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.
START (South Texas Accelerated Research Therapeutics), 4319 Medical Drive, Suite 205, San Antonio, TX 78229, USA. atolcher@start.stoh.com
Anthony W
AW
Tolcher
Leonard J
LJ
Appleman
Geoffrey I
GI
Shapiro
Alain C
AC
Mita
Frank
F
Cihon
Arthur
A
Mazzu
Pavur R
PR
Sundaresan
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