Abstract
In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.
Similar content being viewed by others
References
Shah RR (2006) Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics 7(6):889–908
Roden DM (2004) Drug-induced prolongation of the QT interval. N Engl J Med 350:1013–1022
The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs. Available at: http://www.fda.gov/cder/calendar/meeting/qt4jam.pdf. Accessed March 25, 1997.
Food and Drug Administration (2005) International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Fed Regist 70:61134–61135
Strevel EL, Ing DJ, Siu LL (2007) Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362–3371
Ederhy S, Cohen A, Dufaitre G et al (2009) QT interval prolongation among patients treated with angiogenesis inhibitors. Target Oncol 4:89–97
Gintant GA, Limberis JT, McDermott JS et al (2001) The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol 37:607–618
Weissenburger J, Nesterenko VV, Antzelevitch C (2000) Transmural heterogeneity of ventricular repolarisation under baseline and long QT conditions in the canine heart in vivo: Torsades de pointes develops with halothane but not pentobarbital anesthesia. J Cardiovasc Electrophysiol 11:290–304
Antzelevitch A (2005) Role of transmural dispersion of repolarisation in the genesis of drug-induced torsades de piontes. Heart Rhythm 2(11):S9–S15
National Cancer Institute: Cancer therapy evaluation program, Common terminology for adverse events, version 3.0, DCTD, NCI, NIH, DHHS, 2006. http://ctep.cancer.gov/forms/CTCAEv3.pdf
Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299
Ueda H, Manda T, Matsumoto S et al (1994) FR901228, a novel antitumor bicyclic Depsipeptide produced by Chromobacterium violaceum no. 968. III. Antitumor activities in experimental mice. J Antibiot (Tokyo) 47:315–323
Bates SE, Rosing DR, Fojo T et al (2006) Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res 12:3871–3874
Pickarz RL, Frye AR, Wright JJ et al (2006) Cardiac studies in patients treated with depsipeptide, FK228, in a Phase II trial for T-cell lymphoma. Clin Cancer Res 12:3762–3773
Sandor V, Bakke S, Robey RW et al (2002) Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176) in patients with refractory neoplasms. Clin Cancer Res 8(3):718–728
Marshall JL, Rizvi N, Kauh J et al (2002) A Phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2(6):325–332
Whittaker S, Mcculloch W, Robak T et al (2006) International multicenter Phase II study of the HDCA inhibitor (HDACi) depipeptide (FK228) in cutaneous T-cell lymphoma (CTCL): interim report. J Clin Oncol 24(Suppl.18):(Abstract 3063)
Parker C, Molife R, Karavasilis V et al (2007) Romidepsin (FK228), a hystone deacetylase inhibitor: final results of a Phase II study in metastatic refractory prostate cancer (HRPC). J Clin Oncol 25(18 Suppl):(Abstract 15507)
Niesvizky R, Ely S, Diliberto M et al (2005) Multicenter Phase II trial of the histone deacetylase inhibitor depsipeptide (FK228) for the treatment of relapsed or refractory multiple myeloma (MM): American Society of Hematology Annual Meeting; Abstracts 106(11), (Abstract 2574)
Shah MH, Binkley P, Chan K et al (2006) Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 12(13):3997–4003
Stadler WM, Margolin K, Ferber S et al (2006) A Phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin Genitourin Cancer 5(1):57–60
Marks PA, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202, 1
Zolinza (2006) Whitehouse Station NJ: Merck & Co. [package insert]
Lu Z, Wu CY, Jiang YP et al (2012) Suppression of phosphoinositide 3-kinase signalling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci Transl Med 4:131–150
Rashmi RS, Morganroth J, Devron RS (2013) Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf 36:295–316
Barros F, Gomez-Varela D, Viloria CG et al (1998) Modulation of human erg K + channel gating by activation of a G protein coupled receptor and protein kinase. C J Physiol 511(Pt 2):333–346
Thomas D, Zhang W, Karle CA et al (1999) Deletion of protein kinase. a phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase. A J Biol Chem 274:27457–27462
Davis MJ, Wu X, Nurkiewicz TR et al (2001) Regulation of ion channels by protein tyrosine phosphorylation. Am J Physiol Heart Circ Physiol 281:H1835–H1862
Zhang Y, Wang H, Wang J et al (2003) Normal function of HERG K? channels expressed in HEK293 cells requires basal protein kinase B activity. FEBS Lett 534:125–132
