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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.

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



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.


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.


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.


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.


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


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

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