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

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.

SUBMITTER: Mendzelevski B

PROVIDER: S-EPMC5973962 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Mendzelevski Boaz B Ferber Georg G Janku Filip F Li Bob T BT Sullivan Ryan J RJ Welsch Dean D Chi Wei W Jackson Jeanne J Weng Onglee O Sager Philip T PT

Cancer chemotherapy and pharmacology 20180330 6

<h4>Purpose</h4>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.<h4>Methods</h4>In a two-part, phase 1, open-label study in adults with advanced sol ...[more]

PMID: 29603015

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Project description:BackgroundNumerous antineoplastic drugs such as chemotherapeutics have cardiotoxic side effects and can lead to long QT syndrome (LQTS). When diagnosed and treated in time, the potentially fatal outcomes of LQTS can be prevented. Therefore, regular electrocardiogram (ECG) assessments are critical to ensure patient safety. However, these assessments are associated with patient discomfort and require timely support of the attending oncologist by a cardiologist.ObjectiveThis study aimed to examine whether this approach can be made more efficient and comfortable by a smartphone app (QTc Tracker), supporting single-lead ECG records on site and transferring to a tele-cardiologist for an immediate diagnosis.MethodsTo evaluate the QTc Tracker, it was implemented in 54 cancer centers in Germany. In total, 266 corrected QT interval (QTc) diagnoses of 122 patients were recorded. Moreover, a questionnaire on routine ECG workflow, turnaround time, and satisfaction (1=best, 6=worst) was answered by the centers before and after the implementation of the QTc Tracker.ResultsCompared to the routine ECG workflow, the QTc Tracker enabled a substantial turnaround time reduction of 98% (mean 2.67, 95% CI 1.72-2.67 h) and even further time efficiency in combination with a cardiologic on-call service (mean 12.10, 95% CI 5.67-18.67 min). Additionally, nurses and patients reported higher satisfaction when using the QTc Tracker. In particular, patients' satisfaction sharply improved from 2.59 (95% CI 2.41-2.88) for the routine ECG workflow to 1.25 (95% CI 0.99-1.51) for the QTc Tracker workflow.ConclusionsThese results reveal a significant improvement regarding reduced turnaround time and increased user satisfaction. Best patient care might be guaranteed as the exposure of patients with an uncontrolled risk of QTc prolongations can be avoided by using the fast and easy QTc Tracker. In particular, as regular side-effect monitoring, the QTc Tracker app promises more convenience for patients and their physicians. Finally, future studies are needed to empirically test the usability and validity of such mobile ECG assessment methods.Trial registrationClinicalTrials.gov NCT04055493; https://classic.clinicaltrials.gov/ct2/show/NCT04055493.

Dataset Information

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

Publications

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

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