A phase i open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer

Robin L. Jones, Johanna C. Bendell, David C. Smith, Konstanze Diefenbach, John Lettieri, Oliver Boix, Albert Lockhart, Cindy O'Bryant, Kathleen N. Moore

Research output: Contribution to journalArticle

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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 tmax (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 tmax 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.

Original languageEnglish (US)
Pages (from-to)777-784
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume76
Issue number4
DOIs
StatePublished - Oct 22 2015
Externally publishedYes

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Labels
Safety
Stroke Volume
Neoplasms
Pharmacokinetics
regorafenib
Electrocardiography
Tumors
Scanning

Keywords

  • Cardiovascular profile
  • Left ventricular ejection fraction (LVEF)
  • QT/QTc interval
  • Regorafenib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Jones, R. L., Bendell, J. C., Smith, D. C., Diefenbach, K., Lettieri, J., Boix, O., ... Moore, K. N. (2015). A phase i open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer. Cancer Chemotherapy and Pharmacology, 76(4), 777-784. https://doi.org/10.1007/s00280-015-2827-3

A phase i open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer. / Jones, Robin L.; Bendell, Johanna C.; Smith, David C.; Diefenbach, Konstanze; Lettieri, John; Boix, Oliver; Lockhart, Albert; O'Bryant, Cindy; Moore, Kathleen N.

In: Cancer Chemotherapy and Pharmacology, Vol. 76, No. 4, 22.10.2015, p. 777-784.

Research output: Contribution to journalArticle

Jones, RL, Bendell, JC, Smith, DC, Diefenbach, K, Lettieri, J, Boix, O, Lockhart, A, O'Bryant, C & Moore, KN 2015, 'A phase i open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer', Cancer Chemotherapy and Pharmacology, vol. 76, no. 4, pp. 777-784. https://doi.org/10.1007/s00280-015-2827-3
Jones, Robin L. ; Bendell, Johanna C. ; Smith, David C. ; Diefenbach, Konstanze ; Lettieri, John ; Boix, Oliver ; Lockhart, Albert ; O'Bryant, Cindy ; Moore, Kathleen N. / A phase i open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 76, No. 4. pp. 777-784.
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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 tmax (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 tmax 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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AU - Lettieri, John

AU - Boix, Oliver

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N2 - 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 tmax (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 tmax 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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