Journal
ANNALS OF ONCOLOGY
Volume 22, Issue 11, Pages 2516-2522Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdq784
Keywords
histone deacetylase; pharmacodynamics; pharmacokinetics
Categories
Funding
- S*Bio
- National Medical Research Council [NMRC/TCR/001-NUH/2007)]
- Singapore Cancer Syndicate [SCS-PN0022]
Ask authors/readers for more resources
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 (C-max) 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 C-max. 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available