Abstract
Purpose
To characterize the cardiovascular safety profile of regorafenib in patients with advanced cancer.
Methods
Patients received regorafenib 160 mg/day for 21 days followed by a 7-day break. The primary endpoint was the change from baseline in QTcF at the regorafenib t max (Day 21, Cycle 1 or 2) and changes in left ventricular ejection fraction (LVEF) from baseline on Cycle 2, Day 21. Secondary objectives were pharmacokinetics, safety, anti-tumor activity and effects on electrocardiogram intervals. QT intervals were corrected using the methods of Fridericia (QTcF) and Bazett (QTcB). LVEF was assessed by multigated acquisition scanning.
Results
Fifty-three patients were enrolled, and all received at least one dose of regorafenib 160 mg. Twenty-five patients received regorafenib for 21 days without dose reduction. The mean change from baseline in QTcF at t max was (−)2 ms (90 % CI −8, 3). No patient experienced a change from baseline in QTcF > 60 ms, and two had QTcF changes between 30 and 60 ms. No patient had a QTcF or QTcB > 480 ms. In 27 patients who received at least 80 mg of regorafenib, the mean change from baseline in LVEF% ± SD was 1.7 ± 7.8. In 14 patients without a dose reduction, the mean change from baseline in LVEF% was (−)0.1 ± 8.6 at Cycle 2, Day 21. Four patients experienced a LVEF decrease between 10 and 20 %.
Conclusion
The effects of regorafenib on the QT/QTc interval and LVEF were modest and unlikely to be of clinical significance in the setting of advanced cancer therapy.
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Acknowledgments
This trial was sponsored by Bayer HealthCare Pharmaceuticals. We acknowledge the assistance of Ann Contijoch, Bayer Healthcare Pharmaceuticals, in the preparation of this manuscript.
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R.L. Jones serves as an advisory board member for Immune Design, Daiichi Sankyo, Merck, and Blueprint Medicines. He also reports conducting trials sponsored by Bayer HealthCare Pharmaceuticals, Eisai, Novartis, Johnson & Johnson, Pharmamar, Infinity Pharmaceuticals, Threshold Pharmaceuticals, and Morphotek. D.C. Smith has received research funding from Bayer HealthCare Pharmaceuticals. K. Diefenbach, J. Lettier, and O. Boix are employees of Bayer HealthCare Pharmaceuticals; K. Diefenbach and O Boix also report stock ownership in Bayer HealthCare Pharmaceuticals. A.C. Lockhart has received research funding from Amgen, Bayer, Daiichi Sankyo, EMD Serono, Genentech/Roche, Lilly, Millennium Takeda, Novartis, Sanofi, Teva, and Zenyaku Kogyo. K.N. Moore serves as an advisory board member for Astrazeneca, Immunogen, Genentech, Amgen, and Advaxis. J.C. Bendell and C.L. O'Bryant report no conflicts of interest.
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Jones, R.L., Bendell, J.C., Smith, D.C. et al. A phase I open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer. Cancer Chemother Pharmacol 76, 777–784 (2015). https://doi.org/10.1007/s00280-015-2827-3
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DOI: https://doi.org/10.1007/s00280-015-2827-3