Phase I study of temozolomide and irinotecan for recurrent malignant gliomas in patients receiving enzyme-inducing antiepileptic drugs: A north American brain tumor consortium study Journal Article


Authors: Loghin, M. E.; Prados, M. D.; Wen, P.; Junck, L.; Lieberman, F.; Fine, H.; Fink, K. L.; Metha, M.; Kuhn, J.; Lamborn, K.; Chang, S. M.; Cloughesy, T.; Deangelis, L. M.; Robins, I. H.; Aldape, K. D.; Yung, W. K. A.
Article Title: Phase I study of temozolomide and irinotecan for recurrent malignant gliomas in patients receiving enzyme-inducing antiepileptic drugs: A north American brain tumor consortium study
Abstract: Purpose: To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. Design: Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m2) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m 2, which was escalated to 550 mg/m2 in 50-mg/m2 increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. Results: Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m2. Conclusions: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m2, administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan. ©2007 American Association for Cancer Research.
Keywords: adult; clinical article; controlled study; treatment response; aged; middle aged; clinical trial; neutropenia; area under the curve; diarrhea; drug withdrawal; recommended drug dose; side effect; treatment duration; temozolomide; recurrent cancer; brain tumor; glioma; brain neoplasms; dacarbazine; controlled clinical trial; infection; liver toxicity; multiple cycle treatment; neoplasm recurrence, local; gastrointestinal symptom; leukopenia; nausea; thrombocytopenia; antineoplastic combined chemotherapy protocols; drug administration schedule; 7 ethyl 10 hydroxycamptothecin; camptothecin; bedtime dosage; continuous infusion; irinotecan; drug dose escalation; loading drug dose; lymphocytopenia; bilirubin; chemotherapy induced emesis; drug fatality; cancer regression; health status; morning dosage; glioblastoma; patient compliance; drug infusion; oligodendroglioma; loperamide; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; liver enzyme; anticonvulsive agent; drug metabolite; gliosarcoma; bilirubin blood level; treatment refusal; drug interactions; anticonvulsants; granulocytopenia; north america; enzyme induction; enzyme inducing agent
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 23
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-12-01
Start Page: 7133
End Page: 7138
Language: English
DOI: 10.1158/1078-0432.ccr-07-0874
PUBMED: 18056194
PROVIDER: scopus
PMCID: PMC4802002
DOI/URL:
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
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