Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs Journal Article

Authors: Chang, S. M.; Kuhn, J.; Wen, P.; Greenberg, H.; Schiff, D.; Conrad, C.; Fink, K.; Robins, H. I.; Cloughesy, T.; De Angelis, L.; Razier, J.; Hess, K.; Dancey, J.; Prados, M. D.; North American Brain Tumor Consortium And The National Cancer Institute
Article Title: Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs
Abstract: Objectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs. Study design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria. Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs. Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.
Keywords: adult; cancer chemotherapy; clinical article; controlled study; treatment outcome; middle aged; unclassified drug; clinical trial; fatigue; area under the curve; drug efficacy; drug safety; hypophosphatemia; antineoplastic agents; chemotherapy; recurrent cancer; glioma; brain neoplasms; edema; controlled clinical trial; cohort studies; neoplasm recurrence, local; stomatitis; drug administration schedule; dose-response relationship, drug; temsirolimus; rash; standard; etiracetam; oxcarbazepine; phenobarbital; topiramate; glioblastoma; headache; drug blood level; maximum tolerated dose; phase 1 clinical trial; hypercholesterolemia; anticonvulsive agent; toxicity; drug determination; infusions, intravenous; metoclopramide; clonazepam; rapamycin; fluconazole; sirolimus; drug interactions; phenytoin; hypertriglyceridemia; anticonvulsants; drug use; valproic acid; enzyme induction; carbamazepine; gabapentin; lamotrigine; zonisamide; cytochrome p450 3a4; primidone; cytochrome p-450 enzyme system; fosphenytoin sodium; clobazam; tiagabine; valproate semisodium; cci-779; humans; human; male; female; priority journal; article; desmethoxyrapa; gabatril; lamictil; phenytek
Journal Title: Investigational New Drugs
Volume: 22
Issue: 4
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2004-11-01
Start Page: 427
End Page: 435
Language: English
DOI: 10.1023/b:drug.0000036685.72140.03
PROVIDER: scopus
PUBMED: 15292713
Notes: Invest. New Drugs -- Cited By (since 1996):79 -- Export Date: 16 June 2014 -- CODEN: INNDD -- Source: Scopus
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