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18.08.2017 | PHASE I STUDIES | Ausgabe 2/2018 Open Access

Investigational New Drugs 2/2018

Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies

Zeitschrift:
Investigational New Drugs > Ausgabe 2/2018
Autoren:
Xiaofei Zhou, John Nemunaitis, Shubham Pant, Todd M. Bauer, Manish Patel, John Sarantopoulos, A. Craig Lockhart, Daniel Goodman, Dirk Huebner, Diane R. Mould, Karthik Venkatakrishnan

Summary

Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at intervals over 10 to 24 h via Holter recorders on Days −1 (baseline), 1 and 10. Changes from time-matched baseline values were calculated for various ECG parameters including QTc, heart rate, PR and QRS intervals. Alisertib pharmacokinetics were also assessed during the study, and an exposure-QTc analysis was conducted. Results Fifty patients were included in the QTc analysis. The upper bounds of the 95% confidence intervals for changes from time-matched baseline QTcF and QTcI values were <5 ms across all study days, time points and correction methods. Alisertib did not produce clinically relevant effects on heart rate, PR or QRS intervals. There was no evidence of a concentration-QTc effect relationship. Conclusions Alisertib does not cause QTc prolongation and can be concluded to not have any clinically relevant effects on cardiac repolarization or ECG parameters at the single agent maximum tolerated dose of 50 mg BID.

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