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.

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.

• Authors: Josep Tabernero, Fredy Rojo, Irene Marimón, Maurizio Voi, Joan Albanell, Marta Guix, Federico Vázquez, Joan Carulla, Michael Cooper, Jordi Andreu, Anne Van Vreckem, Joaquim Bellmunt, Veeraswamy Manne, James A Manning, Carmen Garrido, Enriqueta Felip, Josep Maria Del Campo, Mónica García, Sonia Valverde, José Baselga
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 11 Pg. 2521-33 (Apr 10 2005) ISSN: 0732-183X [Print] United States
• PMID: 15710949 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• 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

Topics

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