A Phase I Trial of Riluzole and Sorafenib in Patients with Advanced Solid Tumors | Oncotarget
Channel: Oncotarget
Date: 12/04/2023

Oncotarget published this research paper on April 10, 2023 in Volume 14, entitled, “A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850" by researchers Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ; Department of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ; Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ; Dana-Farber Cancer Institute, Boston, MA; Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ; Department of Medicine, New York University Grossman School of Medicine, Perlmutter Cancer Center of NYU Langone Health, NY.
@RutgersU @NYULangoneHealth @danafarber 
#openaccess   #cancer   #drugdiscovery  #cancertherapy  #cancerpatients  #research   #openscience   #peerreview   #journal   #publication   #researchpaper   #meded  #oncologyresearch 

DOI - https://doi.org/10.18632/oncotarget.28403

Correspondence to - Janice M. Mehnert - Janice.Mehnert@nyulangone.org

Abstract

Background: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers.

Patients and Methods: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles.

Results: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients.

Conclusion: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

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Keywords - GRM1, riluzole, sorafenib, phase I, clinical trial

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