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Investigational New Drugs

, Volume 31, Issue 5, pp 1283–1293 | Cite as

Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study

  • Tim EisenEmail author
  • Yaroslav Shparyk
  • Nicholas Macleod
  • Robert Jones
  • Gudrun Wallenstein
  • Graham Temple
  • Yasser Khder
  • Claudia Dallinger
  • Matus Studeny
  • Arsene-Bienvenu Loembe
  • Igor Bondarenko
PHASE II STUDIES

Summary

Purpose Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Methods Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day −1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Results Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia’s method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Conclusion Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation.

Keywords

Nintedanib BIBF 1120 Renal cell carcinoma RCC QT interval Phase II Angiogenesis inhibitor 

Notes

Acknowledgments

The trial was sponsored by Boehringer Ingelheim Ltd, Bracknell, UK. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Duncan Campbell of GeoMed during the preparation of this manuscript.

Conflicts of interest

Tim Eisen has participated in advisory boards and given talks for Boehringer Ingelheim for which he has received honoraria. Yaroslav Shparyk has received research funding from Boehringer Ingelheim. Nicholas Macleod has received research funding from Boehringer Ingelheim. Robert Jones has received research funding from Boehringer Ingelheim. Gudrun Wallenstein is an employee of Boehringer Ingelheim. Graham Temple is an employee of Boehringer Ingelheim. Yasser Khder is an employee of Boehringer Ingelheim. Claudia Dallinger is an employee of Boehringer Ingelheim. Matus Studeny is an employee of Boehringer Ingelheim. Arsene-Bienvenu Loembe is an employee of Boehringer Ingelheim. Igor Bondarenko has received research funding from Boehringer Ingelheim

Financial support

The trial was sponsored by Boehringer Ingelheim Ltd, Bracknell, UK.

Supplementary material

10637_2013_9962_MOESM1_ESM.doc (276 kb)
ESM 1 (DOC 276 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Tim Eisen
    • 1
    Email author
  • Yaroslav Shparyk
    • 2
  • Nicholas Macleod
    • 3
  • Robert Jones
    • 3
  • Gudrun Wallenstein
    • 4
  • Graham Temple
    • 5
  • Yasser Khder
    • 6
  • Claudia Dallinger
    • 7
  • Matus Studeny
    • 8
  • Arsene-Bienvenu Loembe
    • 8
  • Igor Bondarenko
    • 9
  1. 1.Cambridge University Health PartnersAddenbrooke’s HospitalCambridgeUK
  2. 2.Lviv State Oncology Regional Treatment and Diagnostic CentreLvivUkraine
  3. 3.CRUK Clinical Research Unit (CRU)GlasgowUK
  4. 4.Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
  5. 5.Boehringer Ingelheim Ltd.BracknellUK
  6. 6.Boehringer Ingelheim France S.A.S.ReimsFrance
  7. 7.Boehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  8. 8.Boehringer Ingelheim RCV GmbH & Co. KGViennaAustria
  9. 9.Dnipropetrovsk State Medical AcademyDnipropetrovskUkraine

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