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

Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI. 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/m2, 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. In C-2, three patients receiving cabazitaxel 25 mg/m2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m2. In C-3, two patients receiving 20 mg/m2 experienced DLTs; MTD was 15 mg/m2. 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/m2) than expected (26.4 L/h/m2), but similar in C-2 (23.5 L/h/m2) and C-3 (27.9 L/h/m2). CL/BSA in C-4 was 18.1 L/h/m2. 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. 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.