title: Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours.
abstract: OBJECTIVE
  The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial.
  
  
  METHODS
  Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles.
  
  
  RESULTS
  Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration-time curve (AUC)(0-24) increased by 5% (cohort 1), 54% (cohort 2), 36% (Cohort 3) and 80% (cohort 4) with docetaxel plus sorafenib, while C(max) increased by 16-32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease.
  
  
  CONCLUSIONS
  Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for phase II.
authors.affiliation: Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium. ahmad.awada@bordet.be
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Alain
authors.initials: A
authors.lastname: Hendlisz
authors.forename: Olaf
authors.initials: O
authors.lastname: Christensen
authors.forename: Chetan D
authors.initials: CD
authors.lastname: Lathia
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bartholomeus
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lebrun
authors.forename: Dominique
authors.initials: D
authors.lastname: de Valeriola
authors.forename: Erich
authors.initials: E
authors.lastname: Brendel
authors.forename: Martin
authors.initials: M
authors.lastname: Radtke
authors.forename: Thierry
authors.initials: T
authors.lastname: Delaunoit
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.forename: Thierry
authors.initials: T
authors.lastname: Gil
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D018450:Disease Progression; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077157:Sorafenib; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D000077157:Sorafenib