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


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Article Info

DATE

2017-01-05

AUTHORS

John Sarantopoulos, Alain C. Mita, Aiwu He, James L. Wade, Chung-Tsen Hsueh, John C. Morris, A. Craig Lockhart, David I. Quinn, Jimmy Hwang, James Mier, Wenping Zhang, Claudine Wack, Jian Yin, Pierre-François Clot, Olivier Rixe

ABSTRACT

PurposeCabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.MethodsPatients 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.ResultsIn 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.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. More... »

PAGES

339-351

Journal

TITLE

Cancer Chemotherapy and Pharmacology

ISSUE

2

VOLUME

79

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00280-016-3210-8

DOI

http://dx.doi.org/10.1007/s00280-016-3210-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003925282

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28058445


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20 schema:description PurposeCabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.MethodsPatients 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.ResultsIn 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.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.
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27 I dose-escalation study
28 MTD
29 MethodsPatients
30 adverse events
31 area
32 body surface area
33 cabazitaxel
34 cabazitaxel 25
35 cabazitaxel clearance
36 cancer
37 clearance
38 contraindications
39 correlation
40 cycle 1 dose-limiting toxicities
41 data
42 decline
43 dose
44 dose reduction
45 dose-escalation study
46 dose-limiting toxicity
47 doses
48 events
49 fraction
50 free fraction
51 function
52 grade 3
53 hepatic function
54 hepatic impairment
55 impairment
56 m2
57 maximum
58 neutropenia
59 non-hematologic cancers
60 normal hepatic function
61 parameters
62 patients
63 pharmacokinetic parameters
64 pharmacokinetic profile
65 pharmacokinetics
66 phase I
67 phase I dose-escalation study
68 profile
69 reduction
70 safety
71 safety data
72 severe hepatic impairment
73 significant correlation
74 study
75 substantial decline
76 surface area
77 toxicity
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