Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG).
2057 Background: Angiogenesis is a hallmark of MG with VEGF as a key regulator. Imatinib mesylate (IM) and hydroxyurea (H) have recently demonstrated promising anti-glioma activity. We attempt to extend the efficacy of IM and H by adding a VEGF receptor inhibitor, vatalanib (V; PTK787). METHODS: We employed a "3+3" dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of V when administered with established doses of IM and H in adult recurrent MG patients with < 3 prior recurrences, KPS ≥ 70% and adequate organ function. Patients were stratified based on concurrent enzyme-inducing anticonvulsant (EIAC) administration, and both strata (A- not on EIAC and B- on EIAC) were independently dose-escalated. Response was evaluated after every other 28-day cycle. Pharmacokinetic (PK) studies were performed during cycle 1. RESULTS: Thirty-seven recurrent MG patients enrolled including 34 (92%) with glioblastoma multiforme and 3 (8%) with WHO grade 3 MG. The median age is 53 (range 26 to 76) and 51% are on EIAC. The MTD of V is 1,000 mg bid. DLTs included grade 3 thrombocytopenia, rash, fatigue, hypertension and transaminase elevation. Best responses include partial response (n=8, 22%) and stable disease (n=19, 51%). With a median follow-up of 82 weeks, 6-month progression-free survival is 27%. PK results are pending. CONCLUSIONS: Combination of imatinib, hydroxyurea and vatalanib is safe and well tolerated with an encouraging rate of radiographic response. MTD is 1,000 mg of V bid with standard imatinib and hydroxyurea dosing for recurrent MG patients. [Table: see text].
Kirkpatrick, JP; Rich, JN; Vredenburgh, JJ; Desjardins, A; Quinn, JA; Gururangan, S; Sathornsumetee, S; Egorin, MJ; Friedman, HS; Reardon, DA
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