Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma.
e13007 Background: Malignant glioma (MG), an incurable primary CNS tumor, is characterized by frequent aberrant activation of EGFR, VEGFR, and PDGFR. This study will determine the MTD and DLT of vandetanib (V), a once-daily, oral selective inhibitor of VEGFR and EGFR when combined with imatinib mesylate (IM), an inhibitor of multiple tyrosine kinases including PDGFR and hydroxyurea (H). METHODS: Adult recurrent MG patients with ≤ 3 prior recurrences, KPS ≥ 60% and adequate organ function were stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC). Both strata were independently escalated using a "3+3" design. H is administered at 500 mg BID while IM is administered at 500 mg BID for patients on EIAC and 400 mg QD for those not on EIAC. V is increased by 100 mg in successive cohorts beginning at 100 mg and 200 mg for patients not on and on EIAC, respectively. Evaluations were after every other 28-day cycle. Pharmacokinetics of V and IM were obtained on days 1 and 28 of cycle 1. RESULTS: Twenty-six patients (grade 4 MG, n = 20; grade 3 MG, n = 6) have enrolled. Only 1 DLT (reversible grade 4 transaminase elevation; dose level 1) occurred among 22 non-EIAC patients and enrollment to this stratum is planned to continue at dose level 4. The MTD of V for patients on EIAC is 200 mg/day due to 2 of 3 patients developing grade 3 thrombocytopenia at the 300 mg/day dose level. Evidence of therapeutic benefit to date includes 1 partial response and 15 patients (58%) with stable disease for at least 4 weeks, including 4 patients for ≥4 months. CONCLUSIONS: Combination of V, IM, and H is well-tolerated in recurrent MG patients. Further accrual is ongoing and an update of outcome, toxicity, and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.
Kirkpatrick, JP; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Peters, KB; Boulton, ST; Friedman, AH; Friedman, HS; Reardon, DA
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