Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study.

PURPOSE: Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.

METHODS: Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m(2), respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed.

RESULTS: In C-2, three patients receiving cabazitaxel 25 mg/m(2) experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m(2). In C-3, two patients receiving 20 mg/m(2) experienced DLTs; MTD was 15 mg/m(2). C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3-4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m(2)) than expected (26.4 L/h/m(2)), but similar in C-2 (23.5 L/h/m(2)) and C-3 (27.9 L/h/m(2)). CL/BSA in C-4 was 18.1 L/h/m(2). Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in C-4 (0.77; 0.39-1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3-4 toxicities and pharmacokinetic parameters.

CONCLUSIONS: Mild-moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild-moderate HI, and a contraindication in patients with severe HI, are justified based on safety data.