A phase I trial of pharmacokinetic modulation of carboxyamidotriazole (CAI) with ketoconazole in patients with advanced cancer

Cancer Chemotherapy and Pharmacology
Apurva A DesaiMark J Ratain

Abstract

Carboxyamidotriazole (CAI) is a novel antineoplastic agent in clinical development with limited oral bioavailability. In vitro, ketoconazole has been demonstrated to inhibit CYP3A4-mediated metabolism of CAI. We performed this phase I trial to determine if ketoconazole-mediated CYP3A4 inhibition would lead to favorable alteration of CAI pharmacokinetics, and to evaluate the safety, toxicity and tolerability of the proposed combination. Forty-seven patients were treated using a standard three patients per cohort CAI dose-escalation scheme. In cycle 1, CAI was administered alone on day-6 followed by a single dose of ketoconazole (200 mg) on day 0. CAI and ketoconazole (200 mg/day) were subsequently coadministered on days 1 and 3-28. Plasma samples for pharmacokinetic analysis were obtained following the doses on days-6 and 1. All subsequent cycles were of 28-day duration, and consisted of daily CAI and ketoconazole coadministration. Pharmacokinetic analysis was performed on samples from 44 patients. In most patients administration of ketoconazole produced an increase in CAI AUC and Cmax with a decrease in CAI clearance. Seven patients experienced stable disease for up to 12 months. Gastrointestinal and constitutional toxicities w...Continue Reading

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Citations

Feb 20, 2007·Cancer Chemotherapy and Pharmacology·Wei Peng YongMark J Ratain
Jan 27, 2017·Naunyn-Schmiedeberg's Archives of Pharmacology·Chen ChenLei Guo
Sep 26, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Maylee ChenJoseph S Bertino

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