title: Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies.
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.
  
  
  CONCLUSIONS
  Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval.
authors.affiliation: Therakin Consulting, Sandbach, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.affiliation: Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: AstraZeneca, Cambridge, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: So
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Garnett
authors.affiliation: PHASTAR, London, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bannister
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Fabre
authors.affiliation: AstraZeneca, Gothenburg, Sweden.
authors.forename: Corina
authors.initials: C
authors.lastname: Dota
authors.affiliation: AstraZeneca, Macclesfield, UK. Anitra.Fielding@astrazeneca.com.
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: Cardiac repolarization; Heart rate; Olaparib; Phase I; QT interval; QTc interval; Safety