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

Cancer Chemother Pharmacol. 2004 Nov;54(5):377-84. doi: 10.1007/s00280-004-0841-y. Epub 2004 Jul 3.


Purpose: 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.

Design: 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.

Results: 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 were the most common toxicities.

Conclusions: Coadministration of CAI with ketoconazole increased CAI exposure in most of the patients without altering the toxicity profile of CAI. The highest CAI dose administered on the trial was 300 mg/day. The clinical utility of such a modulation strategy might be explored in future clinical trials of CAI.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antifungal Agents / therapeutic use*
  • Antineoplastic Agents / toxicity*
  • Capsules
  • Chemistry, Pharmaceutical
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Female
  • Humans
  • Ketoconazole / therapeutic use*
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Triazoles / toxicity*


  • Antifungal Agents
  • Antineoplastic Agents
  • Capsules
  • Cytochrome P-450 Enzyme Inhibitors
  • Triazoles
  • carboxyamido-triazole
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole