GAITHERSBURG, MdThe 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. Accelerated approval requires the
company to conduct further research to demonstrate the drugs
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
Temodals 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.
Were tantalized with the borderline significance
level, said Richard M. Simon, DSc, chief of the NCIs
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
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
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 agencys 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%.
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
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.