A phase I trial of gefitinib (ZD1839) plus rapamycin for patients with recurrent malignant glioma

Abstract

1565 Abnormal signaling of the PI3K/Akt pathway is a hallmark of malignant glioma. The primary objective of this phase 1 study is to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Gefitinib, an inhibitor of the EGFR receptor tyrosine kinase, when combined with rapamycin, a macrolide antibiotic capable of inhibiting mTOR, a critical downstream regulator of PI3K/Akt signaling, among patients with recurrent malignant glioma. Eligibility criteria include: recurrent malignant glioma; no more than 3 prior episodes of recurrence; age greater than 18 years; KPS greater than 60%; adequate hepatic, renal, pulmonary and bone marrow function. Patients with prior with EGFR or mTOR-directed therapies are excluded. A standard “3+3” dose escalation design was employed. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC; phenytoin, carbamazepine and phenobarbitol) and both strata are independently escalated. Gefitinib and rapamycin are administered on a continuous daily dosing regimen. Each treatment cycle is 28 days and evaluation for response is performed after every other cycle. Twenty-three patients have been enrolled to date: 20 with recurrent GBM and 3 with recurrent AA. The median age is 51 (range 33 to 66); 65% are male and 52% are on EIAC. Accrual and dose escalation are ongoing. The MTD has yet to be defined for either stratum. A single DLT has been observed thus far and consisted of an episode of grade 3 mucositis. Approximately half of the patients have undergone pharmacokinetic sampling. Seventeen patients continue on study having received 1–3 cycles of therapy while 6 patients have discontinued therapy due to progressive disease. Two marked radiographic responses has been observed to date. An update of the outcome and toxicity of Gefitinib plus rapamycin for patients with recurrent malignant glioma will be presented based on additional follow up and enrollment. No significant financial relationships to disclose.