DISCUSSION
nausea, tumor, cancers, diarrhea, fatigue, toxicity, toxicities, ALS, rash, lymphopenia, tumors
TUMOR, CANCERS, LIVER METASTASES, SIDE EFFECT, DISEASE, PANCREATIC ACINAR CELL CARCINOMA, LYMPHOPENIA, MALIGNANCIES, PATHOGENESIS, TUMORS, METASTASES, DRUG-DRUG INTERACTION
Over-expression of the metabotropic glutamate receptor 1 (GRM1) has been implicated in the facilitation of endothelial cell growth in a number of solid malignancies by way of activation of the MAPK and PI3K/AKT signaling pathways. Riluzole functions as an inhibitor of GRM1 signaling through antagonism of glutamate release, and sorafenib is a multi-kinase inhibitor targeting both the MAPK and PI3K/AKT pathways through the inhibition of RAF1, ARAF and, to a lesser extent BRAF, as well as a set of tyrosine kinases including VEGFR. Our phase I study determined the tolerable dose of this combination and investigated its biologic effects.The 35 patients enrolled on the study experienced toxicities consistent with known side effect profiles of tyrosine kinase inhibitors including fatigue, lymphopenia, nausea, diarrhea, PPE, and rash. While the most common grade ≥3 toxicity and dose limiting toxicity was rash, only 6 patients experienced dose interruptions, 4 of which required subsequent dose reductions. As a result, the MTD was defined as riluzole 100 mg BID and sorafenib 400 mg qam/200 mg qpm.Plasma pharmacokinetic studies for this trial were planned to determine whether significant drug-drug interactions occurred with this regimen. The large inter-individual variability in plasma riluzole levels (35% to 175% CV in the geometric mean among individuals in various sorafenib dose cohorts) observed in this study limits our conclusions. High variability in plasma riluzole levels has been reported in patients with ALS [The PK parameters of sorafenib such as plasma Cmin,ss, accumulation of sorafenib in the plasma after multiple doses, and high interpatient variability in the current combination study were similar to those of pharmacokinetic reports in previous phase I clinical trials of single agent sorafenib [Within the small subset of patients who had both pre- and post-treatment tissue available for correlative testing, consistent and statistically significant decreases in phospho-forms of both ERK and AKT in a majority of patients suggested target engagement by the combination of riluzole and sorafenib, with accompanying decreases in GRM1 expression and increases in the pro-apoptotic protein BIM which suggest efficacy. The lack of consistent decreases in BCL-2 protein expression may reflect the dynamic nature of the apoptotic response. While these studies are hypothesis-generating due to small sample size, the results support our hypothesis that MAPK and PI3K signaling pathways are affected by the riluzole and sorafenib treatment regimen.Although the majority of patients had progressive disease with this combination (51%), one patient with pancreatic acinar cell carcinoma with metastases to the liver and mesenteric lymph nodes whose tumor harbored a KANK4-RAF1 fusion identified by next generation sequencing achieved a partial response that encouragingly lasted for over 8 months. This patient was heavily pretreated with multiple (>5) prior lines of chemotherapy as well as chemoembolization of liver metastases, none of which resulted in a clinical response. In addition to a radiologic and clinical response, this patient displayed statistically significant decreases in GRM1, AKT, and pro-apoptotic protein BIM in analyses of paired tumor tissue, supporting target engagement and activity. The clinical response sustained over several months and the almost 4-fold increase in BIM levels post-treatment in this patient suggests further investigation of this combination in a pre-specified subset of patients may be warranted.Multiple gene fusions involving RAF1 have been implicated in the pathogenesis of solid organ tumors including pancreatic acinar cell carcinomas [In conclusion, the combination of riluzole and sorafenib was not recommended for further broad empiric study, however, the partial response seen in a patient with metastatic pancreatic acinar cell carcinoma harboring a KANK-RAF1 fusion, accompanied by a decrease in GRM1 expression in correlative studies suggests that molecularly defined subsets of cancers may be sensitive to this combination. Alternatively, combination studies of sorafenib of riluzole with next generation riluzole prodrug candidates can be entertained. Further studies in a pre-selected patient population harboring RAF1 aberrations, and including ARAF aberrations and non-canonical BRAF mutations are under consideration.