title: 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.affiliation: Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Bauer
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: E C
authors.initials: EC
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Premkumar
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: V
authors.initials: V
authors.lastname: Dyer
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: J M
authors.initials: JM
authors.lastname: Pluda
authors.forename: E
authors.initials: E
authors.lastname: Reed
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D000368:Aged; D000728:Androgens / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000728:Androgens; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014230:Triazoles; C062058:carboxyamido-triazole