Zhang DY, Wang Y, Lau CP et al (2008) Both EGFR kinase and Src related tyrosine kinases regulate human ether-a-go-go-related gene potassium channels. Cell Signal 20:1815–1821
Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019
Di Lorenzo G, Autorino L, Bruni G et al (2009) Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol 20:1535–1542
Miller KD, Manuel Trigo J, Wheeler C et al (2005) Multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastastic breast cancer. Clin Cancer Res 11(9):3369–3376
Tamura T, Minami H, Yamada Y et al (2006) A phase I dose escalation study of ZD6474 in Japanese patients with solid malignant tumors. J Thorac Oncol 1(9):1002–1009
Hammett T, Oliver S, Ghahramani P et al (2005) The pharmacodynamic effect on cardiac repolarization of combination single dose ZD6474 and ondansetron in healthy subjects. J Clin Oncol 23:16S, abstr 3197
Holden SN, Eckhardt SG, Basser R et al (2005) Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 16:1391–1397
Heymach JV, Johnson BE, Prager D et al (2007) Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 25(27):4270–4277
Kovacs MJ, Reece DE, Marcellus D et al (2006) A phase II study of ZD6474 (Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma—NCIC CTG IND. Invest New Drugs 24(6):529–535, 145
Kiura K, Nakagawa K, Shinkai T et al (2008) A randomized, double-blind, phase IIa dose-finding study of Vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer. J Thorac Oncol 3(4):386–393
Natale RB, Thongprasert S, Greco FA et al (2011) Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol 29:1059–1066
De Boer RH, Arrieta O, Yang C-H et al (2011) Vandetanib plus pemetrexed for the second-line treatment of advanced non–small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 29:1067–1074
Wells SA Jr, Robinson BG, Gagel RF et al (2011) Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30:134–141
Tam CS, Kantarjian H, Garcia-Manero G et al (2008) Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood 112(3):516–518
US Food and Drug Administration (FDA) (2006) Dasatinib (BMS-35825) Oncologic drug advisory committee briefing document NDA 21–96. Washington, DC, FDA, pp 52
Denekamp J (1982) Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer 45:136–139
Denekamp J (1991) The current status of targeting tumour vasculature as a means of cancer therapy: an overview. Int J Radiat Biol 60:401–408
Shi W, Siemann DW (2005) Targeting the tumor vasculature: enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474. In Vivo 19:1045–1050
Nathan PD, Judson I, Padhani A et al (2008) A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors. J Clin Oncol 26(Suppl):3550
Siemann DW, Bibby MC, Dark GG et al (2005) Differentiation and definition of vascular-targeted therapies. Clin Cancer Res 11:416–420
Siemann DW, Chaplin DJ (2007) An update on the clinical development of drugs to disable tumor vasculature. Expert Opin Drug Discov 2:1–11
Haverkamp W, Breithardt G, Camm AJ et al (2000) The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: Clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Cardiovasc Res 47:219–233
Dowlati A, Robertson K, Cooney M et al (2002) A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res 62:3408–3416
Cooney MM, Radivoyevitch T, Dowlati A et al (2004) Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer. Clin Cancer Res 10:96–100
Ng QS, Carnell D, Milner J et al (2005) Phase Ib trial of combrestastatin A4 phosphate in combination with radiotherapy: initial clinical results. J Clin Oncol 23:16S, abstr 3117
Rustin GJ, Galbraith SM, Anderson H et al (2003) Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J Clin Oncol 21:2815–2822
Stevenson JP, Rosen M, Sun W et al (2003) Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J Clin Oncol 21:4428–4438
Bilenker JH, Flaherty KT, Rosen M et al (2005) Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin Cancer Res 11:1527–1533
Jones R, Ewer M (2006) Cardiac and cardiovascular toxicity of nonanthracycline anticancer drugs. Expert Rev Anticancer Ther 6:1249–1269
Rustin GJ, Nathan PD, Boxhall J et al (2005) A phase Ib trial of combretastatin A-4 phosphate (CA4P) in combination with carboplatin or paclitaxel chemotherapy in patients with advanced cancer [Abstract]. J Clin Oncol 23:3013
