A phase I open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer.
OBJECTIVE
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 %.


CONCLUSIONS
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.
Medical Oncology, University of Washington/Seattle Cancer Care Alliance, Seattle, WA, USA. rjones@seattlecca.org.|Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. rjones@seattlecca.org.
Robin L
RL
Jones
Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
Johanna C
JC
Bendell
Internal Medicine Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
David C
DC
Smith
Bayer Pharma AG, Berlin, Germany.
Konstanze
K
Diefenbach
Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
John
J
Lettieri
Bayer Pharma AG, Wuppertal, Germany.
Oliver
O
Boix
Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
A Craig
AC
Lockhart
Department of Clinical Pharmacy, University of Colorado Cancer Center, Aurora, CO, USA.
Cindy
C
O'Bryant
Stephenson Cancer Center, Oklahoma University HSC, Oklahoma City, OK, USA.
Kathleen N
KN
Moore
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D054715:Cardiotoxins / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D003967:Diarrhea / Q000139:chemically induced / Q000503:physiopathology; D003875:Drug Eruptions / Q000503:physiopathology; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced / Q000503:physiopathology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012720:Severity of Illness Index; D013318:Stroke Volume / Q000187:drug effects
D000970:Antineoplastic Agents; D054715:Cardiotoxins; D015507:Drugs, Investigational; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib
Cardiovascular profile; Left ventricular ejection fraction (LVEF); QT/QTc interval; Regorafenib