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

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/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.