Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin

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Abstract:
Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m² romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8–12 mg/m²romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m² over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT-prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate.

Keywords:
Antiemetics; electrocardiography; electrolytes; T-cell; lymphoma; QTc; romidepsin

Autoři: Philip T. Sager ¹; Barbara Balser ²; Julie Wolfson ²; Jean Nichols ³; Richard Pilot ⁴; Suzanne Jones ⁵; Howard A. Burris ⁵
Působiště autorů: Stanford University School of Medicine, San Francisco, California ¹; Veristat, LLC, Holliston, Massachusetts ²; Jean Nichols LLC, Swampscott, Massachusetts ³; Celgene Corporation, Summit, New Jersey ⁴; Sarah Cannon Research Institute, Nashville, Tennessee ⁵
Vyšlo v časopise: Cancer Medicine 2015; 4(8)
Kategorie: Original Research
prolekare.web.journal.doi_sk: https://doi.org/10.1002/cam4.467

© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Souhrn

Keywords:
Antiemetics; electrocardiography; electrolytes; T-cell; lymphoma; QTc; romidepsin

Zdroje

1. Tan, J., S. Cang, Y. Ma, R. L. Petrillo, and D. Liu. 2010. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J. Hematol. Oncol. 3:5.

2. Bolden, J. E., M. J. Peart, and R. W. Johnstone. 2006. Anticancer activities of histone deacetylase inhibitors.Nat. Rev. Drug Discov. 5:769–784.

3.Bradner, J. E., N. West, M. L. Grachan, E. F. Greenberg, S. J. Haggarty, T. Warnow, et al. 2010. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6:238–243.

4. 2014. Istodax (romidepsin) [package insert]. Celgene Corporation, Summit, NJ.

5. Coiffier, B., B. Pro, M. Prince, F. Foss, L. Sokol, M. Greenwood, et al. 2014. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J. Hematol. Oncol. 7:11.

6. Whittaker, S. J., M. Demierre, E. J. Kim, A. H. Rook, A. Lerner, M. Duvic, et al. 2010. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 28:4485–4491.

7. 2011. Zolinza (vorinostat) [package insert]. Merck & Co, Whitehouse Station, NJ.

8. 2014. Beleodaq (belinostat) [package insert]. Spectrum Pharmaceuticals, Irvine, CA.

9. Kristeleit, R., P. Fong, G. W. Aherne, and J. de Bono. 2005. Histone deacetylase inhibitors: emerging anticancer therapeutic agents? Clin. Lung Cancer 7(Suppl. 1):S19–S30.

10. Molife, R., P. Fong, M. Scurr, I. Judson, S. Kaye, and de Bono J. 2007. HDAC inhibitors and cardiac safety. Clin. Cancer Res. 13: 1068 author reply 1068–1069.

11. de Bono, J. S., R. Kristeleit, A. Tolcher, P. Fong, S. Pacey, V. Karavasilis, et al. 2008. Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin. Cancer Res. 14:6663–6673.

12. Lassen, U., L. R. Molife, M. Sorensen, S. A. Engelholm, L. Vidal, R. Sinha, et al. 2010. A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours. Br. J. Cancer 103:12–17.

13. Steele, N. L., J. A. Plumb, L. Vidal, J. Tjørnelund, P. Knoblauch, A. Rasmussen, et al. 2008. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin. Cancer Res. 14:804–810.

14. Shah, M. H., P. Binkley, K. Chan, J. Xiao, D. Arbogast, M. Collamore, et al. 2006. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin. Cancer Res.12:3997–4003.

15. Stadler, W. M., K. Margolin, S. Ferber, W. McCulloch, and J. A. Thompson. 2006. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin. Genitourin. Cancer 5:57–60.

16. Kelly, W. K., O. A. O'Connor, L. M. Krug, J. H. Chiao, M. Heaney, T. Curley, et al. 2005. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 23:3923–3931.

17. Fischer, T., A. Patnaik, K. Bhalla, J. Beck, J. Morganrogh, G. H. Laird, et al. 2005. Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies. J. Clin. Oncol. 23:3106.

18. Marsoni, S., G. Damia, and G. Camboni. 2008. A work in progress: the clinical development of histone deacetylase inhibitors. Epigenetics 3:164–171.

