title: Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors.
abstract: OBJECTIVE
  To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor.
  
  
  METHODS
  Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel.
  
  
  RESULTS
  Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion.
  
  
  CONCLUSIONS
  Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.
authors.affiliation: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792, USA. hhbailey@wisc.edu
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: Dona B
authors.initials: DB
authors.lastname: Alberti
authors.forename: James P
authors.initials: JP
authors.lastname: Thomas
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mulkerin
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Binger
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Robert E
authors.initials: RE
authors.lastname: Martell
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007093:Imidazoles; D001569:Benzodiazepines; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; D017239:Paclitaxel