Study of Low-Intensity Focused Ultrasound in Combination With Immunotherapy in Newly Diagnosed Unmethylated Glioblastoma

NCT07343986 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: HSR231550
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1 study for patients with newly diagnosed MGMT unmethylated IDH wild-type glioblastoma utilizing autologous activated T-cells armed with bispecific antibody (EGFR-BATs) that recognize the tumor. The investigators hypothesized that the combination of infusions of EGFR BATs and low-intensity focused ultrasound would induce blood-brain barrier opening and increase the permeability of the adoptive immunotherapy. The investigators will radiolabel the EGFR BATs with 89Zr-oxine for subsequent PET imaging to determine the trafficking and uptake of this approach. There is a concern that several infusions of EGFR BATs before BBB opening could change the immune tumor microenvironment that would not allow a permissive BBB after LIFU. Therefore, Arm A will have two LIFU with BBB opening after the 4th and the 8th infusion, and Arm B will have three LIFU with BBB opening after the 1st, 4th, and 8th infusions. This study will determine the safety and feasibility of the combination of low-intensity focused ultrasound (LIFU) with microbubbles BBB opening and EGFR BATs and the access of the adoptive cell immunotherapy to the tumor microenvironment to inform future studies.

Conditions

Glioblastoma (GBM)

Keywords

Focused Ultrasound; Unmethylated; Immune Therapy

Outcome Measures

Primary Outcomes (4)

• The safety of this treatment will be evaluated through the number of participants experiencing Grade ≥3 dose-limiting toxicities (DLTs).

  The safety will be evaluated by determining the number of participants who experience Grade ≥3 DLTs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 during EGFR BAT and LIFU BBB opening after RT/TMZ. The scale displays Grades 1 through 5 and refers to the severity of the AE. A higher grade (e.g., 5) represents a worse outcome.

  8 weeks

• The feasibility of this treatment will be determined by the proportion of participants achieving ≥75% of the recommended EGFR BATs dose

  The feasibility of this treatment will be determined by calculating the proportion of participants achieving ≥75% (60 x 10\^9 EGFR BATs) of the recommended Phase II EGFR BAT dose.

  8 weeks

• Incidence and severity of treatment-emergent adverse events (AEs) based on physical examination, vital signs, laboratory parameters, serum chemistry and hematology

  Safety will be quantified using AE counts and severity grading per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Physical examinations, vital signs, and laboratory studies will be recorded.

  8 weeks

• Brain uptake of 89Zr-oxine-labeled EGFR BATs measured by PET standardized uptake values (SUV) with and without LIFU BBB opening

  Three PET imaging scans will be taken to quantify trafficking of labeled EGFR BATs into the GBM microenvironment. PET signal (SUV) will be compared across time points and between LIFU BBB-opened and non-opened regions.

  8 weeks

Secondary Outcomes (12)

• Change from baseline in peripheral immune response markers (CTL cytotoxicity)

  8 weeks

• Change from baseline in peripheral immune response markers (IFN-γ ELISpot Counts)

  8 weeks

• Change from baseline in peripheral immune response markers (Th1/Th2 serum cytokine concentrations)

  8 weeks

• PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment after infusions and Low Intensity Focused Ultrasound (LIFU).

  8 weeks

• PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment with versus without Low Intensity Focused Ultrasound (LIFU).

  8 weeks

Study Arms (2)

Arm A

ACTIVE COMPARATOR

Arm A will have Low-Intensity Focused Ultrasound (LIFU) after infusions 4 and 8.

Drug: anti-EGFR bispecific-armed T cells; Device: Low-Intensity Focused Ultrasound

Arm B

ACTIVE COMPARATOR

Arm B will have Low-Intensity Focused Ultrasound (LIFU) after infusions 1, 4 and 8.

Drug: anti-EGFR bispecific-armed T cells; Device: Low-Intensity Focused Ultrasound

Interventions

anti-EGFR bispecific-armed T cells DRUG

IN PROGRESS

Also known as: EGFR BATs

Arm A; Arm B

Low-Intensity Focused Ultrasound DEVICE

Low-Intensity Focused Ultrasound will be used to open the blood-brain barrier

Also known as: LIFU

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed supratentorial glioblastoma or gliosarcoma IDH wildtype and MGMT unmethylated that express EGFR (score ≥ 1 by IHC)) and confirmed by UVA pathology review.
• Age ≥ 18 and ≤ 70 years at the time of signing informed consent.
• Karnofsky Performance Status (KPS) ≥ 70.
• Be willing and able to provide written informed consent for the trial.
• Females of childbearing potential, and males, must be willing to use an effective method of contraception.
• Maximal surgical debulking of the tumor was performed where residual contrast enhancement is 2 cm3 or less on immediate post-operative MRI. Intraoperative post-resection MRI is acceptable.
• Able to communicate during the LIFU BBB opening procedure.
• BBB opening target(s) must lie in non-eloquent area(s).
• The brain tumor to be treated must be in the treatment envelope of the NaviFUS system with a minimum distance of 30 mm from the inner skull table.
• Females of childbearing potential should have a negative serum pregnancy test. Males who are partners of females of childbearing potential must agree to use an acceptable method of contraception throughout the study and for 1 month following completion of the EGFR BATs infusions.
• Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days before leukapheresis.

You may not qualify if:

• Patients with a diagnosis of another malignancy within 2 years of being on-study. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or any type of in situ cancer. Patients must not be on any treatment for another malignancy.
• Patients undergoing only biopsy (partial resection or greater is required).
• Patients with cerebellar or brainstem tumors.
• Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
• Patients with extracranial metastases.
• Patients with evidence of acute intracranial hemorrhage.
• Known hypersensitivity to cetuximab or another EGFR antibody.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to Lumason® ultrasound contrast agent.
• Alpha 1,3 Galactose IgE ("alpha gal") test result outside of the reference range (indicating likely hypersensitivity to cetuximab).
• Patients with claustrophobia.
• Clips, shunts, or other non-MRI compatible metallic implanted objects in the skull or the brain.
• Evidence of active bleeding or bleeding diathesis.
• Unable to discontinue use of anticoagulant therapy as per local standard.
• Scalp atrophy or scars in the expected location of the ultrasound transducer.

Sponsors & Collaborators

• University of Virginia: lead
• Focused Ultrasound Foundation: collaborator
• NaviFUS Corporation: collaborator

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22903, United States

RECRUITING

Related Publications (1)

• Fadul CE, Thakur A, Kim J, Kassay-McAllister J, Schalk D, Lopes MB, Donahue J, Purow B, Dillon P, Le T, Schiff D, Liu Q, Lum LG. Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide. J Neurooncol. 2024 Jan;166(2):321-330. doi: 10.1007/s11060-024-04564-y. Epub 2024 Jan 23.

  PMID: 38263486 BACKGROUND

MeSH Terms

Conditions

Glioblastoma

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

Study Officials

• Camilo Fadul, M.D.

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bettina Wagner, B.A.

CONTACT

434-243-7336; WXQ9ET@uvahealth.org

CJ Woodburn, B.S.

CONTACT

434-243-9900; CJW4V@uvahealth.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Joan and Ronald Butcher, Professor of Neurology

Study Record Dates

• First Submitted: November 25, 2025
• First Posted: January 15, 2026
• Study Start: March 23, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: May 6, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)