Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours

Eur J Cancer. 2012 Mar;48(4):465-74. doi: 10.1016/j.ejca.2011.12.026. Epub 2012 Jan 27.

Abstract

Aim: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzenesulfonates / administration & dosage*
  • Benzenesulfonates / adverse effects
  • Benzenesulfonates / pharmacokinetics
  • Cohort Studies
  • Disease Progression
  • Docetaxel
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Sorafenib
  • Taxoids / administration & dosage*
  • Taxoids / adverse effects
  • Taxoids / pharmacokinetics
  • Treatment Outcome

Substances

  • Benzenesulfonates
  • Phenylurea Compounds
  • Pyridines
  • Taxoids
  • Docetaxel
  • Niacinamide
  • Sorafenib