Fotemustine combined with procarbazine in recurrent malignant gliomas: A phase I study with evaluation of lymphocyte O-6-alkylguanine-DNA alkyltransferase activity

The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O-6-alkylguanine-DNA alkyltransferase (ATase) deplet ion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100 mg/day oral PCZ for 12 consecutive day s and a 1-h intravenous infusion of fotemustine given 4 h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125 mg/m(2)/day). After a 6-w eek rest period, a maximum of 4 maintenance cycles (PCZ 300 mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured o n days 1, 5 and 12 over 4 h after PCZ intake. Fifteen patients had previous ly received at least one nitrosourea-based chemotherapy, associated with PC Z in 12 cases. The MTD of fotemustine was 125 mg/m(2) (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, h alf of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase ac tivity by PCZ was evidenced. One partial response and 7 stable diseases wer e obtained leading to a disease control rate of 50%. The median times to pr ogression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease cont rol rate in heavily pretreated glioma patients and merits further investiga tion in phase II studies.