1. Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies.
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Swaisland, Helen, Plummer, Ruth, So, Karen, Garnett, Sally, Bannister, Wendy, Fabre, Marc-Antoine, Dota, Corina, and Fielding, Anitra
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LONG QT syndrome ,POLY ADP ribose ,ENZYME inhibitors ,DRUG efficacy ,MEDICATION safety ,CLINICAL trials ,COMPARATIVE studies ,CROSSOVER trials ,DRUG resistance in cancer cells ,DOSE-effect relationship in pharmacology ,ELECTROCARDIOGRAPHY ,HEART beat ,HETEROCYCLIC compounds ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,TUMORS ,EVALUATION research ,DISEASE complications - Abstract
Background: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc interval.Methods: Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QTc interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia's formula (QTcF).Results: Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF least squares means after olaparib multiple dosing versus control (day -1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QTcF was observed at most time points versus control. QTcF results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms.Conclusion: Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval. [ABSTRACT FROM AUTHOR]- Published
- 2016
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