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.

• Authors: Boaz Mendzelevski, Georg Ferber, Filip Janku, Bob T Li, Ryan J Sullivan, Dean Welsch, Wei Chi, Jeanne Jackson, Onglee Weng, Philip T Sager
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 81 Issue 6 Pg. 1129-1141 (06 2018) ISSN: 1432-0843 [Electronic] Germany
• PMID: 29603015 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Aminopyridines
• Protein Kinase Inhibitors
• Pyrroles
• ulixertinib
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Aged
• Aminopyridines (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Electrocardiography, Ambulatory
• Female
• Heart Rate (drug effects)
• Humans
• Long QT Syndrome (etiology)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors)
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Pyrroles (administration & dosage, adverse effects)