Abstract
2064 Background: Effective treatments for recurrent malignant gliomas are limited. MGMT is one of the mechanisms of resistance for malignant gliomas. Depletion of MGMT may improve antitumor activity by increasing activity of alkylators. We used this concept in performing a phase I trial of temozolomide (TMZ) and laromustine (chloretazine). Methods: Patients were enrolled in standard 3 x 3 phase I trial with goal of performing a phase II trial at the MTD. Patients were treated with TMZ at 75 mg/m2days 1-7 and then chloretazine at 100, 150, or 125mg/m2 on day 7 (2 hours after TMZ) of a 6 week cycle. Patients were treated until progression or intolerable side effects. Patients had MRI scans every 6 weeks with a physical exam and weekly CBC’s were performed. Results: A total of 14 pts were accrued (10 GBM, 3 AA and 1 AOA), 10 M and 4 F with a median age and KPS of 51 (25-68) and 90 (80-100). Median number of cycles was 1 (1-4). Dose level 100 mg/m2 had 7 pts with 1 grade 4 thrombocytopenia, dose level 150 mg/m2had5 pts with1 grade 4 thrombocytopenia and 1 grade 3 fatigue. Does level 125 mg/m2 had 2 pts with 1 grade 4 leukopenia and thrombocytopenia. 10 pts had PD after 1 cycles, 4 were removed for toxicity. 3 pts who did not progress had SD. PFS-6 was 7%. Conclusions: The optimal dose for phase II was felt to be TMZ 75 mg/m2 x 7days and chloretazine 100 mg/m2 on day 7. The main toxicity of this regimen attempting to take advantage of MGMT depletion strategy is myelosuppression; similar to other trials using this strategy.
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