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

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

doi:10.1007/s00280-016-3210-8

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

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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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/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. Results: 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. 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.

Original language	English (US)
Pages (from-to)	339-351
Number of pages	13
Journal	Cancer Chemotherapy and Pharmacology
Volume	79
Issue number	2
DOIs	https://doi.org/10.1007/s00280-016-3210-8
State	Published - Feb 1 2017

Funding

The authors would like to thank participating patients and their families, in addition to the staff at participating sites. This study was supported by Sanofi. The authors received editorial support in the form of medical writing services provided by Danielle Lindley of MediTech Media, funded by Sanofi. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this manuscript. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors would like to thank the Institute for Drug Development at the Cancer Therapy and Research Center, University of Texas Health Science Centre, San Antonio, Texas, for the Cancer Center Support Grant (P30CA054174).

Keywords

Cabazitaxel
Hepatic impairment
Maximum tolerated dose
Pharmacokinetics
Phase I

ASJC Scopus subject areas

Oncology
Toxicology
Pharmacology
Cancer Research
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00280-016-3210-8

Cite this

Sarantopoulos, J., Mita, A. C., He, A., Wade, J. L., Hsueh, C. T., Morris, J. C., Lockhart, A. C., Quinn, D. I., Hwang, J., Mier, J., Zhang, W., Wack, C., Yin, J., Clot, P. F., & Rixe, O. (2017). Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study. Cancer Chemotherapy and Pharmacology, 79(2), 339-351. https://doi.org/10.1007/s00280-016-3210-8

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

abstract = "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/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. Results: 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. 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.",

keywords = "Cabazitaxel, Hepatic impairment, Maximum tolerated dose, Pharmacokinetics, Phase I",

author = "John Sarantopoulos and Mita, {Alain C.} and Aiwu He and Wade, {James L.} and Hsueh, {Chung Tsen} and Morris, {John C.} and Lockhart, {A. Craig} and Quinn, {David I.} and Jimmy Hwang and James Mier and Wenping Zhang and Claudine Wack and Jian Yin and Clot, {Pierre Fran{\c c}ois} and Olivier Rixe",

note = "Publisher Copyright: {\textcopyright} 2017, The Author(s).",

year = "2017",

month = feb,

day = "1",

doi = "10.1007/s00280-016-3210-8",

language = "English (US)",

volume = "79",

pages = "339--351",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

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Sarantopoulos, J, Mita, AC, He, A, Wade, JL, Hsueh, CT, Morris, JC, Lockhart, AC, Quinn, DI, Hwang, J, Mier, J, Zhang, W, Wack, C, Yin, J, Clot, PF & Rixe, O 2017, 'Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study', Cancer Chemotherapy and Pharmacology, vol. 79, no. 2, pp. 339-351. https://doi.org/10.1007/s00280-016-3210-8

TY - JOUR

T1 - Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment

T2 - a phase I dose-escalation study

AU - Sarantopoulos, John

AU - Mita, Alain C.

AU - He, Aiwu

AU - Wade, James L.

AU - Hsueh, Chung Tsen

AU - Morris, John C.

AU - Lockhart, A. Craig

AU - Quinn, David I.

AU - Hwang, Jimmy

AU - Mier, James

AU - Zhang, Wenping

AU - Wack, Claudine

AU - Yin, Jian

AU - Clot, Pierre François

AU - Rixe, Olivier

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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/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. Results: 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. 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.

AB - 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/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. Results: 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. 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.

KW - Cabazitaxel

KW - Hepatic impairment

KW - Maximum tolerated dose

KW - Pharmacokinetics

KW - Phase I

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U2 - 10.1007/s00280-016-3210-8

DO - 10.1007/s00280-016-3210-8

M3 - Article

C2 - 28058445

AN - SCOPUS:85008507391

SN - 0344-5704

VL - 79

SP - 339

EP - 351

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 2

ER -

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

Abstract

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UN SDGs

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