e13560 Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.
Depletion of histone deacetylase 3 antagonizes PI3K-mediated overgrowth ofDrosophilaorgans through the acetylation of histone H4 at lysine 16