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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2018 Jun; Vol. 81 (6), pp. 1129-1141. Date of Electronic Publication: 2018 Mar 30. - Publication Year :
- 2018
-
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.<br />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.<br />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 C <subscript>max</subscript> , 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.<br />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.<br />Registration: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.
- Subjects :
- Aged
Aminopyridines adverse effects
Dose-Response Relationship, Drug
Electrocardiography, Ambulatory
Female
Humans
Male
Middle Aged
Mitogen-Activated Protein Kinase 1 antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 antagonists & inhibitors
Protein Kinase Inhibitors adverse effects
Pyrroles adverse effects
Aminopyridines administration & dosage
Heart Rate drug effects
Long QT Syndrome etiology
Neoplasms drug therapy
Protein Kinase Inhibitors administration & dosage
Pyrroles administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 81
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 29603015
- Full Text :
- https://doi.org/10.1007/s00280-018-3564-1