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

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/m(2); Cohorts 2 and 3: 100 mg/m(2)) 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/m(2) plus sorafenib 400 mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II. (C) 2012 Elsevier Ltd. All rights reserved.