A phase Ib study of troriluzole (BHV-4157) in combination with nivolumab

79 Background: The Metabotropic Glutamate Receptor 1 (GRM1) is overexpressed in many solid tumors. It activates MAPK and PI3K/AKT pathways and promotes an immune-suppressive tumor microenvironment. In an immunocompetent melanoma mouse model, GRM1 blockade using riluzole or its pro-drug troriluzole (BHV-4157) and PD-1 blockade inhibit tumor growth in an additive manner. We conducted a phase Ib trial of troriluzole and the PD-1 antibody nivolumab. Methods: Patients with advanced or refractory solid tumors were treated with increasing doses of troriluzole. Troriluzole monotherapy was given for a 14-day lead-in period and then patients received troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Results: We enrolled 14 patients with advanced solid tumors (melanoma=3, NSCLC=3, renal cell cancer=2, NSCLC=2, head and neck cancer=2). Eleven patients had prior therapy with anti-PD-(L)1. PK sampling demonstrated that the prodrug was cleaved efficiently without regard to food (Table). The most common TEAEs (all grades) occurring in >40% of patients were transaminitis, increased lipase and nausea. DLT occurred in 3 patients: 1) grade 3 anorexia, 2) grade 3 fatigue and, 3) atrial fibrillation. The MTD was determined to be troriluzole 140 mg QAM + 280 mg PO QHS. The response rate was 7 % (1/14); this occurred in a PD-L1 treated patient. The 6-month PFS rate was 21%. Correlative studies will be presented. Conclusions: The combination of troriluzole and nivolumab was safe and well-tolerated in this highly PD-1 refractory population. Clinical trial information: NCT03229278. [Table: see text]