A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer.
OBJECTIVE
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.
Tolcher
Anthony W
AW
START (South Texas Accelerated Research Therapeutics), 4319 Medical Drive, Suite 205, San Antonio, TX 78229, USA. atolcher@start.stoh.com
Appleman
Leonard J
LJ
Shapiro
Geoffrey I
GI
Mita
Alain C
AC
Cihon
Frank
F
Mazzu
Arthur
A
Sundaresan
Pavur R
PR
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015716:Electrocardiography, Ambulatory; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077157:Sorafenib; D016277:Ventricular Function, Left / Q000187:drug effects
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib