This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Loghin, M. E. Articles by Yung, W.K. A. Search for Related Content PubMed PubMed Citation Articles by Loghin, M. E. Articles by Yung, W.K. A.

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

Authors' Affiliations: Departments of ¹ Neuro-Oncology and ² Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas; ³ Neuro-Oncology Services, ⁴ Department of Neurological Surgery, University of California, San Francisco, California; ⁵ Dana-Farber Cancer Institute, Boston, Massachusetts; ⁶ Department of Neurology, University of Michigan Hospital, Ann Arbor, Michigan; ⁷ University of Pittsburgh Medical Center Cancer Pavilion, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁸ National Cancer Institute, Neuro-Oncology Branch, Bethesda, Maryland; ⁹ Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas; ¹⁰ University of Wisconsin Hospital; ¹¹ Department of Medicine, University of Wisconsin, Madison, Wisconsin; ¹² The University of Texas Health Science Center at San Antonio, San Antonio, Texas; ¹³ University of California Los Angeles, Los Angeles, California; and ¹⁴ Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: W.K. Alfred Yung, Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Unit 431, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3751; Fax: 713-794-4999; E-mail: wyung{at}mdanderson.org.

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/m², 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.