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A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850

Kristen R Spencer1,2, Daniella E Portal1,2, Joseph Aisner1,2

  • 1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.

Oncotarget
|April 10, 2023
PubMed
Abstract

Insights

This Phase I trial found that combining riluzole with sorafenib is safe for advanced cancers. The combination showed target engagement and a partial response in a patient with a RAF1 fusion, suggesting further study in selected patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Metabotropic glutamate receptor 1 (GRM1) overexpression is linked to cancer development.
  • Riluzole (glutamate release inhibitor) and sorafenib (multi-kinase inhibitor) demonstrated synergistic antitumor effects in preclinical cancer models.
  • A Phase I clinical trial was conducted to evaluate the safety and pharmacodynamics of combining riluzole and sorafenib in advanced cancers.

Purpose of the Study:

  • To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose (MTD) of combined riluzole and sorafenib.
  • To assess the pharmacokinetic and pharmacodynamic properties of the drug combination.
  • To evaluate preliminary antitumor activity of the combination therapy.

Main Methods:

  • A 3+3 dose-escalation Phase I trial design was employed.
  • Patients with refractory solid tumors received escalating doses of sorafenib in combination with a fixed dose of riluzole (100 mg PO BID).
  • Pharmacokinetic analyses and tumor tissue assessments (p-ERK, p-AKT, GRM1, BIM) were performed to evaluate drug interactions and target engagement.

Main Results:

  • The maximum tolerated dose (MTD) was established at riluzole 100 mg PO BID with sorafenib 400 mg AM/200 mg PM.
  • Pharmacokinetic studies did not indicate significant drug-drug interactions between riluzole and sorafenib.
  • Tumor analyses showed decreased phospho-ERK and phospho-AKT, reduced GRM1 expression, and increased BIM, indicating target engagement. One partial response was observed in a patient with pancreatic acinar cell carcinoma harboring a KANK4-RAF1 fusion.

Conclusions:

  • The combination of riluzole and sorafenib is safe and well-tolerated in patients with advanced solid tumors.
  • Pharmacodynamic effects suggest that the combination engages its intended molecular targets.
  • The observed response in a patient with a RAF1 fusion warrants further investigation in a genomically selected patient cohort.
Keywords:
GRM1clinical trialphase Iriluzolesorafenib

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