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

We conducted a Phase II clinical trial of the antiproliferative, antimetast atic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacok inetic 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 show n 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 a nd 5.0 mu g/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were wi thin the predicted range. Fourteen of 15 patients were evaluable for respon se. All of the 14 evaluable patients demonstrated progressive disease at si milar to 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progress ion 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 re sponses were noted, a 27.7% decrease in serum vascular endothelial growth f actor concentration was observed. CAI does not possess clinical activity in patients with androgen-independen t prostate cancer and soft tissue metastases, Pharmacokinetically guided do sing, although found to be feasible using a Bayesian approach, was not foun d to be of practical benefit. Although plasma CAI concentrations were maint ained within the designated range, grade III toxicity requiring drug discon tinuation was still observed.