Abstract B007: OKI-179 is a novel, oral, class I specific histone deacetylase inhibitor in phase 1 clinical trials

Multiple histone deacetylase (HDAC) inhibitors are approved for use as single agents in hematological cancers, including T-cell lymphomas and multiple myeloma. However, these compounds have failed to address unmet needs in other hematological malignancies and solid tumors, due in part to the promiscuous inhibitory properties of pan inhibitors, a lack of suitable therapeutic indices for combination therapy, and, in some cases, a non-oral route of administration. Of the approved agents, romidepsin is the most potent and selective, but is limited by its need for IV infusion and therapeutic index. With these challenges in mind, our team designed OKI-179, a novel, oral pro-drug analog of largazole, a compound reminiscent of the romidepsin-depsipeptide class of natural products. OKI-179 demonstrates potent inhibition of the Class 1 HDACs, HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs. It shows potent antiproliferative and apoptotic effects against a wide range of cell lines, activity in xenograft cancer models, and good oral PK properties in mouse, rat and dog models. OKI-179 inhibits the growth in mice of colorectal (HCT-116) and triple negative breast (MDA-MB-231) xenograft models potently and dose-dependently as a single agent. OKI-179 potently and dose-dependently causes the upregulation of MHC Class 1 in B16F10 murine melanoma cells; patients with low MHC presentation respond poorly to checkpoint inhibitors. Importantly, the combination of OKI-179 and a murine anti-PD1 agent demonstrates significant synergistic tumor growth inhibition in the syngeneic CT26 murine CRC model and in a genetic model of DLBCL. OKI-179 is currently being investigated in a first-in-human phase 1 dose-escalation trial, with the goals of determining safety, MTD, RP2D, PK, PD, and preliminary efficacy signals. In the first dosing cohorts, the drug was well-tolerated, achieved good exposure following oral administration, and preliminary signs of on-target PD effects were observed. An update of the clinical experience will be presented and discussed, along with translational data that will guide subsequent clinical development. Citation Format: Jennifer R Diamond, Jodi A Kagihara, Xuedong Liu, Gilad Gordon, Amy M Heim, James Winkler, John A DeMattei, Anthony D Piscopio, S. Gail Eckhardt. OKI-179 is a novel, oral, class I specific histone deacetylase inhibitor in phase 1 clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B007. doi:10.1158/1535-7163.TARG-19-B007