A Phase Ii Trial Of Riluzole, An Antagonist Of Metabotropic Glutamate Receptor (Grm1) Signaling, In Advanced Melanoma.

8557 Background: Preclinical studies demonstrate that GRM1 is a potential therapeutic target in melanoma, with > 60% of human melanomas ectopically expressing GRM1. Moreover, GRM1 over-expression renders melanoma cells more sensitive to treatment with riluzole, an oral agent that blocks glutamate release. Our phase 0 trial of riluzole in patients (pts) with resectable melanoma demonstrated a 34% (4 of 12 pts) PET response to 14 days of riluzole at 100 mg bid, with responding pts demonstrating decreased levels of pERK and pAKT in post treatment tumor biopsies. To further explore the activity of riluzole in advanced melanoma, we performed a phase II trial with the primary objective of response rate. Methods: Eligibility included pts with stage III (unresectable) or IV melanoma, ECOG PS ≤ 2 who received no more than 1 prior chemotherapy regimen. 100 mg bid of riluzole was administered for 6 week cycles. Paired tumor biopsies were collected in most pts to compare levels of pERK and pAKT. The trial employed a Simon two stage minimax design to test the response rate of 5 vs. 20% at alpha=0.05 and power=80%, requiring 1 response of 13 pts in stage 1 to continue to enroll 14 additional pts in stage 2. Results: 13 pts have been enrolled in stage 1, all with GRM1 positive tumors. No RECIST responses have yet been seen in 12 of 13 pts with 1 pt awaiting restaging. Stable disease was noted at first re evaluation in 5 of 12 pts. Riluzole was well tolerated with dizziness (30%) and fatigue (30%) the most common toxicities. 1 pt was taken off study for grade 3 dizziness. 1 pt remains on study with stable disease at 34 weeks. Of 8 paired tumor samples, 6 showed a significant decrease in pERK with 3 of these also showing a significant decrease in pAKT post-treatment. These last 3 pts each experienced stable disease at first re evaluation. Testing for B-raf and N-ras mutational status is in progress. Conclusions: Riluzole was well tolerated. Although no responses were yet seen by RECIST criteria, initial stable disease was seen in 42% of previously progressing pts. While biologically active, the modest antitumor activity suggests that riluzole should be tested in combination with other anticancer agents. Funded by NIH 1R21CA139473-02.