Phase I Clinical and Pharmacokinetic Study of Irinotecan in Adults with Recurrent Malignant Glioma1
- Mark R. Gilbert,
- Jeffrey G. Supko,
- Tracy Batchelor,
- Glenn Lesser,
- Joy D. Fisher2,
- Steven Piantadosi and
- Stuart Grossman
- Emory University School of Medicine, Atlanta, Georgia 30322 [M. R. G.]; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 [J. G. S., T. B.]; Wake Forest University School of Medicine, Winston-Salem, North Carolina [G. L.]; and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland [J. D. F., S. P., S. G.]
Abstract
Purpose: A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs).
Experimental Design: Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m2/week for both groups of patients (+/−EIA). Groups of ≥3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose.
Results: Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m2/week in the +EIA cohort and 117 mg/m2/week in the −EIA cohort for the weekly × 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from ∼50 liters/h/m2 at the lower dose levels (125–238 mg/m2) to a mean ± SD value of 29.7 ± 9.0 liters/h/m2 (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 ± 10.6 liters/h/m2, was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients.
Conclusions: The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by Grants U01-CA62475, P30-CA0516, and U01-CA62406 from the National Cancer Institute, NIH, Department of Health and Human Services (Bethesda, MD).
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↵2 To whom requests for reprints should be addressed, at NABTT Central Office, Johns Hopkins, Bunting/Blaustein CRB G87, 1650 Orleans Street, Baltimore, MD 21231. Phone: (410) 955-3657; Fax: (410) 614-9335; E-mail: jfisher{at}jhmi.edu
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↵3 The abbreviations used are: topo I, topoisomerase I; AUC, area under the plasma-concentration curve from time 0 to infinity; CYP450, cytochrome P450; MTD, maximum tolerated dose; MRI, magnetic resonance imaging; CT, computed tomography; EIA, enzyme-inducing anticonvulsant; NCI, National Cancer Institute; CL, total body clearance; CNS, central nervous system; NPC, 7-ethyl-10-(4-amino-1-piperidino)-carbonyloxycamptothecin; DLT, dose-limiting toxicity; SN-38, 7-ethyl-10-hydroxy-camptothecin; SN-38G, SN-38 glucuronide.
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- Accepted March 6, 1903.
- Received October 29, 1902.
- Revision received March 3, 1903.
