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A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors

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Summary

Objective The objective was to determine the maximum tolerated dose and the dose-limiting toxicity of panobinostat (LBH589) when administered as a single agent to adult patients with advanced solid tumors or cutaneous T-cell lymphoma whose disease had progressed despite standard therapy or for whom no standard therapy existed. Methods Panobinostat was administered orally once daily on Monday, Wednesday, and Friday of each week. A total of 13 patients were treated with one of three initial doses: 10 mg (n = 3), 15 mg (n = 4), or 20 mg (n = 6). Results No dose-limiting toxicity was observed in 12 evaluable patients. The most frequently reported adverse events, regardless of whether they were related to the study drug, were diarrhea and nausea in 10 patients (76.9%). Thrombocytopenia was reported in 12 of 13 patients (92.3%). Five of 11 patients (45.4%) had stable disease. Conclusion Panobinostat administered orally once daily on Monday, Wednesday, and Friday of each week was well tolerated at doses up to 20 mg in Japanese patients. Dose escalation did not proceed after exploration of the 20 mg dose due to emerging global clinical data at that time.

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References

  1. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784. doi:10.1038/nrd2133

    Article  PubMed  CAS  Google Scholar 

  2. Prince HM, Bishton MJ, Harrison SJ (2009) Clinical studies of histone deacetylase inhibitors. Clin Cancer Res 15:3958–3969. doi:10.1158/1078-0432.CCR-08-2785

    Article  PubMed  CAS  Google Scholar 

  3. Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241. doi:10.1016/j.canlet.2009.02.019

    Article  PubMed  CAS  Google Scholar 

  4. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R (2006) Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 12:634–642. doi:10.1158/1078-0432.CCR-05-1132

    Article  PubMed  CAS  Google Scholar 

  5. O’Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, Curly T, Moskowitz C, Portlock C, Horwitz S, Zelenetz AD, Frankel S, Richon V, Marks P, Kelly WK (2006) Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 24:166–173. doi:10.1200/JCO.2005.01.9679

    Article  PubMed  Google Scholar 

  6. Shao W, Growney J, Feng Y, Wang P, Yan-Neale Y, O’Connor G, Kwon P, Yao Y, Fawell S, Atadja P (2008) Potent anticancer activity of a pan-deacetylase inhibitor panobinostat (LBH589) as a single agent in in vitro and in vivo tumor models. AACR Meeting Abstracts 2008:735

  7. Ellis L, Pan Y, Smyth GK, George DJ, McCormack C, Williams-Truax R, Mita M, Beck J, Burris H, Ryan G, Atadja P, Butterfoss D, Dugan M, Culver K, Johnstone RW, Prince HM (2008) Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res 14:4500–4510. doi:10.1158/1078-0432.CCR-07-4262

    Article  PubMed  CAS  Google Scholar 

  8. Prince HM, George D, Patnaik A, Mita M, Dugan M, Butterfoss D, Masson E, Culver KW, Burris HA III, Beck J (2007) Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma. ASCO Meet Abstr 25:3500

    Google Scholar 

  9. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, Crowley C, Yocum RC, Bexarotene Worldwide Study Group (2001) Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19:2456–2471

    PubMed  CAS  Google Scholar 

  10. Woo MM, Culver K, Li W, Liu A, Scott J, Parker K, Jalaluddin M, Laird G, Cooper MR, Schran HF (2008) Panobinostat (LBH589) pharmacokinetics (PK): implication for clinical safety and efficacy. Ann Oncol 19:487P

    Google Scholar 

  11. Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27:5459–5468. doi:10.1200/JCO.2009.22.1291

    Article  PubMed  CAS  Google Scholar 

  12. Chang AN, Cantor AB, Fujiwara Y, Lodish MB, Droho S, Crispino JD, Orkin SH (2002) GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc Natl Acad Sci USA 99:9237–9242. doi:10.1073/pnas.142302099

    Article  PubMed  CAS  Google Scholar 

  13. Matsuoka H, Unami A, Fujimura T, Noto T, Takata Y, Yoshizawa K, Mori H, Aramori I, Mutoh S (2007) Mechanisms of HDAC inhibitor-induced thrombocytopenia. Eur J Pharmacol 571:88–96. doi:10.1016/j.ejphar.2007.06.015

    Article  PubMed  CAS  Google Scholar 

  14. Bates SE, Rosing DR, Fojo T, Piekarz RL (2006) Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res 12:3871–3874. doi:10.1158/1078-0432.CCR-06-1017

    Article  PubMed  CAS  Google Scholar 

  15. Strevel EL, Ing DJ, Siu LL (2007) Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362–3371. doi:10.1200/JCO.2006.09.6925

    Article  PubMed  CAS  Google Scholar 

  16. Weber HA, Tai F, Paul S, Schindler J, Woo MM, Spence S, Marlowe J, Lin R (2009) QT interval measurements in patients with hematologic malignancies and solid tumors treated with oral panobinostat (LBH589). ASH Annu Meet Abstr 114:3781

    Google Scholar 

  17. Witt O, Monkemeyer S, Ronndahl G, Erdlenbruch B, Reinhardt D, Kanbach K, Pekrun A (2003) Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood 101:2001–2007. doi:10.1182/blood-2002-08-2617

    Article  PubMed  CAS  Google Scholar 

  18. Wolk M, Martin JE, Reinus C (2006) Development of fetal haemoglobin-blood cells (F cells) within colorectal tumour tissues. J Clin Pathol 59:598–602. doi:10.1136/jcp.2005.029934

    Article  PubMed  CAS  Google Scholar 

  19. Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, Bhalla KN, Liu A, Parker K, Scott JW, Bishton M, Prince HM (2009) Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol 147:97–101. doi:10.1111/j.1365-2141.2009.07837.x

    Article  PubMed  CAS  Google Scholar 

  20. San-Miguel JF, Sezer O, Siegel D, Guenther A, Mateos M, Prosser I, Cavo M, Blade J, Boccadoro M, Bengoudifa BR, Klebsattel M, Bourquelot PM, Anderson KC (2009) A Phase IB, multi-center, open-label dose-escalation study of oral panobinostat (LBH589) and I.V. Bortezomib in patients with relapsed multiple myeloma. ASH Annu Meet Abstr 114:3852

    Google Scholar 

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Correspondence to Nobuyuki Yamamoto.

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Fukutomi, A., Hatake, K., Matsui, K. et al. A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Invest New Drugs 30, 1096–1106 (2012). https://doi.org/10.1007/s10637-011-9666-9

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  • DOI: https://doi.org/10.1007/s10637-011-9666-9

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