Lloyd GK, Nicholson B, Neuteboom STC et al (2003) NPI-2358: a new vascular/tubulin modifying agent greatly potentiates standard chemotherapy in xenograft models. EORTC-NCI-AACR Molecular Targets and Therapeutics Meeting, Boston, MA
Neuteboom STC, Medina E, Palladino MA et al (2008) NPI-2358, A novel tumor vascular disrupting agent potentiates the anti-tumor activity of docetaxel in the non small cell lung cancer model MV522 [abstract]. Eur J Cancer 6(Suppl):141
End DW, Smets G, Todd AV et al (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131–137
Britten CD, Rowinsky EK, Soignet S et al (2001) A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778123 in patients with solid malignancies. Clin Cancer Res 7:3894–3903
Rubin E, Abbruzzese J, Morrison B et al (2000) Phase I trial of farnesyl protein transferase inhibitor L-778123 on a 14- or 28-day dosing schedule. Proc Am Soc Clin Oncol 19(abstr. 689):178a
Hahn SM, Bernhard EJ, Regine W et al (2002) A phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 8:1065–1072
Martin NE, Brunner TB, Kiel KD et al (2004) A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res 10:5447–5454
Livneh E, Fishman DD (1997) Linking protein kinase C to cell-cycle control. Eur J Biochem 248:1–9
Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614
Da Rocha AB, Mans DR, Regner A et al (2002) Targeting protein kinase C: new therapeutic opportunities against high-grade gliomas? Oncologist 7:17–33
Gescher A (1998) Analogs of staurosporine: potential anticancer drugs? Gen Pharmacol 31:721–728
Goekjian PG, Jirousek MR (2001) Protein kinase C inhibitors as novel anticancer drugs. Expert Opin Investig Drugs 10:2117–2140
Blobe GC, Obeid LM, Hannun YA (1994) Regulation of protein kinase C and role in cancer biology. Cancer Metastasis Rev 13:411–431
Balendran A, Hare GR, Kieloch A et al (2000) Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett 484:217–223
Partovian C, Simons M (2004) Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase Calpha in endothelial cells. Cell Signal 16:951–957
Graff JR, McNulty AM, Hanna KR et al (2005) The protein kinase C beta–selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462–7469
Keyes KA, Mann L, Sherman M et al (2004) LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53:133–140
Carducci MA, Musib L, Kies MS et al (2006) Phase I dose escalation and pharmacokinetic study of Enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24:4092–4099
Beerepoot L, Rademaker-Lakhai J, Witteveen E et al (2006) Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer. J Clin Oncol 24:18S, abstr. 2046
Robertson MJ, Kahl BS, Vose JM et al (2007) Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 25:1741–1746
Chen J, Marechal V, Levine AJ (1993) Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol 13:4107–4114
Wasylyk C, Salvi R, Argentini M et al (1999) p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53. Oncogene 18(11):1921–1934
Chene P, Fuchs J, Bohn J et al (2000) A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J Mol Biol 299(1):245–253
Wang H, Nan L, Yu D et al (2002) Anti-tumor efficacy of a novel antisense anti-MDM2 mixed-backbone oligonucleotide in human colon cancer models: p53-dependent and p53-independent mechanisms. Mol Med 8(4):185–199
Tabernero J, Dirix L, Schoffski P et al (2009) Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of HDM-2 antagonist JNJ-26854165 in patients with advanced refractory solid tumors. J Clin Oncol 27(15S):3514, Meeting Abstracts
Tabernero J, Dirix L, Schoffski P et al (2011) A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin Cancer Res 17:6313–6321
Ratnam K, Low JA (2007) Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology. Clin Cancer Res 13(5):1383–1388
Yuan Y, Liao YM, Chung TH et al (2011) Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol 4:16
Zemrak WR, Kenna GA (2008) Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health-Syst Pharm 65:1029–1038
Hagiwara T, Satoh S, Kasai Y et al (2001) A comparative study of the various fluoroquinolone antibacterial agents on the cardiac action potential in guinea pig right ventricular myocardium. Jpn J Pharmacol 87:231–234, 1
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Locatelli, M., Criscitiello, C., Esposito, A. et al. QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review. Targ Oncol 10, 27–43 (2015). https://doi.org/10.1007/s11523-014-0325-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11523-014-0325-x