19. Piekarz, R. L., A. R. Frye, J. J. Wright, S. M. Steinberg, D. J. Liewehr, D. R. Rosing, 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.

20. Noonan, A. M., R. A. Eisch, D. J. Liewehr, T. M. Sissung, D. J. Venzon, T. P. Flagg, et al. 2013.Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel. Clin. Cancer Res. 19:3095–3104.

21. Sandor, V., S. Bakke, R. W. Robey, M. H. Kang, M. V. Blagosklonny, J. Bender, et al. 2002. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.Clin. Cancer Res. 8:718–728.

22. Piekarz, R. L., R. Frye, M. Turner, J. J. Wright, S. L. Allen, M. H. Kirschbaum, et al. 2009. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J. Clin. Oncol. 27:5410–5417.

23. Cabell, C., S. Bates, R. Piekarz, S. Whittaker, Y. H. Kim, M. Currie, et al. 2009. Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin. Blood 114:3709.

24. Peacock, J. M., T. Ohira, W. Post, N. Sotoodehnia, W. Rosamond, and A. R. Folsom. 2010. Serum magnesium and risk of sudden cardiac death in the atherosclerosis risk in communities (ARIC) study. Am. Heart J.160:464–470.

25. Del Gobbo, L. C., F. Imamura, J. H. Wu, M. C. de Oliveira Otto, S. E. Chiuve, and D. Mozaffarian. 2013.Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am. J. Clin. Nutr. 98:160–173.

26. Santoro, A., E. Mancini, G. London, L. Mercadal, H. Fessy, B. Perrone, et al. 2008. Patients with complex arrhythmias during and after haemodialysis suffer from different regimens of potassium removal. Nephrol. Dial. Transplant. 23:1415–1421.

27. Osadchii, O. E. 2010. Mechanisms of hypokalemia-induced ventricular arrhythmogenicity. Fundam. Clin. Pharmacol. 24:547–559.

28. Navari, R. M., and J. M. Koeller. 2003. Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine3 receptor antagonists. Ann. Pharmacother. 37:1276–1286.

29. Keefe, D. L. 2002. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern? Oncologist 7:65–72.

30. Center for Biologics Evaluation and Research. 2005. Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. US Department of Health and Human Services, Rockville, MD.

31. Sarapa, N., and M. R. Britto. 2008. Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents. Expert Opin. Drug Saf. 7:305–318.

32. Tablets, Zofran. 2013. Oral Solution and Injection (ondansetron hydrochloride dihydrate) Product Monograph. GlaxoSmithKline Inc, Mississauga, ON.

33. Zhu, H., Y. Wang, J. V. Gobburu, and C. E. Garnett. 2010. Considerations for clinical trial design and data analyses of thorough QT studies using drug-drug interaction. J. Clin. Pharmacol. 50:1106–1111.

34. Sager, P. T. 2008. Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug-induced torsades de pointes. Br. J. Pharmacol. 154:1544–1549.

35. Sager, P. T., T. Nebout, and B. Darpo. 2005. ICH E14: a new regulatory guidance on the clinical evaluation of QT/QTc internal prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Drug Inf. J.39:387–394.

36. Rock, E. P., J. Finkle, H. J. Fingert, B. P. Booth, C. E. Garnett, S. Grant, et al. 2009. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am. Heart J. 157: 827–836, 836.e1.

37. Brell, J. M. 2010. Prolonged QTc interval in cancer therapeutic drug development: defining arrhythmic risk in malignancy. Prog. Cardiovasc. Dis. 53:164–172.

38. Curigliano, G., G. Spitaleri, H. J. Fingert, F. de Braud, C. Sessa, E. Loh, et al. 2008. Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development. Eur. J. Cancer44:494–500.

39. Tornoe, C. W., C. E. Garnett, Y. Wang, J. Florian, M. Li, and J. V. Gobburu. 2011. Creation of a knowledge management system for QT analyses. J. Clin. Pharmacol. 51:1035–1042.

40. Garnett, C. E., H. Zhu, M. Malik, A. A. Fossa, J. Zhang, F. Badilini, et al. 2012. Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am. Heart J. 163:912–930