title: Phase I study of the farnesyltransferase inhibitor BMS-214662 given weekly in patients with solid tumors.
abstract: OBJECTIVE
  A phase I trial of BMS-214662, a selective farnesyltransferase inhibitor with significant preclinical antitumor activity in which drug was given as a weekly 1-hour infusion for four of six weeks, was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamic effect on farnesyltransferase activity in peripheral blood mononuclear cells.
  
  
  METHODS
  BMS-214662 was given to 27 patients with solid tumors at 10 escalating dose levels (28-220 mg/m(2)) allowing intrapatient dose escalation; pharmacokinetics and pharmacodynamics were done at the first seven dose levels.
  
  
  RESULTS
  Grade 4 neutropenia (four patients) was the most common dose-limiting toxicity followed by aminotransferase elevation (grade 3 alanine aminotransferase and grade 4 aspartate aminotransferase) and grade 3 dehydration. Most frequent toxicities were neutropenia in 11 (14%), anemia in 15 (19%), fatigue in 9 (12%), and nausea and diarrhea in 6 (8%) of courses, respectively. One minor response lasting 18 weeks in a patient with non-small cell lung cancer, serum calcitonin level reduction accompanied by disease stabilization in two of four patients with medullary thyroid carcinoma, and stable disease in 16 of 25 evaluable patients was seen. No correlation was observed between dose and C(max), total body clearance (mean, 26.15 +/- 10.88 L per hour per m(2)), volume of distribution at steady state (mean, 39.51 +/- 17.91 L/m(2)), or half-life (mean, 2.63 +/- 1.81 hours); a moderate correlation existed between dose given and systemic drug exposure (AUC). Substantial inhibition of peripheral blood mononuclear cell farnesyltransferase activity but near complete recovery by 24 hours was seen.
  
  
  CONCLUSIONS
  BMS-214667 was well tolerated as a weekly 1-hour i.v. infusion for four of six weeks with evidence of pharmacodynamic effect. The study was terminated before maximum tolerated dose was reached. Alternative schedules of drug administration might result in improved pharmacodynamic profile.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. vpapadim@mdanderson.org
authors.forename: Vali
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Sofia
authors.initials: S
authors.lastname: Agelaki
authors.forename: Hai T
authors.initials: HT
authors.lastname: Tran
authors.forename: Merrill
authors.initials: M
authors.lastname: Kies
authors.forename: Robert
authors.initials: R
authors.lastname: Gagel
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: Gregory
authors.initials: G
authors.lastname: Ayers
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Fadlo
authors.initials: F
authors.lastname: Khuri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D019540:Area Under Curve; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine