Background: Metabotropic glutamate receptor 1 (GRM1) activates MAPK and PI3K/AKT signaling and is implicated in multiple cancers including breast, prostate and melanoma. GRM1 overexpression stimulates tumor angiogenesis via enhanced microvesicle secretion to facilitate endothelial cell growth. Riluzole (R) is a clinically available inhibitor of GRM1 signaling. Sorafenib (S), a kinase inhibitor that inhibits MAPK and PI3K/AKT signaling through C-RAF and B-RAF inhibition with antiangiogenic effects, was identified in preclinical screens to have synergistic antitumor activity when combined with R. This phase I trial identified the maximum tolerated dose (MTD) of R combined with S in patients (pts) with advanced cancer. Methods: Pts with refractory solid tumors were enrolled utilizing a standard 3+3 dose-escalation design. R was given in 28 day cycles at the highest dose used in clinical practice (100 mg BID) in combination with S, beginning at 200 mg daily and escalating in 200 mg increments per cohort. Restaging evaluations were performed every 2 cycles using RECIST criteria. Results: 29 pts enrolled, median age 59 (22-85), 13F, 16M, PS 0 (48%), 1 (35%) or 2 (17%). The most common toxicities were nausea (31%), fatigue (62%) and diarrhea (41%), anorexia (31%), rash (27% PPE, 31% other), and hypophosphatemia (34%). Grade 3-4 toxicities included hypophosphatemia (10%), elevated lipase (10%), LFT abnormalities (10%), rash/PPE (14%), and fatigue (13%). The most frequent dose limiting toxicity (DLT) was rash, observed in 3 pts at the MTD, dose level (DL) 4 (R 200 mg bid/S 400 mg bid). Best responses were SD in 9 pts (31%), lasting > 3 months in 1 pt each with sarcoma, lung, colon, ovarian, and melanoma; and 1 GIST (9+ cycles with modest tumor reduction). Conclusions: R combined with S is safe with DLT of rash. While rash is a known side effect of sorafenib, its incidence and severity appeared increased in this study. An expansion cohort in pts with melanoma and sarcoma at DL3 (R 200 mg bid/S 400mg qam/200 mg qpm) is ongoing. Planned correlative assessments include circulating microvesicle quantification and immunohistochemical and western blotting to assess changes in activated signaling targets in pre and post treatment tumors. Clinical trial information: NCT01303341