Salvador Fudio1, Josep Tabernero2, Vivek Subbiah3, Sant P Chawla4, Victor Moreno5, Federico Longo6, Rafael Lopez7, Antonio Anton8, Jose Manuel Trigo9, Geoffrey Shapiro10, Woondong Jeong11, Victor Manuel Villalobos12, Rubin Lubomirov13, Carlos Fernandez-Teruel13, Vicente Alfaro13, Valentina Boni14. 1. PharmaMar, Avda. De los Reyes, 1, Pol. Ind. La Mina-Norte, Colmenar Viejo, Madrid, 28770, Spain. sfudio@pharmamar.com. 2. Vall d'Hebrón University Hospital and Institute of Oncology (VHIO), 08035, Barcelona, Spain. 3. The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. 4. Sarcoma Oncology Center, Santa Monica, CA, 90403, USA. 5. Fundación Jiménez Díaz, 28040, Madrid, Spain. 6. Hospital Ramon y Cajal, 28034, Madrid, Spain. 7. IDIS, CIBERONC, Hospital Clínico Universitario de Santiago de Compostela, 15706, Santiago De Compostela, Spain. 8. Hospital Universitario Miguel Servet, 50009, Zaragoza, Spain. 9. Hospital Virgen de la Victoria, 29010, Málaga, Spain. 10. Dana-Farber Cancer Institute, Boston, MA, 02215, USA. 11. Cancer Therapy and Research Center, San Antonio, TX, 78229, USA. 12. University of Colorado, Denver, CO, 80045, USA. 13. PharmaMar, Avda. De los Reyes, 1, Pol. Ind. La Mina-Norte, Colmenar Viejo, Madrid, 28770, Spain. 14. START Madrid-CIOCC, Hospital Universitario San Chinarro, 28050, Madrid, Spain.
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.
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 ICHE14 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: J F M Leal; M Martínez-Díez; V García-Hernández; V Moneo; A Domingo; J A Bueren-Calabuig; A Negri; F Gago; M J Guillén-Navarro; P Avilés; C Cuevas; L F García-Fernández; C M Galmarini Journal: Br J Pharmacol Date: 2010-11 Impact factor: 8.739
Authors: María Elena Elez; Josep Tabernero; David Geary; Teresa Macarulla; S Peter Kang; Carmen Kahatt; Arturo Soto-Matos Pita; Carlos Fernandez Teruel; Mariano Siguero; Martin Cullell-Young; Sergio Szyldergemajn; Mark J Ratain Journal: Clin Cancer Res Date: 2014-02-21 Impact factor: 12.531