Phase II trial of imatinib mesylate and hydroxyurea for grade III malignant gliomas

Abstract

1573 Background: We evaluated the combination of imatinib mesylate (Gleevec) and hydroxyurea in WHO grade III malignant gliomas following the encouraging response of this combination demonstrated in glioblastoma multiforme. Methods: Eligibility: adult patients with recurrent/relapsing AA or AO with measurable disease; 2 weeks since surgical resection or 4 weeks since radiotherapy or chemotherapy; Karnofsky 60% and adequate organ function. Imatinib and hydroxyurea were given orally daily. Imatinib was administered at 400 mg daily to patients not on enzyme inducing antiepileptic drugs (EIAED) while those on EIAED received 500 mg twice a day. Hydroxyurea was administered to all patients at 500 mg twice a day. Each cycle was 28 days of therapy. Results: Thirty-nine patients with recurrent AA (n= 32) or AO (n=7), following prior radiation therapy and chemotherapy, have been enrolled, including 21 (54%) not on EIAED and 18 (46%) on EIAED. Patient characteristics were comparable between both strata. Median age was 39 years (range, 21–59 years). The most frequent grade III-IV toxicities were neutropenia (n=11), leukopenia (n=8), thrombocytopenia (n=6), deep venous thrombosis (n=3), fatigue (n=2) and pulmonary edema (n=2). One patient presented grade V brain hemorrhage at the time of disease progression. Four patients achieved a partial response, for an overall response rate of 10%. Thirteen patients (33%) achieved disease stabilization. Twelve patients (67%) not on EIAED had progressive disease as their best response compared to only 4 patients (27%) on EIAED. The median time to progression for all patients, and for those not on EAIED and on EIAED was 14.1 weeks, 10.9 weeks and 26.0 weeks, respectively. Conclusions: Daily imitanib mesylate plus hydroxyurea demonstrates encouraging activity and is well tolerated among patients with recurrent AA or AO. As observed with glioblastoma multiforme patients, patients on EAIED seem to demonstrate a better response. [Table: see text]