A Phase I Study To Evaluate The Safety Of Trigriluzole (Bhv-4157) In Combination With Pd-1 Blocking Antibodies.

TPS80Background: The Metabotropic Glutamate Receptor 1 (GRM1) is expressed in 60-100% of human melanomas, breast cancers, and other solid tumors. Riluzole, an FDA-approved drug for ALS, inhibits GRM1 signal transduction. A phase 0 trial in melanoma patients demonstrated that riluzole suppressed signaling through the MAPK and PI3K/AKT pathways but no objective responses were seen in a phase 2 study.The clinical use of riluzole outside of ALS has been limited by: (i) poor oral bioavailability, (ii) extensive first-pass hepatic metabolism, (iii) high variability in PK parameters, (iv) food-related decrease in bioavailability, and (v) dose-related hepatotoxicity. Trigriluzole (BHV-4157) is a third generation prodrug of riluzole with improved PK/PD properties. In our MASS20 in vivo murine model of melanoma, GRM1 signal transduction appears to suppress tumor immunity through up-regulation of M-CSF and CCL2 expression with a subsequent increase in the percentage of M2 macrophages in the tumor microenvironment. I...