Identification of Treatment Concentrations of Defactinib or VS-6766 for the Treatment of Patients With Glioblastoma

NCT05798507 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 4 other identifiers: STUDY00004876NCI-2023-00602WINSHIP5751-22P30CA138292
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Recurrent Glioblastoma; Glioblastoma

Outcome Measures

Primary Outcomes (4)

• Concentration of defactinib that accumulates in the glioblastoma (GBM) and brain around tumor

  Defactinib concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving Defactinib. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.

  At time of surgery

• Concentration of avutometinib (VS-6766) that accumulates in the GBM and brain around tumor

  VS-6766 concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving VS-6766. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.

  At time of surgery

• Incidence of adverse events associated with defactinib

  Will be assessed by quantification of the recognized side effects of this agent including fatigue, nausea, diarrhea, vomiting, hyperbilirubinemia, decreased appetite, peripheral edema, dizziness, and headache and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.

  Up to 2 weeks post surgery

• Incidence of adverse events associated with VS-6766

  Will be assessed by quantification of the recognized side effects of this agent including rash, creatine phosphokinase elevation, visual disturbances, hypoalbuminemia, and fatigue and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.

  Up to 2 weeks post surgery

Secondary Outcomes (2)

• Pyk2 and FAK phosphorylation in tumor, brain around tumor, and serum

  At time of surgery

• MEK and Erk in tumor, brain around tumor, and serum

  At time of surgery

Study Arms (2)

Arm I (Defactinib)

EXPERIMENTAL

Patients receive 1 dose of defactinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study.

Procedure: Biospecimen Collection; Drug: Defactinib

Arm II (Avutometinib)

EXPERIMENTAL

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.

Drug: Avutometinib; Procedure: Biospecimen Collection

Interventions

Avutometinib DRUG

Given PO

Also known as: CH-5126766, CH5126766, CKI-27, R-7304, Raf/MEK Inhibitor VS-6766, RG 7304, RG-7304, RG7304, RO5126766, VS 6766, VS-6766, VS6766

Arm II (Avutometinib)

Biospecimen Collection PROCEDURE

Undergo blood and tissue sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm I (Defactinib); Arm II (Avutometinib)

Defactinib DRUG

Given PO

Arm I (Defactinib)

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Clinically significant gastrointestinal abnormalities, requirement for systemic anticoagulation or potent CYP 2C8 inhibitors, and history of clinically significant cardiac or pulmonary disorders
• Minors will be excluded from the investigation. Glioblastoma is the major form of brain cancer in people over 50 years old. Pediatric cases of glioblastoma are relatively rare. Besides this, there are crucial molecular differences between adult and pediatric gliomas. Our preliminary data for proposed investigation were obtained on GBM specimens and cultures developed from GBM tissues donated by adult subjects. Results of investigation of adult glioma tissue cannot simply be extrapolated to children. Therefore, our primary research focus is the investigation of GBM in adults. If appropriate, a separate, age-specific study in children will be performed
• Pregnant women will be excluded from the study as altered hormonal and immunological status can affect the study results
• Prisoners will be excluded from the study
• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
• History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of VS-6766
• Exposure to medications (with or without prescription), supplements, herbal remedies, or foods with potential for drug-drug interactions with VS-6766 within 14 days prior to the first dose of VS-6766 and during the course of therapy, including:
• VS-6766: strong CYP3A4, inhibitors or inducers, due to potential drug-drug interactions with VS-6766 and/or defactinib
• Defactinib: strong CYP3A4, CYP2C9, and P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with VS-6766 and/or defactinib
• Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy
• Active skin disorder that has required systemic therapy within the past 1 year
• History of rhabdomyolysis
• Concurrent ocular disorders:
• Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes

Sponsors & Collaborators

• Emory University: lead
• National Cancer Institute (NCI): collaborator
• Verastem, Inc.: collaborator

Study Sites (1)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Related Publications (1)

• Del Valle MM, Colon EM, Kettimuthu K, Maner-Smith K, Olson JJ, Kucheryavykh LY. Window of opportunity study measuring defactinib and avutometinib delivery in glioblastomas. Cancer Chemother Pharmacol. 2026 Mar 6;96(1):22. doi: 10.1007/s00280-026-04870-4.

  PMID: 41790275 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

RO5126766; Specimen Handling; defactinib

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Kimberly B. Hoang, MD

  Emory University Hospital/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 3, 2023
• First Posted: April 4, 2023
• Study Start: July 28, 2023
• Primary Completion (Estimated): December 3, 2026
• Study Completion (Estimated): December 3, 2027
• Last Updated: December 15, 2025

Record last verified: 2025-12

Locations

US (1)