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

Pigment Cell Melanoma Res. 2018 Jul;31(4):534-540. doi: 10.1111/pcmr.12694. Epub 2018 Apr 10.

Abstract

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 six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis-generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.

Keywords: angiogenic factors and receptors; clinical trials; glutamate; melanoma; riluzole; skin cancers.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Down-Regulation / drug effects*
  • Female
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Melanoma* / drug therapy
  • Melanoma* / metabolism
  • Melanoma* / pathology
  • Middle Aged
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / biosynthesis
  • Riluzole / administration & dosage*
  • Riluzole / adverse effects

Substances

  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Riluzole