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|Title:||Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies||Authors:||Yong, W.P.
|Issue Date:||Nov-2011||Citation:||Yong, W.P., Goh, B.C., Soo, R.A., Toh, H.C., Ethirajulu, K., Wood, J., Novotny-Diermayr, V., Lee, S.C., Yeo, W.L., Chan, D., Lim, D., Seah, E., Lim, R., Zhu, J. (2011-11). Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies. Annals of Oncology 22 (11) : 2516-2522. ScholarBank@NUS Repository. https://doi.org/10.1093/annonc/mdq784||Abstract:||Background: The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Patients and methods: Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs). Results: Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 6 0.6 h and 53.0 6 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and Cmax. Stable disease was seen in several tumor types treated at ‡40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose. Conclusions: SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.||Source Title:||Annals of Oncology||URI:||http://scholarbank.nus.edu.sg/handle/10635/117118||ISSN:||09237534||DOI:||10.1093/annonc/mdq784|
|Appears in Collections:||Staff Publications|
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