Identification of Treatment Concentrations of Defactinib or VS-6766 for the Treatment of Patients with Glioblastoma
Brain & Spinal Cord Tumor
21 Years and older, Male and Female
WINSHIP5751-22 (primary)
NCI-2023-00602
STUDY00004876
Summary
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.
Objectives
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. Patients undergo echocardiography at screening and undergo blood collection and donate resected tumor tissue while on study.
ARM II: Patients receive 1 dose of avutometinib PO while on study, prior to planned tumor resection. Patients undergo echocardiography at screening and undergo blood collection and donate resected tumor tissue while on study.
Eligibility
- New or recurrent glioblastoma diagnosed by neuroimaging techniques for which surgical resection is indicated
- Age older than 21 years
- An Eastern Cooperative Group (ECOG) performance status =< 1
- Hemoglobin (Hb) >= 9.0 g/dL. If a red blood cell transfusion has been administered the Hb must remain stable and >= 9.0 g/dL for at least 1 week prior to first dose of study therapy.
- Platelets >= 100,000/mm^3
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Total bilirubin =< 1.5 × upper limit of normal (ULN) per the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 umole/L)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 × ULN (or < 5x ULN in patients with liver metastases)
- Creatinine clearance rate of >= 50 mL/min as calculated by the Cockcroft-Gault formula or serum creatinine of =< 1.5 x ULN
- Albumin >= 3.0 g/dL (451 umole/L)
- Creatine phosphokinase (CPK) =< 2.5 x ULN
- Left ventricular ejection fraction >= 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan
- Baseline QTc interval < 460 ms for women and =< 450 ms for men (average of triplicate readings) (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to subjects with a right or left bundle branch block
- Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade =< 2
- Male and female patients with reproductive potential agree to use highly effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] recommendations) during the trial and for 3 months following the last dose of VS-6766 for male patients, and 1 month following the last dose of VS-6766 for female patients.
Treatment Sites in Georgia
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts...
Click here to learn more about clinical trials.