Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure-response analysis.

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.

• 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 87 Issue 1 Pg. 113-124 (01 2021) ISSN: 1432-0843 [Electronic] Germany
• PMID: 33108504 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carbolines
• Heterocyclic Compounds, 4 or More Rings
• PM 01183

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Carbolines (administration & dosage, adverse effects, pharmacokinetics)
• Electrocardiography
• Female
• Heterocyclic Compounds, 4 or More Rings (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Prospective Studies