title: Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.
abstract: OBJECTIVE
  To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474.
  
  
  RESULTS
  Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively.
  
  
  CONCLUSIONS
  The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center at San Antonio, 78229, USA. manuelh@oncology.uthscsa.edu
authors.forename: M
authors.initials: M
authors.lastname: Hidalgo
authors.forename: C
authors.initials: C
authors.lastname: Aylesworth
authors.forename: L A
authors.initials: LA
authors.lastname: Hammond
authors.forename: C D
authors.initials: CD
authors.lastname: Britten
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: J
authors.initials: J
authors.lastname: Stephenson
authors.forename: G
authors.initials: G
authors.lastname: Schwartz
authors.forename: A
authors.initials: A
authors.lastname: Patnaik
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Molpus
authors.forename: S
authors.initials: S
authors.lastname: Felton
authors.forename: E
authors.initials: E
authors.lastname: Gupta
authors.forename: K J
authors.initials: KJ
authors.lastname: Ferrante
authors.forename: A
authors.initials: A
authors.lastname: Tortora
authors.forename: D S
authors.initials: DS
authors.lastname: Sonnichsen
authors.forename: J
authors.initials: J
authors.lastname: Skillings
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives; D012995:Solubility; D043823:Taxoids
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; C426424:7-methylthiomethylpaclitaxel; D017239:Paclitaxel