title: Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors.
abstract: OBJECTIVE
  BMS-214662 is a novel farnesyltransferase (FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration.
  
  
  METHODS
  Infusion of BMS-214662 was prolonged from 2, 4, 8, 16, 24 h in single patient cohorts and repeated weekly for 3 out of 4 weeks. The initial dose was 56 mg/m(2). When the infusion duration reached 24 h, the dose was escalated at a constant multiples of 1.4 in single patient cohorts until the occurrence of toxicity greater than grade 1, upon which groups of at least three patients were evaluated at each dose level. The plasma pharmacokinetics and FT inhibition in PBMCs were measured in all patients at the prospective maximum tolerated dose.
  
  
  RESULTS
  Nineteen patients participated in the study (11 males/8 females) and the weekly dose was increased to a maximum of 300 mg/m(2) given as a 24 h i.v. infusion. Drug-related toxicity greater than grade 1 first occurred at 300 mg/m(2), with two patients experiencing dose-limiting toxicity. One patient developed a grade 3 hyponatremia and another developed reversible grade 3 diarrhea, grade 2 renal toxicity, and grade 3 transaminitis. A 275 mg/m(2) dose was then evaluated, where one of the three patients treated experienced reversible grade 4 renal toxicity and grade 3 diarrhea. In view of the identical renal toxicity at 275 mg/m(2) in another study and limited drug availability, there was no further accrual to this dose level and the study was closed. No evidence of antitumor activity was observed. The plasma pharmacokinetics of BMS-214662 was linear with high interpatient variability. In the three patients evaluated at the 275 mg/m(2) dose level, the maximum inhibition of FT activity in PBMCs was 47+/-23% of the baseline.
  
  
  CONCLUSIONS
  Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs.
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology and Brigham and Women's Hospital, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Shields-Warren Building 460, 44 Binney Street, Boston, MA 02115, USA. jeder@partners.org
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Leonard
authors.initials: L
authors.lastname: Appleman
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Thomas
authors.initials: T
authors.lastname: Puchalski
authors.forename: Xiaoying
authors.initials: X
authors.lastname: He
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Sonnichsen
authors.forename: Michael
authors.initials: M
authors.lastname: Cooper
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
mesh_terms: D000328:Adult; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D001569:Benzodiazepines; D051231:Farnesyltranstransferase; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine