A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer

PURPOSE: 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 (±8.6) LVEF(%) after 2 cycles (n = 31) and −1.2 (±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.