A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma

Summary

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg po bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1-positive tumors were enrolled. No objective responses were observed and accrual was stopped. Stable disease was noted in 6 (46%) patients, with 1 patient on study for 42 weeks. Riluzole was well-tolerated, with fatigue (62%) as the most common adverse event. MAPK and PI3K/AKT downregulation was noted in 33% of paired tumor biopsies. Hypothesis generating correlative studies suggested that downregulation of angiogenic markers and increased leuckocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed inter-patient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance development of agents with improved bioavailability.

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