Last updated on November 2017

A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination With PD-L1 Inhibitor, Durvalumab, in Advanced or Metastatic Solid Tumors and Non Small Cell Lung Cancer


Brief description of study

A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination With PD-L1 Inhibitor, Durvalumab, in Advanced or Metastatic Solid Tumors and Non Small Cell Lung Cancer

Detailed Study Description

Advanced tumors evade host immune responses by down regulation of major histocompatibility complex (MHC) molecules and tumor antigens and by creating an immune suppressive microenvironment around the tumor. Histone deacetylases (HDACs) have been implicated in the epigenetic regulation of innate and adaptive immunity. Increasing evidence supports the proposal that spectrum-selective inhibitors of class I HDACs can reverse immune evasion and elicit antitumor host response through immunostimulatory mechanisms. The immunomodulatory properties of class I HDAC inhibitors are reported to be mediated through multiple mechanisms including: 1) induction of programmed cell death ligand 1 (PD-L1) expression on the tumor cell surface, 2) induction of tumor associated antigens (TAAs) and MHC Class I and Class II molecules on tumor cells, 3) induction of immunogenic cell death via activation and cross presentation of tumor antigens by antigen presenting cells (APCs), 4) enhanced function of T effector cells, and 5) decreased function of immunosuppressive cell subsets including T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSCs). In addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell cycle progression and inducing apoptosis in tumor. The combination of a class I HDAC inhibitor with an anticancer immunotherapy has the potential to enhance activity over that observed with either agent alone. Mocetinostat is a spectrum-selective Class I/IV HDAC inhibitor specifically targeting HDACs 1, 2, 3 and 11. Class I and IV HDACs are of particular interest from an immunostimulatory and immune priming perspective. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of PD-L1 to programmed cell death 1 (PD-1) and CD80 expressed on host immune effector cells, preventing immune suppression signaling. Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid tumors or hematological malignancies. In this study, the treatment regimen will begin with a 7-Day Lead-in Period of mocetinostat followed by start of the combination regimen of mocetinostat and durvalumab. The Recommended Phase 2 Dose (RP2D) of mocetinostat will be established in the Phase 1 dose escalation segment, followed by evaluation of the clinical activity of the combination regimen in patients having NSCLC.

Clinical Study Identifier: TX17613

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Mirati Research Site
Dallas, TX USA
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