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

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 me...

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Published in:	Clinical cancer research Vol. 13; no. 23; pp. 7133 - 7138
Main Authors:	LOGHIN, Monica E, PRADOS, Michael D, CHANG, Susan M, CLOUGHESY, Timothy, DEANGELIS, Lisa M, ROBINS, Lan H, ALDAPE, Kenneth D, ALFRED YUNG, W. K, WEN, Patrick, JUNCK, Larry, LIEBERMAN, Frank, FINE, Howard, FINK, Karen L, METHA, Minesh, KUHN, John, LAMBORN, Kathleen
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-12-2007
Subjects:	Adult Aged Anticonvulsants - therapeutic use Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Biological and medical sciences Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain/central nervous system cancers Camptothecin - administration & dosage Camptothecin - adverse effects Camptothecin - analogs & derivatives Camptothecin - pharmacokinetics Dacarbazine - administration & dosage Dacarbazine - adverse effects Dacarbazine - analogs & derivatives Drug Administration Schedule Drug Interactions Drug therapy Enzyme Induction Female Glioma - drug therapy Glioma - metabolism Humans Irinotecan Male Malignant glioma Medical sciences Middle Aged Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - metabolism Neurology Pharmacology. Drug treatments Temozolomide Tumors of the nervous system. Phacomatoses United States North America America Camptothecin derivatives Antineoplastic agent Human Drug Intracranial Nervous system diseases Relapse Enzyme DNA topoisomerase Enzyme inhibitor Anticonvulsant Malignant tumor Intracranial tumor Cerebral disorder Malignant glioma Irinotecan Alkylating agent Isomerases Treatment Central nervous system disease Phase I trial Temozolomide Topoisomerase I inhibitor Cancer
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Summary:	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/m 2 ) 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/m 2 in 50-mg/m 2 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/m 2 . Conclusions: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m 2 , 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-07-0874