Please use this identifier to cite or link to this item: https://doi.org/10.1093/annonc/mdq784
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dc.titlePhase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies
dc.contributor.authorYong, W.P.
dc.contributor.authorGoh, B.C.
dc.contributor.authorSoo, R.A.
dc.contributor.authorToh, H.C.
dc.contributor.authorEthirajulu, K.
dc.contributor.authorWood, J.
dc.contributor.authorNovotny-Diermayr, V.
dc.contributor.authorLee, S.C.
dc.contributor.authorYeo, W.L.
dc.contributor.authorChan, D.
dc.contributor.authorLim, D.
dc.contributor.authorSeah, E.
dc.contributor.authorLim, R.
dc.contributor.authorZhu, J.
dc.date.accessioned2014-12-12T08:01:45Z
dc.date.available2014-12-12T08:01:45Z
dc.date.issued2011-11
dc.identifier.citationYong, 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
dc.identifier.issn09237534
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/117118
dc.description.abstractBackground: 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.
dc.sourceScopus
dc.subjectHistone deacetylase
dc.subjectPharmacodynamics
dc.subjectPharmacokinetics
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1093/annonc/mdq784
dc.description.sourcetitleAnnals of Oncology
dc.description.volume22
dc.description.issue11
dc.description.page2516-2522
dc.description.codenANONE
dc.identifier.isiut000296292700025
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