An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors

Pierre Maison-Blanche; Shaker Dakhil; Ari Baron; Sylvie Rottey; Fred Millard; Gedske Daugaard; Jean-Pascal Machiels; William Conkright; Sunil Sharma; Patricia M M B Soetekouw; Jeffrey Yachnin; Lisa Sengeløv; Peter Van Veldhuizen; Sanjiv S Agarwala; Dorothée Sémiond; Mustapha Chadjaa; Liji Shen; James L Wade

doi:10.1007/s00280-014-2460-6

An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors

Pierre Maison-Blanche, Shaker Dakhil, Ari Baron, Sylvie Rottey, Fred Millard, Gedske Daugaard, Jean-Pascal Machiels, William Conkright, Sunil Sharma, Patricia M M B Soetekouw, Jeffrey Yachnin, Lisa Sengeløv, Peter Van Veldhuizen, Sanjiv S Agarwala, Dorothée Sémiond, Mustapha Chadjaa, Liji Shen, James L Wade

Department of Clinical Medicine

1 Citation (Scopus)

Abstract

PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events.

METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety.

RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively.

CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

Original language	English
Journal	Cancer Chemotherapy and Pharmacology
Volume	73
Issue number	6
Pages (from-to)	1241-1252
Number of pages	12
ISSN	0344-5704
DOIs	https://doi.org/10.1007/s00280-014-2460-6
Publication status	Published - Jun 2014

Keywords

Adult
Aged
Dose-Response Relationship, Drug
Electrocardiography
Female
Heart
Heart Rate
Humans
Male
Middle Aged
Neoplasms
Prospective Studies
Taxoids

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10.1007/s00280-014-2460-6

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Maison-Blanche, P., Dakhil, S., Baron, A., Rottey, S., Millard, F., Daugaard, G., Machiels, J.-P., Conkright, W., Sharma, S., Soetekouw, P. M. M. B., Yachnin, J., Sengeløv, L., Van Veldhuizen, P., Agarwala, S. S., Sémiond, D., Chadjaa, M., Shen, L., & Wade, J. L. (2014). An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 73(6), 1241-1252. https://doi.org/10.1007/s00280-014-2460-6

Maison-Blanche, P, Dakhil, S, Baron, A, Rottey, S, Millard, F, Daugaard, G, Machiels, J-P, Conkright, W, Sharma, S, Soetekouw, PMMB, Yachnin, J, Sengeløv, L, Van Veldhuizen, P, Agarwala, SS, Sémiond, D, Chadjaa, M, Shen, L & Wade, JL 2014, 'An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 73, no. 6, pp. 1241-1252. https://doi.org/10.1007/s00280-014-2460-6

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title = "An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors",

abstract = "PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events.METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety.RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively.CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.",

keywords = "Adult, Aged, Dose-Response Relationship, Drug, Electrocardiography, Female, Heart, Heart Rate, Humans, Male, Middle Aged, Neoplasms, Prospective Studies, Taxoids",

author = "Pierre Maison-Blanche and Shaker Dakhil and Ari Baron and Sylvie Rottey and Fred Millard and Gedske Daugaard and Jean-Pascal Machiels and William Conkright and Sunil Sharma and Soetekouw, {Patricia M M B} and Jeffrey Yachnin and Lisa Sengel{\o}v and {Van Veldhuizen}, Peter and Agarwala, {Sanjiv S} and Doroth{\'e}e S{\'e}miond and Mustapha Chadjaa and Liji Shen and Wade, {James L}",

year = "2014",

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doi = "10.1007/s00280-014-2460-6",

language = "English",

volume = "73",

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journal = "Cancer Chemotherapy and Pharmacology",

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T1 - An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors

AU - Maison-Blanche, Pierre

AU - Dakhil, Shaker

AU - Baron, Ari

AU - Rottey, Sylvie

AU - Millard, Fred

AU - Daugaard, Gedske

AU - Machiels, Jean-Pascal

AU - Conkright, William

AU - Sharma, Sunil

AU - Soetekouw, Patricia M M B

AU - Yachnin, Jeffrey

AU - Sengeløv, Lisa

AU - Van Veldhuizen, Peter

AU - Agarwala, Sanjiv S

AU - Sémiond, Dorothée

AU - Chadjaa, Mustapha

AU - Shen, Liji

AU - Wade, James L

PY - 2014/6

Y1 - 2014/6

N2 - PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events.METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety.RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively.CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

AB - PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events.METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety.RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively.CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

KW - Adult

KW - Aged

KW - Dose-Response Relationship, Drug

KW - Electrocardiography

KW - Female

KW - Heart

KW - Heart Rate

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasms

KW - Prospective Studies

KW - Taxoids

U2 - 10.1007/s00280-014-2460-6

DO - 10.1007/s00280-014-2460-6

M3 - Journal article

C2 - 24718982

SN - 0344-5704

VL - 73

SP - 1241

EP - 1252

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 6

ER -

An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors

Abstract

Keywords

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