A pharmacokinetically guided Phase II study of carboxyamido-triazole in androgen-independent prostate cancer.

Abstract

We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing. Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 microg/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at approximately 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed. CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases. Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed.

• Authors: K S Bauer, W D Figg, J M Hamilton, E C Jones, A Premkumar, S M Steinberg, V Dyer, W M Linehan, J M Pluda, E Reed
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 9 Pg. 2324-9 (Sep 1999) ISSN: 1078-0432 [Print] United States
• PMID: 10499600 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgens
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Triazoles
• carboxyamido-triazole

Topics

• Adenocarcinoma (drug therapy, metabolism)
• Aged
• Androgens (physiology)
• Angiogenesis Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Humans
• Male
• Middle Aged
• Neoplasms, Hormone-Dependent (drug therapy, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism)
• Triazoles (adverse effects, pharmacokinetics, therapeutic use)