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Targeted Oncology
Published in: Targeted Oncology 1/2015

01-03-2015 | Review

QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review

Authors: Marzia Locatelli, Carmen Criscitiello, Angela Esposito, Ida Minchella, Aron Goldhirsch, Carlo Cipolla, Giuseppe Curigliano

Published in: Targeted Oncology | Issue 1/2015

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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.
Literature
1.
Shah RR (2006) Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics 7(6):889–908CrossRefPubMed
2.
3.
4.
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
5.
Strevel EL, Ing DJ, Siu LL (2007) Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362–3371CrossRefPubMed
6.
Ederhy S, Cohen A, Dufaitre G et al (2009) QT interval prolongation among patients treated with angiogenesis inhibitors. Target Oncol 4:89–97CrossRefPubMed
7.
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 37:607–618CrossRefPubMed
8.
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 11:290–304CrossRefPubMed
9.
10.
11.
Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299CrossRefPubMed
12.
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) 47:315–323CrossRef
13.
Bates SE, Rosing DR, Fojo T et al (2006) Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res 12:3871–3874CrossRefPubMed
14.
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 12:3762–3773CrossRef
15.
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):718–728PubMed
16.
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):325–332CrossRefPubMed
17.
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)
18.
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)
19.
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)
20.
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):3997–4003CrossRefPubMed
21.
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):57–60CrossRefPubMed
22.
Marks PA, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202, 1CrossRefPubMed
23.
Zolinza (2006) Whitehouse Station NJ: Merck & Co. [package insert]
24.
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
25.
Rashmi RS, Morganroth J, Devron RS (2013) Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf 36:295–316CrossRef
26.
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
27.
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 274:27457–27462CrossRef
28.
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–H1862PubMed
29.
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 534:125–132CrossRefPubMed
30.
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 20:1815–1821CrossRefPubMed
31.
32.
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 20:1535–1542CrossRefPubMed
33.
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):3369–3376CrossRefPubMed
34.
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):1002–1009CrossRefPubMed
35.
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
36.
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 16:1391–1397CrossRefPubMed
37.
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):4270–4277CrossRefPubMed
38.
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, 145PubMed
39.
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):386–393CrossRefPubMed
40.
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 29:1059–1066CrossRefPubMed
41.
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 29:1067–1074CrossRefPubMed
42.
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 30:134–141CrossRefPubMedCentralPubMed
43.
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):516–518CrossRefPubMedCentralPubMed
44.
US Food and Drug Administration (FDA) (2006) Dasatinib (BMS-35825) Oncologic drug advisory committee briefing document NDA 21–96. Washington, DC, FDA, pp 52
45.
46.
Denekamp J (1991) The current status of targeting tumour vasculature as a means of cancer therapy: an overview. Int J Radiat Biol 60:401–408CrossRefPubMed
47.
Shi W, Siemann DW (2005) Targeting the tumor vasculature: enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474. In Vivo 19:1045–1050PubMed
48.
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
49.
Siemann DW, Bibby MC, Dark GG et al (2005) Differentiation and definition of vascular-targeted therapies. Clin Cancer Res 11:416–420PubMed
50.
Siemann DW, Chaplin DJ (2007) An update on the clinical development of drugs to disable tumor vasculature. Expert Opin Drug Discov 2:1–11CrossRef
51.
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 47:219–233CrossRefPubMed
52.
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 62:3408–3416PubMed
53.
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 10:96–100CrossRefPubMed
54.
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
55.
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 21:2815–2822CrossRefPubMed
56.
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 21:4428–4438CrossRefPubMed
57.
Bilenker JH, Flaherty KT, Rosen M et al (2005) Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin Cancer Res 11:1527–1533CrossRefPubMed
58.
Jones R, Ewer M (2006) Cardiac and cardiovascular toxicity of nonanthracycline anticancer drugs. Expert Rev Anticancer Ther 6:1249–1269CrossRefPubMed
59.
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
60.
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
61.
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):141CrossRef
62.
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 61:131–137PubMed
63.
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 7:3894–3903PubMed
64.
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
65.
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 8:1065–1072PubMed
66.
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 10:5447–5454CrossRefPubMed
67.
Livneh E, Fishman DD (1997) Linking protein kinase C to cell-cycle control. Eur J Biochem 248:1–9CrossRefPubMed
68.
Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614CrossRefPubMed
69.
Da Rocha AB, Mans DR, Regner A et al (2002) Targeting protein kinase C: new therapeutic opportunities against high-grade gliomas? Oncologist 7:17–33CrossRefPubMed
70.
71.
Goekjian PG, Jirousek MR (2001) Protein kinase C inhibitors as novel anticancer drugs. Expert Opin Investig Drugs 10:2117–2140CrossRefPubMed
72.
Blobe GC, Obeid LM, Hannun YA (1994) Regulation of protein kinase C and role in cancer biology. Cancer Metastasis Rev 13:411–431CrossRefPubMed
73.
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 484:217–223CrossRefPubMed
74.
Partovian C, Simons M (2004) Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase Calpha in endothelial cells. Cell Signal 16:951–957CrossRefPubMed
75.
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 65:7462–7469CrossRefPubMed
76.
Keyes KA, Mann L, Sherman M et al (2004) LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53:133–140CrossRefPubMed
77.
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 24:4092–4099CrossRefPubMed
78.
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. 2046CrossRef
79.
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 25:1741–1746CrossRefPubMed
80.
81.
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):1921–1934CrossRefPubMed
82.
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):245–253CrossRefPubMed
83.
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):185–199PubMedCentralPubMed
84.
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
85.
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 17:6313–6321CrossRefPubMed
86.
Ratnam K, Low JA (2007) Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology. Clin Cancer Res 13(5):1383–1388CrossRefPubMed
87.
88.
Zemrak WR, Kenna GA (2008) Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health-Syst Pharm 65:1029–1038CrossRefPubMed
89.
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, 1CrossRefPubMed
Metadata
Title
QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review
Authors
Marzia Locatelli
Carmen Criscitiello
Angela Esposito
Ida Minchella
Aron Goldhirsch
Carlo Cipolla
Giuseppe Curigliano
Publication date
01-03-2015
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 1/2015
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-014-0325-x

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