Tolcher, Anthony W.Appleman, Leonard J.Shapiro, GeoffreyMita, Alain C.Cihon, FrankMazzu, ArthurSundaresan, Pavur R.2011-12-242010Tolcher, Anthony W., Leonard J. Appleman, Geoffrey I. Shapiro, Alain C. Mita, Frank Cihon, Arthur Mazzu, and Pavur R. Sundaresan. 2010. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemotherapy and Pharmacology 67(4): 751-764.0344-5704http://nrs.harvard.edu/urn-3:HUL.InstRepos:5978691Purpose: To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer. Methods: Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib. Results: LVEF (SD) mean change from baseline was -0.8 (\(\pm\)8.6) LVEF(%) after 2 cycles (n=31) and -1.2 \(\pm\)7.8) LVEF(%) after 4 cycles of sorafenib (n=24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations (\(t_{max}\)) after 1 cycle (n=31) were small (QTcB: 4.2 ms; QTcF: 9.0 ms). Mean changes observed after 1 cycle in BP (n=31) and HR (n=30) at maximum sorafenib concentrations (\(t_{max}\)) were moderate (up to 11.7 mm Hg and -6.6 bpm, respectively). No correlation was found between the AUC and (\(C_{max}\)) of sorafenib and its main metabolites and any cardiovascular parameters. Conclusions: The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment.en-USJournal Article2011-12-2410.1007/s00280-010-1372-3