A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma.
1580 Background: This study attempts to extend the anti-glioma activity of imatinib mesylate (Gleevec, IM) plus hydroxyurea (H), by adding RAD001 (R), an orally bioavailable inhibitor of mTOR, a critical intracellular mediator of signal transduction and metabolism. METHODS: We employ a "3+3" dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IM + H + R administered daily among adult recurrent malignant glioma patients s with ≤ 3 prior recurrences, KPS > 60% and adequate organ function. Patients are stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC), and both strata are independently escalated. Initial dose level for each stratum: IM - 400 mg/day; H - 500 mg bid; R - 2.5 mg/day. Each treatment cycle is 28 days. Response is evaluated every other cycle. Pharmacokinetic (PK) studies are performed on days 1 and 28 of cycle 1. RESULTS: Twenty-two recurrent GBM patients have enrolled. The median age is 53 (range 37 to 75), 41% are male, and 45% are on EIAC. Two DLTs (grade 4 hypercholesterolemia and thrombocytopenia) occurred among 5 patients on dose level one (non-EIAC stratum). No other DLTs have occurred. The dose escalation schema has been amended to include alternate day R dosing. IM PK were consistent with those previously reported for patients on IM and HU. IM clearance on day 1 was 492 ± 247 ml/min in the EIAC stratum and 231 ± 100 ml/min in the non-EIAC stratum. On day 28, IM clearance was decreased in both strata (243 ± 93 ml/min in the EIAC stratum and 116 ± 47 ml/min in the non-EIAC stratum) PK results for HU and R are pending. Nine patients continue on study having received 2-8 cycles of therapy. Four partial responses have been observed and accrual is ongoing. CONCLUSIONS: Further accrual is warranted. An update of outcome, toxicity and pharmacokinetic analyses will be presented. [Table: see text].
Reardon, D; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Gururangan, S; Egorin, MJ; Salvado, A; Friedman, HS
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