Safety and pharmacokinetics (PK) of cabazitaxel (C) in patients (pts) with hepatic impairment (HI).

Background: C studies excluded pts with HI. A Phase I dose-escalation study (NCT01140607 ) assessed the effect of HI on C PK and safety in pts with advanced solid tumors. Methods: Pts with normal hepatic function (NHF; bilirubin [B] ≤ ULN; aspartate aminotransferase [AST] ≤ ULN), mild (MiHI; B > 1-≤ 1.5 x ULN or AST > 1.5 x ULN), moderate (ModHI; B > 1.5- ≤3 x ULN) or severe (SHI; B > 3-10 x ULN) HI received C dose escalation starting at 25, 20, 10 or 10 mg/m2, respectively. Endpoints were cycle 1 (C1) dose-limiting toxicities (DLTs), safety and PK. Plasma PK were derived by non-compartmental analysis. HI effect was assessed by linear mixed-effects modeling on clearance normalized to body surface area (CL/BSA) and exposure normalized to dose. Results: Pts (43 [6 NHF, 18 MiHI, 12 ModHI, 7 SHI]) had a median age of 60 years (range 18-79); 52% were male; 81% had ECOG performance status 1. Colon and liver tumors were most common (19%; prostate 7%). Maximum tolerated doses (MTD) were 20 (MiHI) and 15 mg/m2 (ModHI). The SHI cohort was discontinued early (first pt treated at 20 mg/m2 died). Median number of C cycles (range) at MTD were: NHF 3 (1-4); MiHI 2 (1- 31); ModHI 2 (1-3). In evaluable pts, C1 DLTs were seen in 3/4 NHF, 3/11 MiHI and 1/6 ModHI pts at MTD, and 0/6 SHI pts at 10 and 15 mg/m2. The most frequent DLT was grade 4 febrile neutropenia (FN). The most frequent C-related, grade 3-4 toxicities were neutropenia (42%), FN (16%) and anemia (12%). PK was assessed in 36 pts (6 NHF, 15 MiHI, 9 ModHI, 6 SHI). CL/BSA was lower (geometric mean 13.4 L/h/m2) than typical values (26.4 L/h/m2) in NHF, but similar in MiHI (23.5 L/h/m2) and ModHI (27.9 L/h/m2). CL/BSA in SHI was 18.1 L/h/m2. Compared with MiHI, CL/BSA increased 19% in ModHI (geometric mean ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in SHI (0.77; 0.39- 1.53) (39% with erratic PK profiles excluded [0.61; 0.36-1.05]), and AUClast/dose decreased 14% in ModHI (0.86; 0.50-1.46) and increased 17% in SHI (1.17; 0.63-2.14). No change in C free fraction was seen. A pt with cholangiocarcinoma on study had stable disease at cycle 32. Conclusions: Cabazitaxel tolerability was similar in pts with MiHI, ModHI or NHF, and consistent with prior reports. There is no evidence that MiHI or ModHI results in a substantial decline in C CL.