Published in:
Open Access
01-01-2021 | Solid Tumor | Original Article
Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis
Authors:
Salvador Fudio, Josep Tabernero, Vivek Subbiah, Sant P. Chawla, Victor Moreno, Federico Longo, Rafael Lopez, Antonio Anton, Jose Manuel Trigo, Geoffrey Shapiro, Woondong Jeong, Victor Manuel Villalobos, Rubin Lubomirov, Carlos Fernandez-Teruel, Vicente Alfaro, Valentina Boni
Published in:
Cancer Chemotherapy and Pharmacology
|
Issue 1/2021
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Abstract
Purpose
This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors.
Methods
Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis.
Results
A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern.
Conclusions
ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.