title: Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days.
abstract: The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin. Patients were enrolled at four dose levels: BMS-184476 (mg m(-2))/carboplatin (mg min ml(-1)): 40/5, 50/5, 50/6 and 60/6. Dose-limiting toxicity at 60/6 was neutropenia. Among 27 evaluable patients, 11 demonstrated stable disease for a median of 8.5 cycles. In 22 patients, the pharmacokinetics of BMS-184476 appeared independent of dose of BMS-184476. The mean+/-s.e.m. values for clearance (Cl), volume of distribution at steady state and apparent terminal half-life of BMS-184476 in the four dose groups during cycle 1 were 192+/-25 ml min m(-2), 377+/-69 l m(-2) and 33.7+/-5.9 h, respectively. An increase in the dose of carboplatin from 5 to 6 mg min ml(-1) may have decreased Cl of BMS-184476. BMS-184476 in combination with carboplatin was well tolerated at a dose of 50/6 and shows evidence of antitumour activity in a pretreated population.
authors.affiliation: Abramson Family Cancer Center, University of Pennsylvania Cancer Center, 51 N. 39th St., MAB, Philadelphia, PA 19104, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Bilenker
authors.forename: J P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: M L
authors.initials: ML
authors.lastname: Gallagher
authors.forename: D
authors.initials: D
authors.lastname: Vaughn
authors.forename: M B
authors.initials: MB
authors.lastname: Cohen
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000633:toxicity*; D016190:Carboplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D043823:Taxoids; C426424:7-methylthiomethylpaclitaxel; D016190:Carboplatin