A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

Pierre Maison-Blanche; Jan B Vermorken; Tuncay Goksel; Jean-Pascal Machiels; Sanjiv Agarwala; Sylvie Rottey; Gedske Daugaard; Constantin Volovat; Max Scheulen; Lisa Sengeløv; Dana Grecea; Alexandru Eniu; Elke Jäger; Eyal Meiri; Stefano Cascinu; Dirk Strumberg; Gokhan Demir; Michael Clemens; Graziella Pinotti; Mario Nardi; Troy Guthrie; Emmanuelle Boelle; Emmanuelle Magherini

doi:10.1097/fjc.0b013e31828b73ff

A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

Pierre Maison-Blanche, Jan B Vermorken, Tuncay Goksel, Jean-Pascal Machiels, Sanjiv Agarwala, Sylvie Rottey, Gedske Daugaard, Constantin Volovat, Max Scheulen, Lisa Sengeløv, Dana Grecea, Alexandru Eniu, Elke Jäger, Eyal Meiri, Stefano Cascinu, Dirk Strumberg, Gokhan Demir, Michael Clemens, Graziella Pinotti, Mario NardiTroy Guthrie, Emmanuelle Boelle, Emmanuelle Magherini

Department of Clinical Medicine

3 Citations (Scopus)

Abstract

The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m² docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 μg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.

Original language	English
Journal	Journal of Cardiovascular Pharmacology
Volume	61
Issue number	6
Pages (from-to)	495-504
Number of pages	10
ISSN	0160-2446
DOIs	https://doi.org/10.1097/fjc.0b013e31828b73ff
Publication status	Published - Jun 2013

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10.1097/fjc.0b013e31828b73ff

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Maison-Blanche, P., Vermorken, J. B., Goksel, T., Machiels, J.-P., Agarwala, S., Rottey, S., Daugaard, G., Volovat, C., Scheulen, M., Sengeløv, L., Grecea, D., Eniu, A., Jäger, E., Meiri, E., Cascinu, S., Strumberg, D., Demir, G., Clemens, M., Pinotti, G., ... Magherini, E. (2013). A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel. Journal of Cardiovascular Pharmacology, 61(6), 495-504. https://doi.org/10.1097/fjc.0b013e31828b73ff

A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel. / Maison-Blanche, Pierre; Vermorken, Jan B; Goksel, Tuncay et al.
In: Journal of Cardiovascular Pharmacology, Vol. 61, No. 6, 06.2013, p. 495-504.

Research output: Contribution to journal › Journal article › Research › peer-review

Maison-Blanche, P, Vermorken, JB, Goksel, T, Machiels, J-P, Agarwala, S, Rottey, S, Daugaard, G, Volovat, C, Scheulen, M, Sengeløv, L, Grecea, D, Eniu, A, Jäger, E, Meiri, E, Cascinu, S, Strumberg, D, Demir, G, Clemens, M, Pinotti, G, Nardi, M, Guthrie, T, Boelle, E & Magherini, E 2013, 'A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel', Journal of Cardiovascular Pharmacology, vol. 61, no. 6, pp. 495-504. https://doi.org/10.1097/fjc.0b013e31828b73ff

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title = "A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel",

abstract = "The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m2 docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 μg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.",

author = "Pierre Maison-Blanche and Vermorken, {Jan B} and Tuncay Goksel and Jean-Pascal Machiels and Sanjiv Agarwala and Sylvie Rottey and Gedske Daugaard and Constantin Volovat and Max Scheulen and Lisa Sengel{\o}v and Dana Grecea and Alexandru Eniu and Elke J{\"a}ger and Eyal Meiri and Stefano Cascinu and Dirk Strumberg and Gokhan Demir and Michael Clemens and Graziella Pinotti and Mario Nardi and Troy Guthrie and Emmanuelle Boelle and Emmanuelle Magherini",

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T1 - A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

AU - Maison-Blanche, Pierre

AU - Vermorken, Jan B

AU - Goksel, Tuncay

AU - Machiels, Jean-Pascal

AU - Agarwala, Sanjiv

AU - Rottey, Sylvie

AU - Daugaard, Gedske

AU - Volovat, Constantin

AU - Scheulen, Max

AU - Sengeløv, Lisa

AU - Grecea, Dana

AU - Eniu, Alexandru

AU - Jäger, Elke

AU - Meiri, Eyal

AU - Cascinu, Stefano

AU - Strumberg, Dirk

AU - Demir, Gokhan

AU - Clemens, Michael

AU - Pinotti, Graziella

AU - Nardi, Mario

AU - Guthrie, Troy

AU - Boelle, Emmanuelle

AU - Magherini, Emmanuelle

PY - 2013/6

Y1 - 2013/6

N2 - The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m2 docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 μg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.

AB - The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m2 docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 μg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.

U2 - 10.1097/fjc.0b013e31828b73ff

DO - 10.1097/fjc.0b013e31828b73ff

M3 - Journal article

C2 - 23429593

SN - 0160-2446

VL - 61

SP - 495

EP - 504

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

IS - 6

ER -

A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

Abstract

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