A phase I study of sunitinib plus irinotecan in the treatment of patients with recurrent malignant glioma.
e13024 Background: Malignant glioma (MG), an incurable primary CNS tumor, are highly angiogenic due to overexpression of VEGF/VEGFR. The current study was designed to determine the MTD and DLT of sunitinib (S), a once-daily, oral selective inhibitor of VEGFR when combined with irinotecan (I), a topoisomerase-1 inhibitor among recurrent MG patients. METHODS: We employed a '3+3' dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S, administered once daily for the first 28 days of each 42 day cycle, with I, administered every 2 weeks. The initial S and I doses were 25 mg/day and 75 mg/m(2). Key eligibility criteria included KPS ≥ 70%, adequate organ function and no concurrent CYP3A-inducing anti-epileptics. Pharmacokinetic studies for S are obtained during cycle 1 among 6 additional patients treated at the MTD. RESULTS: Eleven patients (grade 4 MG, n = 6; grade 3 MG, n = 5) have enrolled. No DLTs were observed in cohort 1, but 2 patients experienced hematologic DLT (grade 3 thrombocytopenia, n = 2; grade 4 neutropenia, n = 1) in cohort 2. Therefore the MTD for this regimen is 25 mg of S plus 75 mg/m(2) of I. Evidence of therapeutic benefit to date includes 8 patients (73%) with stable disease including 3 who continue on therapy. CONCLUSIONS: Combination of sunitinib plus irinotecan is well tolerated in recurrent MG patients at the defined MTD dose level. Accrual to the PK dose expansion cohort continues. No significant financial relationships to disclose.
Friedman, HS; Vredenburgh, JJ; Desjardins, A; Janney, DE; Peters, KB; Friedman, AH; Gururangan, S; Reardon, DA
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