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Open Access 01-04-2011 | Original Article

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

Authors: Anthony W. Tolcher, Leonard J. Appleman, Geoffrey I. Shapiro, Alain C. Mita, Frank Cihon, Arthur Mazzu, Pavur R. Sundaresan

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2011

Abstract

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.

Khakoo AY, Kassiotis CM, Tannir N et al (2008) Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 112:2500–2508PubMedCrossRef

Kerkela R, Grazette L, Yacobi R et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916PubMedCrossRef

Machiels JP, Bletard N, Pirenne P et al (2008) Acute cardiac failure after sunitinib. Ann Oncol 19:597–599PubMedCrossRef

Schmidinger M, Zielinski CC, Vogl UM et al (2008) Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 26:5204–5212PubMedCrossRef

Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019PubMedCrossRef

Wu CF, Chuang WP, Li AH, Hsiao CH (2009) Cardiac magnetic resonance imaging in sunitinib malate-related cardiomyopathy: no late gadolinium enhancement. J Chin Med Assoc 72:323–327PubMedCrossRef

Telli ML, Witteles RM, Fisher GA, Srinivas S (2008) Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 19:1613–1618PubMedCrossRef

Schmidinger M, Bojic A, Vogl UM, Lamm W, Zielinski CC (2009) Management of cardiac adverse events occurring with sunitinib treatment. Anticancer Res 29:1627–1629PubMed

Di Lorenzo G, Autorino R, Bruni G et al (2009) Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol 20:1535–1542PubMedCrossRef

10.

Hutson TE, Figlin RA, Tabesh M, Niculescu L, Motzer RJ (2010) Sunitinib-associated changes in left ventricular ejection fraction (LVEF) in treatment-naïve patients (pts) with metastatic renal cell carcinoma (mRCC). Am Soc Clin Oncol (Genitourinary cancers symposium Abstract 370)

11.

Wilhelm SM, Carter C, Tang L et al (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRef

12.

Izumiya Y, Shiojima I, Sato K et al (2006) Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47:887–893PubMedCrossRef

13.

Chen MH, Kerkela R, Force T (2008) Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 118:84–95PubMedCrossRef

14.

Hasinoff BB, Patel D, O’Hara KA (2008) Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Mol Pharmacol 74:1722–1728PubMedCrossRef

15.

Will Y, Dykens JA, Nadanaciva S et al (2008) Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol Sci 106:153–161PubMedCrossRef

16.

Force T, Krause DS, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332–344PubMedCrossRef

17.

Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRef

18.

Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRef

19.

Escudier B, Eisen T, Stadler WM et al (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27:3312–3318PubMedCrossRef

20.

Snow H, Brueckner A, Gelder M, Voliotis D, Kelley S (2008) Sorafenib is not associated with a high incidence of cardiovascular events in many tumor types. Ann Oncol 19:179

21.

Sarapa N, Morganroth J, Couderc J-P et al (2004) Electrocardiographic identification of drug-induced QT prolongation: assessment by different recording and measurement methods. Ann Noninvasive Electrocardiol 1:48–57CrossRef

22.

Demolis JL, Kubitza D, Tenneze L, Funck-Brentano C (2000) Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther 68:658–666PubMedCrossRef

23.

Clark JW, Eder JP, Ryan D, Lathia C, Lenz H-J (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006 in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472–5480PubMedCrossRef

24.

Lenihan DJ (2008) Tyrosine kinase inhibitors: can promising new therapy associated with cardiac toxicity strengthen the concept of teamwork? J Clin Oncol 26:5154–5155PubMedCrossRef

25.

Recanatini M, Poluzzi E, Masetti M, Cavalli A, De PF (2005) QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev 25:133–166PubMedCrossRef

26.

ICH Harmonised Tripartite Guideline (2005) The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic. Drugs E14

27.

Kubitza D, Mueck W, Becka M (2008) Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf 31:67–77PubMedCrossRef

28.

Bello CL, Mulay M, Huang X et al (2009) Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic-pharmacodynamic evaluation of sunitinib. Clin Cancer Res 15:7045–7052PubMedCrossRef

29.

Wu S, Chen JJ, Kudelka A, Lu J, Zhu X (2008) Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 9:117–123PubMedCrossRef

30.

Zhu X, Stergiopoulos K, Wu S (2009) Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 48:9–17PubMedCrossRef

31.

Zhu X, Wu S, Dahut WL, Parikh CR (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49:186–193PubMedCrossRef

32.

Ranpura V, Pulipati B, Chu D, Zhu X, Wu S (2010) Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am J Hypertens 23:460–468PubMedCrossRef

33.

Rini BI, Schiller JH, Fruehauf J et al (2008) Association of diastolic blood pressure (dBP) >90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736). J Clin Oncol 26:3543CrossRef

34.

Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH (2010) Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 28:949–954PubMedCrossRef

35.

Rini BI, Cohen DP, Lu D et al. (2010) Hypertension (HTN) as a biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib. Am Soc Clin Oncol (Genitourinary cancers symposium Abstract 312)

36.

Rixe O, Dutcher J, Motzer R et al (2009) Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol 27:5045

37.

Scartozzi M, Galizia E, Chiorrini S et al (2009) Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 20:227–230PubMedCrossRef

38.

Maitland ML, Moshier K, Imperial J et al (2006) Blood pressure (BP) as a biomarker for sorafenib (S), an inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway. J Clin Oncol 24:2035CrossRef

39.

Izzedine H, Ederhy S, Goldwasser F et al (2009) Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 20:807–815PubMedCrossRef

40.

Strumberg D, Richly H, Hilger RA et al (2005) Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 23:965–972PubMedCrossRef

41.

Strumberg D, Clark JW, Awada A et al (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437PubMedCrossRef

42.

van Heeckeren WJ, Bhakta S, Ortiz J et al (2006) Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 24:1485–1488PubMedCrossRef

43.

Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA (2009) Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncol 10:391–399PubMedCrossRef

44.

Wong MK, Jarkowski A (2009) Response to sorafenib after sunitinib-induced acute heart failure in a patient with metastatic renal cell carcinoma: case report and review of the literature. Pharmacotherapy 29:473–478PubMedCrossRef

45.

Mego M, Reckova M, Obertova J et al (2007) Increased cardiotoxicity of sorafenib in sunitinib-pretreated patients with metastatic renal cell carcinoma. Ann Oncol 18:1906–1907PubMedCrossRef

46.

Kamada P, Dudek AZ (2010) Sorafenib therapy for metastatic renal carcinoma in patients with low cardiac ejection fraction: report of two cases and literature review. Cancer Invest 28:501–504PubMedCrossRef

Title: A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer
Authors: Anthony W. Tolcher
Leonard J. Appleman
Geoffrey I. Shapiro
Alain C. Mita
Frank Cihon
Arthur Mazzu
Pavur R. Sundaresan
Publication date: 01-04-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1372-3

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Purpose

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