GAITHERSBURG, Md—The Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended the accelerated approval of Temodal Capsules (temozolomide, Schering-Plough) for the treatment of anaplastic astrocytoma at first relapse following treatment with a nitrosourea and procarbazine(Drug information on procarbazine). Accelerated approval requires the company to conduct further research to demonstrate the drug’s safety and efficacy.
The ODAC panel declined, however, to recommend that the FDA approve the drug for use in patients with relapsed glioblastoma multiforme. That decision came in an 11 to 0 vote, with one abstention.
Temodal, the first of a new class of drugs called imidazotetrazines, is an oral cytotoxic agent that acts by damaging the DNA of cancer cells.
Schering-Plough presented data from three studies: a randomized, controlled, open-label phase III pivotal trial that compared Temodal against procarbazine in patients with relapsed glioblastoma multiforme; a phase II study of Temodal in patients with relapsed glioblastoma multiforme; and a phase II study of the drug in patients with relapsed anaplastic astrocytoma. All three studies used 6-month progression-free survival as the primary endpoint. Secondary endpoints were response rates, quality of life, and overall survival.
FDA staff, however, pointed out that the agency “has not accepted tumor response rate or time to tumor progression as the primary basis for approval of drugs for the treatment of malignant gliomas.” ODAC members agreed 11 to 1 that a demonstrated improvement in survival was required for the committee to recommend Temodal’s approval for use in malignant glioma.
The company presented data that showed a median survival of 7.34 months and a 6-month survival of 60% for the 112 Temodal patients in its pivotal study. The 113 patients in the procarbazine arm had a median survival of 5.82 months and 48% survival at 6 months. These survival data had a P value of .067. The FDA review team reported almost identical survival rates with a P value of .07.
“We’re tantalized with the borderline significance level,” said Richard M. Simon, DSc, chief of the NCI’s Biometric Research Branch. However, Dr. Simon criticized the study design as not providing an adequate means of comparison between the two arms. As a result, he said, “there is no evidence of a survival benefit.”
The phase II study of Temodal in patients with relapsed anaplastic astro-cytomas was better received. The study consisted of 162 patients treated in 32 centers. According to Sara Zaknoen, MD, of the Schering-Plough Research Institute, 46% of the patients had a 6-month progression-free survival (median, 5.3 months). Overall survival was 75% at 6 months and 56% at 12 months. Median overall survival was 13.6 months.
“Perhaps the most encouraging results were seen in the response rates,” Dr. Zaknoen said. “There were 13 complete responders and 44 partial responders, for a combined response rate of 35%.”
FDA reviewer Martin Cohen, MD, said the agency’s examination of data from 143 patients with evaluable histology showed a combined response rate of 33%, with a median response of 218 days (7.27 months). The FDA review team put median progression-free survival at 6.64 months and 6-month progression-free survival at 52%. The FDA listed overall median survival at 14.61 months and 6-month overall survival at 77.3%.
Adverse Events
In the three studies, 11 patients (9 on Temodal) developed pulmonary emboli and 16 (15 on Temodal) suffered venous thrombosis, according to the FDA analysis. Other adverse events included anemia, neutropenia, and thrombocyto-penia. Thirty-nine patients died within 30 days of treatment; 14 were considered treatment related. Thirty of these patients received Temodal. In the anaplastic astrocytoma study, only one of nine deaths was attributed to treatment.
ODAC members were specifically asked by the FDA to decide whether the phase II study in anaplastic astrocytoma patients showed that Temodal is effective for the treatment of such patients who have had prior treatment with a nitrosourea and procarbazine. They agreed by a unanimous 12 to 0 vote that it was. And by the same vote, they agreed that the safety of Temodal was acceptable for use in anaplastic astrocytoma relapse.
Schering-Plough said following the vote that it would continue working closely with the FDA in its review of Temodal for use in glioblastoma multiforme. The company also has an NDA pending for its use as first-line treatment of advanced metastatic melanoma.
Temodal also recently received approval from the European Commission that will allow marketing of the drug for glioblastoma multiforme in all 15 nations in the European Union.
