title: Phase I and pharmacokinetic study of weekly oral therapy with vinorelbine in patients with advanced breast cancer (ABC).
abstract: BACKGROUND
  A phase I dose-escalation study of a new formulation of oral vinorelbine was conducted to determine the maximum tolerated dose (MTD) of a once weekly regimen and preliminary pharmacokinetic profile in patients with advanced breast cancer (ABC). Twenty-six patients were treated at dose levels ranging from 60 to 100 mg/m2/week. Pharmacokinetics was assessed during the first administration.
  
  
  METHODS
  All patients had histologically confirmed locally advanced or metastatic breast cancer and had received no more than two prior chemotherapy regimens for ABC.
  
  
  RESULTS
  The MTD was 100 mg/m2/week due to the occurrence of dose-limiting neutropenia, nausea/vomiting and constipation in five of six patients. Toxicities at 80 mg/m2/week were manageable, neutropenia being the main toxicity (grade 3-4 seen in 10 of 13 patients). Nausea, vomiting and diarrhoea were common but rarely severe. Vinorelbine was rapidly absorbed with maximum blood concentration (Cmax) of 103.8 +/- 41.6 ng x ml(-1) observed 1.2 +/- 0.8 hours (Tmax) after administration of 80 mg/m2. Pharmacokinetic exposure increased linearly with dose. Area under the concentration-time curve (AUC) and concentration measured 24 hours after drug intake (C24h) were significantly correlated with depletion of neutrophils. Objective tumour responses were reported in 6 of the 14 evaluable patients treated at doses > or = 80 mg/m2/week.
  
  
  CONCLUSIONS
  The safety profile of oral vinorelbine appears comparable to that of intravenous dosing. The recommended phase II dose is 80 mg/m2/week and requires regular monitoring of neutrophil counts.
authors.affiliation: Centre Oscar Lambret, Lille, France. j-bonneterre@o-lambret.fr
authors.forename: J
authors.initials: J
authors.lastname: Bonneterre
authors.forename: B
authors.initials: B
authors.lastname: Chevalier
authors.forename: C
authors.initials: C
authors.lastname: Focan
authors.forename: L
authors.initials: L
authors.lastname: Mauriac
authors.forename: M
authors.initials: M
authors.lastname: Piccart
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007408:Intestinal Absorption; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D012449:Safety; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine