Fotemustine combined with procarbazine in recurrent malignant gliomas: a phase I study with evaluation of lymphocyte 06-alkylguanine-DNA alkyltransferase activity.

Abstract

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 O6-alkylguanine-DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100 mg/day oral PCZ for 12 consecutive days 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/m2/day). After a 6-week 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 on days 1, 5 and 12 over 4 h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125 mg/m2 (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.

• Authors: A Boiardi, A Silvani, E Ciusani, A Watson, G Margison, E Berger, C Lucas, B Giroux
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 52 Issue 2 Pg. 149-56 (Apr 2001) ISSN: 0167-594X [Print] United States
• PMID: 11508814 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Nitrosourea Compounds
• Organophosphorus Compounds
• Procarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• fotemustine

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Brain Neoplasms (drug therapy, metabolism)
• Female
• Glioma (drug therapy, metabolism)
• Humans
• Lymphocytes (drug effects, enzymology)
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Nitrosourea Compounds (administration & dosage, adverse effects)
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Organophosphorus Compounds (administration & dosage, adverse effects)
• Procarbazine (administration & dosage, adverse effects)