Abstract B196: Entinostat: A novel class 1 isoform selective histone deacetylase inhibitor (HDACi) with unique pharmacological properties
Authors: Ordentlich Peter , Lee Gloria , Kunkel Lori , Sausville Edward 
Published: June 2012

Several distinct HDACi have been characterized. While we do not fully understand how structure and selectivity correlate with efficacy and toxicity, targeting selective isoforms involved in maintaining tumor proliferation may be sufficient for antitumor activity. Entinostat (ENT) is a benzamide Class I selective compound and has low nM MEC50 values against HDAC1, and low µM to HDAC 2 , 3 and 9, with no inhibition of Class II HDAC 4,6,7 and 8 (Khan 2008). In contrast, the hydroxamate, vorinostat (VOR) has µM inhibition of Class II HDACs. HDACi kinetic properties also influence activity of both histones and other proteins involved in diverse biologic processes. VOR has a fast-on/fast-off rate to HDAC 1 and 3. In contrast, ENT has a slow tight binding that translates into sustained inhibition of HDAC enabling prolonged activation (or repression) of genes even after elimination of the inhibitor.

To better understand differences and similarities of PK/PD profiles of ENT and VOR data from the Ph 1 studies were reviewed. In the NCI Ph 1 study (Ryan 2005, Kummar 2007) 71 patients (68 solid tumors) were treated either daily (n=2) every 2 weeks (wks) (n=28) or weekly for 4 wks with 2 wks off (n=41). Ph 1 data for VOR has been previously summarized (Kelly 2005).

ENT displayed both intra-and inter-patient variability as seen with most oral cancer agents. Daily dosing was not tolerated and PK data suggested that ENT had a 30–50x longer t1/2 than predicted from animal models. Subsequently doses were tested every 2 wks or weekly and up to 10 mg/m2 were tolerated. ENT absorption was variable with a median Tmax of 2 hours (range 0.5 to 60 hrs), the elimination is bi-exponential and the terminal halflife was 30 to 80 hours (hrs). ENT is detectable within 8 hrs and remains above baseline throughout the treatment cycle even after 5 days (Gojo 2007). In contrast VOR has a t1/2 ranging from 91–127 minutes. The AUC with both agents appears to have a linear increase with dose. PK parameters have led to once wkly or every 2 wk dosing with ENT and qD dosing with VOR. Pharmacodynamic analysis on histone acetylation in peripheral blood mononuclear cells is evident at 8-12 hs with ENT and 4–10 with VOR, and acetylation increases with time and continued treatment with both agents, however is not dose related with ENT. Acetylation persists for at least 2 to 3 wks following the last ENT administration in contrast to 10 hrs with VOR. Antitumor activity in Ph 1 was demonstrated with both agents; with SD (for &gt; 90 days) in 30–40% of patients with multiple tumor types. PRs were seen with ENT in melanoma and sarcoma, and mesothelioma and thyroid cancer with VOR. Responses were not dose related. The most common toxicities with both drugs are primarily gastrointestinal, asthenia, and electrolyte abnormalities. Grade 3/4 cytopenias occur in 10–16% of solid tumor patients with both agents and is dose dependent with ENT. With every 2 wks or weekly dosing continuous target inhibition (up to 3 wks without interruption) can be achieved with ENT. Normal cells appear to be relatively resistant to prolonged exposure and therapy is well tolerated. Potent Class I HDACi (and/or related proteins) targeted by ENT is sufficient to induce antitumor activity in a broad spectrum of tumors. Structural differences, prolonged PD effects and impact on other cellular processes may provide important antitumor activity with ENT not achieved with other HDACi.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B196.