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Neuro-Oncology 2004 6(1):44-54; doi:10.1215/S1152851703000292
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© 2004 by the Society forNeuro-Oncology

Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignantglioma: A North American Brain Tumor Consortium study

Michael D. Prados2, W.K.A. Yung, Kurt A. Jaeckle, H. Ian Robins, Minesh P. Mehta, Howard A. Fine, Patrick Y. Wen, Timothy F. Cloughesy, Susan M. Chang, M. Kelly Nicholas, David Schiff, Harry S. Greenberg, Larry Junck, Karen L. Fink, Kenneth R. Hess and John Kuhn

Departments of Neurological Surgery (M.D.P., S.M.C.)and Neuro-Oncology (M.K.N.), University of Californiaat San Francisco, San Francisco, CA 94143; Departmentsof Neuro-Oncology (W.K.A.Y.) and Biostatistics(K.R.H.), The University of Texas M.D. Anderson Cancer Center, Houston, TX77030; Departments of Neurology andHematology/Oncology, Mayo Clinic Jacksonville, Jacksonville, FL 32224(K.A.J.); Departments of Medicine (H.I.R.) and Radiotherapy (M.P.M.), University of Wisconsin, Madison, WI53792; Neuro-Oncology Branch, National CancerInstitute, Bethesda, MD 20892 (H.A.F.); Center forNeuro-Oncology, Dana Farber Cancer Institute, Boston, MA 02115 (P.Y.W.); Neuro-Oncology Program, University of California, LosAngeles, Los Angeles, CA 90095 (T.F.C.); Division ofNeuro-Oncology, University of Virginia Health Science Center, Charlottesville,VA 22908 (D.S.); Department of Neurology, Universityof Michigan, Ann Arbor, MI 48109 (H.S.G., L.J.); Department of Neurology, The University of TexasSouthwestern Medical Center, Dallas, TX 75390 (K.L.F.); College of Pharmacy, University of Texas Health ScienceCenter at San Antonio, San Antonio, TX 78229 (J.K.); USA

2 Address correspondence to Michael Prados, University of California at SanFrancisco, 400 Parnassus Avenue, Room A808, San Francisco, CA 94143-0372, USA(pradosm{at}neurosurg.ucsf.edu).


  Abstract

This study was conducted to determine the maximum tolerated dose anddose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks toadults with progressive malignant glioma who were treated with enzyme-inducingantiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics withthose in patients not on EIAED therapy treated at the recommended phase 2 dosefor other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeksand remained fixed in patients not on EIAED therapy, but the dose wasescalated by 50-mg/m2 increments in patients on EIAED therapy.CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC(7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]carbonyloxycamptothecin)were characterized in both groups. Patients on EIAEDs received 350 to 800mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrheadespite maximal doses of loperamide. The systemic levels of CPT-11, APC,SN-38G, and SN-38 were all lower in the EIAED group. There was amoderate-to-fair relationship between CPT-11 dose and the area under the curve(AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2,but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. Atthe 750-mg/m2 dose, the AUC for CPT-11 (21.6 µg x h/ml)matched the AUC (21.6 µg x h/ml) in the non-EIAED group treated with350 mg/m2 of CPT-11. We conclude that the recommended phase 2 doseof CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3weeks. A phase 2 study of patients with recurrent malignant glioma is ongoingto assess the efficacy of CPT-11 when the dose is stratified according to theuse of EIAEDs.

Received June 25, 2003; Accepted September 22, 2003


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