximately 11.5 years. The majority of study patients were male and Caucasian with a KPS of 80 or better. The majority of patients had T-ALL.
For patients who had relapsed or had been refractory to two or more induction regimens complete response was observed in five patients (13 percent) and CR+CR* was observed in nine patients (23 percent). Both T-ALL and T-LBL patients achieved CR or CR*.
Stem cell transplantation was performed in four of nine CR or CR* patients (44 percent) who had relapsed or had been refractory to two or more induction regimens and one patient received systemic therapy during nelarabine induced remission.
For patients who were not transplanted and who did not receive additional therapy remission durations were 9.3, 6.1, 3.6 and 3.3 weeks
The adult efficacy population consisted of 28 patients who had relapsed or had been refractory to two or more induction regimens. A supporting efficacy population consisted of 11 patients who had only one prior induction regimen.
The mean age of both groups was approximately 30 years with a range of 16 years to 66 years. The majority of study patients were male and Caucasian a KPS of 80 or better. The majority of patients in both groups had T-ALL.
The CR and CR + CR* rates for patients who had relapsed or had been refractory to two or more induction regimens were 18 percent and 21 percent, respectively. Both T-ALL and T-LBL patients achieved CR or CR*.
Stem cell transplantation was performed in one of six CR or CR* patients who had relapsed or had been refractory to two or more induction regimens. For patients who were not transplanted remission durations were 195+, 30, 19, 15 and 4 weeks.
The principal nelarabine toxicities included hematologic toxicity, febrile neutropenia, infection complicating neutropenia, laboratory abnormalities including increased transaminases, gastrointestinal toxicity, fatigue, and asthenia.
For both pediatric and adult patients neurotoxicity was dose-limiting. Neurologic adverse events included headache, somnolence, hypoesthesia, sensory and/or motor neuropathy, seizures, paresthesias, tremor, and ataxia. One patient had status epilepticus (seizures). There have also been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
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 "Understanding the Approval Process for New Cancer Treatments.") 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.
For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.
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