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Cancer Chemother Pharmacol. 2018 Jun;81(6):1129-1141. doi: 10.1007/s00280-018-3564-1. Epub 2018 Mar 30.

Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies.

Author information

1
Cardiac Safety Consultants Ltd, 4 Hallswelle Road, London, NW11 0DJ, UK. Boaz.Mendzelevski@CardiacSafetyConsultants.com.
2
Statistik Georg Ferber GmbH, Riehen, Switzerland.
3
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
6
BioMed Valley Discoveries Inc., Kansas City, MO, USA.
7
Shanghai Hengrui Pharmaceutical Co., Ltd, Shanghai, China.
8
Bioclinica Inc, Princeton, NJ, USA.
9
Stanford University, Stanford, CA, USA.

Abstract

PURPOSE:

The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.

METHODS:

In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.

RESULTS:

A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.

CONCLUSIONS:

Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.

REGISTRATION:

The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

KEYWORDS:

Cardiac safety; ECG; Exposure:response modeling; Holter; Oncology; QT; QTc

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