Abstract
PurposeThis 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.MethodsPatients 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.ResultsA 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.ConclusionsECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.
Highlights
Lurbinectedin (ZepzelcaTM), known as PM01183, is a highly selective inhibitor of oncogenic transcription, with in vitro activity in the low nanomolar range [1]
Lurbinectedin inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis [3]
The study protocol was submitted to the QT Interdisciplinary Review Team at the U.S Food and Drug Administration (FDA), which considered the tested dose reasonable, and the ECG/pharmacokinetic (PK) collection, sample size, and study design acceptable to fulfil the aims of the study
Summary
Lurbinectedin (ZepzelcaTM), known as PM01183, is a highly selective inhibitor of oncogenic transcription, with in vitro activity in the low nanomolar range [1]. QT evaluation had to be performed in a cancer patient population at a therapeutic dose This QT evaluation study was nested into a basket clinical trial that was conducted to determine whether lurbinectedin had any effects on the QT interval or any other ECG parameter, in patients with solid tumors at the recommended dose of 3.2 mg/m2 administered q3wk as a 1-h i.v. infusion, and not receiving any concomitant medication known to prolong QT interval. This population, with advanced solid cancer and several co-morbidities, allowed assessment of the QTc interval in a real-life population similar to the population for which therapeutic use of lurbinectedin is approved
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