PRIMARY OBJECTIVES:~I. Estimate (or characterize) the concentration of defactinib or avutometinib (VS-6766) that accumulates in the glioblastoma (GBM) and brain around tumor.~II. Assess the safety of the administration of a single oral dose of defactinib or VS-6766 in patients with glioblastoma.~III. Assess the inhibition of Pyk2/FAK or MEK, Erk signaling in tumor and brain around tumor.~IV. Assess the pharmacodynamics of defactinib or VS-6766 in patients with glioblastoma.~OUTLINE: This is a dose-escalation study of defactinib and avutometinib. Patients are assigned to 1 of 2 arms.~ARM I: Patients receive 1 dose of defactinib orally (PO) while on study, prior to planned tumor resection.~ARM II: Patients receive 1 dose of avutometinib PO while on study, prior to planned tumor resection.~Patients undergo blood collection and donate resected tumor tissue while on study.
This early phase I trial tests brain concentration level and safety of defactinib or VS-6766 for the treatment of patients with glioblastoma. Recently, two new drugs that seem to work together have been shown to have promising treatment effects in tissue culture and animal models of glioblastoma. Each inhibits a different glioblastoma growth pathway and when used together may create a larger effect on tumor growth than either alone. Growth pathway describes a series of chemical reactions in which a group of molecules in a cell work together to control cell growth. It is known that glioblastoma tumor cells can grow because of lack of regulation. Both Pyk2 and the closely related kinase (FAK) proteins help regulate tumor cell invasion, unless they are produced in large amounts (over expressed). Specifically, Raf and FAK/Pyk2 regulation of cell division is activated quite a bit more in gliomas compared to normal tissues. Recently developed inhibitors of Raf (VS-6766) and FAK (defactinib) which belong to a class of medications called kinase inhibitors, are aimed to bring their activity to proper levels and may stop tumor growth.