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, Albert Lockhart, David I. Quinn, Jimmy Hwang, James Mier, Wenping Zhang, Claudine Wack, Jian Yin, Pierre François Clot, Olivier Rixe

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)339-351
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume79
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

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Pharmacokinetics
Safety
Liver
Toxicity
Body Surface Area
Maximum Tolerated Dose
cabazitaxel
Liver Neoplasms
Neutropenia

Keywords

  • Cabazitaxel
  • Hepatic impairment
  • Maximum tolerated dose
  • Pharmacokinetics
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment : a phase I dose-escalation study. / Sarantopoulos, John; Mita, Alain C.; He, Aiwu; Wade, James L.; Hsueh, Chung Tsen; Morris, John C.; Lockhart, Albert; Quinn, David I.; Hwang, Jimmy; Mier, James; Zhang, Wenping; Wack, Claudine; Yin, Jian; Clot, Pierre François; Rixe, Olivier.

In: Cancer Chemotherapy and Pharmacology, Vol. 79, No. 2, 01.02.2017, p. 339-351.

Research output: Contribution to journalArticle

Sarantopoulos, J, Mita, AC, He, A, Wade, JL, Hsueh, CT, Morris, JC, Lockhart, A, 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
Sarantopoulos, John ; Mita, Alain C. ; He, Aiwu ; Wade, James L. ; Hsueh, Chung Tsen ; Morris, John C. ; Lockhart, Albert ; Quinn, David I. ; Hwang, Jimmy ; Mier, James ; Zhang, Wenping ; Wack, Claudine ; Yin, Jian ; Clot, Pierre François ; Rixe, Olivier. / Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment : a phase I dose-escalation study. In: Cancer Chemotherapy and Pharmacology. 2017 ; Vol. 79, No. 2. pp. 339-351.
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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.",
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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, Albert

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.

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KW - Hepatic impairment

KW - Maximum tolerated dose

KW - Pharmacokinetics

KW - Phase I

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