Phase I pharmacokinetic and pharmacodynamic study of weekly 1-hour and 24-hour infusion BMS-214662, a farnesyltransferase inhibitor, in patients with advanced solid tumors

J Clin Oncol. 2005 Apr 10;23(11):2521-33. doi: 10.1200/JCO.2005.00.398. Epub 2005 Feb 14.

Abstract

Purpose: BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples.

Patients and methods: Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule.

Results: high (> 80%) but short-lived (< or = 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling.

Conclusion: BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Apoptosis / drug effects
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / adverse effects*
  • Benzodiazepines / pharmacokinetics*
  • Benzodiazepines / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Farnesyltranstransferase
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects*
  • Imidazoles / pharmacokinetics*
  • Imidazoles / pharmacology
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Signal Transduction

Substances

  • Imidazoles
  • Benzodiazepines
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • 7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine