title: Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors.
abstract: BACKGROUND
  Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe.
  
  
  METHODS
  In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations.
  
  
  RESULTS
  Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%.
  
  
  CONCLUSIONS
  Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.
authors.affiliation: Hospital Universitario Vall d'Hebron, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Calvo
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: S
authors.initials: S
authors.lastname: Hiret
authors.forename: J
authors.initials: J
authors.lastname: Rodon
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: H
authors.initials: H
authors.lastname: Senellart
authors.forename: J
authors.initials: J
authors.lastname: Van den Brande
authors.forename: J
authors.initials: J
authors.lastname: Dyck
authors.forename: A
authors.initials: A
authors.lastname: Pétain
authors.forename: P
authors.initials: P
authors.lastname: Ferre
authors.forename: J
authors.initials: J
authors.lastname: Bennouna
mesh_terms: D000328:Adult; D000368:Aged; D002214:Capsules; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050257:Tubulin Modulators / Q000008:administration & dosage*; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D002214:Capsules; D050257:Tubulin Modulators; C111217:vinflunine; D014747:Vinblastine