Background: 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. In an immunocompetent mouse model, treatment with trigriluzole and anti-PD-1 antibody was more effective than either drug alone. Methods: Subjects with advanced or refractory solid cancers or lymphoma will be treated with increasing doses of trigriluzole in this phase 1b study. The dosing cohorts of trigriluzole will be using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Trigriluzole monotherapy will be given for a 14-day lead in period and then patients will receive trigriluzole in combination with nivolumab 240mg IV every 2 weeks. After the maximum tolerated dose (MTD) of trigriluzole is identified, it will be checked in a cohort of 6 patients in combination with pembrolizumab. Total sample size will be 12 – 27 subjects. PD-1-directed therapy prior to entry is allowed. Blood samples and optional biopsies will be collected for correlative analysis. PBMCs and fresh tumor tissue will be grafted into NSG mice to create a patient-derived autologous double-humanized murine model for each participant. Clinical trial information: NCT03229278