title: Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases.
  
  
  METHODS
  Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days.
  
  
  RESULTS
  Forty-five patients received BMS-599626 (100-660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated C(max) and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥ 4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated.
  
  
  CONCLUSIONS
  BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.
authors.affiliation: Service des Innovations Thérapeutiques Précoces, Department of Medicine, Gustave Roussy Institute, Villejuif, France. soria@igr.fr
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: C
authors.initials: C
authors.lastname: Massard
authors.forename: J-P
authors.initials: JP
authors.lastname: Armand
authors.forename: D
authors.initials: D
authors.lastname: De Andreis
authors.forename: S
authors.initials: S
authors.lastname: Ropert
authors.forename: E
authors.initials: E
authors.lastname: Lopez
authors.forename: A
authors.initials: A
authors.lastname: Catteau
authors.forename: J
authors.initials: J
authors.lastname: James
authors.forename: J-F
authors.initials: JF
authors.lastname: Marier
authors.forename: M
authors.initials: M
authors.lastname: Beliveau
authors.forename: R E
authors.initials: RE
authors.lastname: Martell
authors.forename: J
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002219:Carbamates / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D014227:Triazines / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines; C545531:(4-((1-(3-fluorophenyl)methyl)-1H-indazol-5-ylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazin-6-yl)carbamic acid 3-morpholinylmethyl ester