Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure–QTc in patients with advanced or refractory solid tumors
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To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors.
Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2–4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration–QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data.
Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration–QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as − 0.00269 ms/(ng/mL) and − 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval.
ECG data and the concentration–QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters.
Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.
KeywordsConcentration–QTc modeling ECG analysis Erdafitinib Holter data Oncology QT interval
Authors thank the study participants, without whom this study would never have been accomplished, and all the investigators, their medical, nursing and laboratory staff for their participation in this study. Erdafitinib (BALVERSA™, JNJ-42756493) was discovered in collaboration with Astex Pharmaceuticals. The authors also thank Dr. Himabindu Gutha (SIRO Clinpharm Pvt. Ltd.) for writing assistance, Dr. Harry Ma (Janssen Research & Development, LLC) for additional editorial support and Frederic Saad for helping with the creation of the dataset.
Study support: Janssen Research & Development, LLC, USA.
Hong Xie, Juan José Perez-Ruixo, Daniele Ouellet: conception and design; Elodie Valade, Anne-Gaëlle Dosne, Hong Xie, Daniele Ouellet: collection and assembly of data; Elodie Valade, Anne-Gaëlle Dosne, Hong Xie, Robert Kleiman, Lilian Y Li, Juan José Perez-Ruixo, Daniele Ouellet: data analysis and interpretation. Dr. Kleiman is an employee of eResearch Technology Inc. (ERT), Philadelphia. All other authors are/were employees of Janssen Research & Development and shareholders in the parent company (Johnson & Johnson).
All authors participated in the original design of the studies, supervising recruitment and monitoring of data quality, and contributed to the data interpretation, development and review of this manuscript and confirm that they have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data and approved submission to this journal.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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