NgFUS NIVO: NeuroNavigation-Guided Focused Ultrasound With Nivolumab in Relapsed and Progressive DMG and Other High Grade Brain Tumors

A Safety and Feasibility Study of NeuroNavigation-Guided Low Intensity Focused Ultrasound With Microbubbles to Enhance Nivolumab Delivery for the Treatment of Relapsed and Progressive Diffuse Midline Glioma and Other High Grade Brain Tumors

This is an open-label phase 1 safety and feasibility study evaluating a novel combination therapy for progressive and relapsed diffuse midline glioma (DMG) and other progressive and relapsed high-grade brain tumors. This study combines intravenous nivolumab therapy infused following transient blood-brain barrier opening (BBBO) using low-intensity focused ultrasound with microbubble (LIFU-MB) treatment using NeuroNavigation-Guided Focused Ultrasound (NgFUS).

There are two groups in this study:

• Group A: Patients with relapsed or progressive diffuse midline glioma in the brainstem
• Group B: Patients with relapsed or progressive high grade brain tumor that clinically require surgical resection

The primary outcome is to evaluate the safety and feasibility of 3 cycles of nivolumab with BBB disruption using NgFUS with microbubbles in pediatric patients with progressive or relapsed brainstem DMG or with high grade brain tumors after surgery. Secondary outcomes include preliminary efficacy and immunological effects.

Study Overview

• Status: Not yet recruiting
• Conditions: Medulloblastoma Recurrent; Ependymoma Recurrent; Brain Tumor Recurrent; High Grade Gliomas; Atypical Teratoid/Rhabdoid Tumor (ATRT) of the CNS; Diffuse Midline Glioma or Diffuse Intrinsic Pontine Glioma
• Intervention / Treatment: Device: NeuroNavigation-Guided Focused Ultrasound (NgFUS); Drug: Lumason; Drug: Nivolumab

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Julia Batarseh; Phone Number: 202-476-5578; Email: jamore@childrensnational.org
• Study Contact Backup: Name: Elizabeth Paronett; Phone Number: 202-476-8907; Email: eparonett@childrensnational.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 3 and ≤ 25 years.

• Diagnosis of brainstem DMG/DIPG or any high-grade brain tumor.

  • Group A: Relapsed or progressive brainstem DMG.
  • Group B: Relapsed or progressive high-grade intracranial brain tumor requiring surgical resection.
• Lansky/Karnofsky rating ≥ 60.
• Patients must have received at least one line of prior therapy upfront for their disease.
• At least four weeks from radiation therapy, prior immunotherapy, or monoclonal antibody therapy.
• At least 2 weeks from prior myelosuppressive chemotherapy and post nadir meeting organ function criteria.
• At least 1 week or 5 half-lives (whichever is longer) from last targeted therapy.
• If on steroids, stable or decreasing dose for at least 7 days prior to study entry and ≤ 0.4 mg/m2/day of dexamethasone or equivalent.
• Stable or improving neurological status for 7 days prior to study entry.

• Organ function:

  • Absolute Neutrophil Count (ANC) ≥750/μL.
  • Absolute Lymphocyte Count (ALC) >500/μL.
  • Platelets ≥75K, unsupported.
  • Coagulation studies: PT and PTT <1.5 ULN and INR (<1.5).
  • Bilirubin ≤1.5x upper limit of normal (ULN).
  • AST/ALT ≤5x ULN.
  • Serum creatinine within normal limits for age.
  • Pulse oximetry >93% on room air.
  • Ejection Fraction (EF) above institutional lower limit of normal (LLN).
• For females of childbearing potential (FOCBP): negative pregnancy test within 7 days of study entry.
• Patients of childbearing or child-fathering potential must agree to use contraceptive measures for at least 5 months following nivolumab infusion.
• Patient or parent/guardian capable of providing informed consent.

Exclusion Criteria:

• Symptoms and signs of increased intracranial pressure.
• Patients with metallic ventricular peritoneal shunts. Subjects with nonmetallic VP shunts or similar will have a technical evaluation of the screening non-contrast CT scan of the head. During the mapping of the target area, if the technical NaviFUS specialist determines that the patient cannot be treated within the safety limits of the system, the patient will not be eligible and will be considered a screen failure.

• Tumor presenting with the following imaging characteristics:

  • Evidence of uncal herniation.
  • Edema and/or mass effect that causes hydrocephalus.
  • Significant areas of necrosis within the tumor that the neurosurgeon feels cannot be avoided during the ultrasound sonication.
  • Evidence of a significant new hemorrhage. Area of microhemorrhage (defined as less than 5 mm in diameter) in the treatment area can be acceptable but requires the review of the neurosurgeon.
  • Containing calcifications in the focused ultrasound sonication beam path and system tools cannot tailor the treatment around these calcification spots.
  • Patients who are deemed to have overly bulky tumor by the PI of the study.

• The sonication pathway to the tumor involves:

  • More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp.
  • Clips, or other non-MRI compatible metallic implanted objects in the skull or the brain, except for shunts.
• Patients receiving anti-coagulant therapy, or medications known to increase risk of hemorrhage, (e.g., ASA, non-steroidal anti-inflammatory drugs [NSAIDs], statins). There is no required washout for eligibility assessment, but patients should be off agents for at least 3 days at the time of procedure or until 5 half-lives of the agent, whichever is longer.
• History of a bleeding disorder, coagulopathy or with a history of clinically significant spontaneous tumor hemorrhage.
• Cerebral or systemic vasculopathy, including intracranial thrombosis, vascular malformation, cerebral aneurysm, or vasculitis.
• Immunosuppression (corticosteroids to prevent/treat brain edema are permitted).
• Patients with uncontrolled HIV.
• Active seizure disorder or epilepsy (clinically significant seizures despite medical treatment) within four weeks prior to first cycle/NaviFUS BBBO procedure captured by history.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to Lumason® ultrasound contrast agent or known hypersensitivity to sulphur hexafluoride microsphere or its components, e.g., polyethylene glycol.
• Patients unable to fit comfortably into the MRI scanner (generally >250 lbs.).
• Evidence of cranial or systemic infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Patients with relapsed or progressive diffuse midline glioma in the brainstem; Patients with relapsed or progressive diffuse midline glioma in the brainstem, receiving nivolumab with NgFUS either every 2 weeks or every 4 weeks.	Device: NeuroNavigation-Guided Focused Ultrasound (NgFUS); NeuroNavigation-Guided Focused Ultrasound, every 2 or 4 weeks for 3 cycles of 28 days; Drug: Lumason; Lumason is a sulfur hexafluoride microsphere ultrasound contrast agent which will be used as a mechanical resonator. Lumason will be given in combination with NgFUS every 2 or 4 weeks for 3 cycles of 28 days.; Drug: Nivolumab; Nivolumab is a monoclonal antibody targeting the immune checkpoint axis PD-1/PD-L1. Nivolumab will be given prior to NgFUS with microbubbles (Lumason) every 2 or 4 weeks for 3 cycles of 28 days.
Experimental: Group B: Patients with relapsed or progressive high grade brain tumors requiring surgical resection; Patients with relapsed or progressive high grade brain tumors that clinically require surgical resection, receiving one dose of NgFUS prior to surgery, and nivolumab with NgFUS every 4 weeks following recovery from surgery.	Device: NeuroNavigation-Guided Focused Ultrasound (NgFUS); NeuroNavigation-Guided Focused Ultrasound, every 2 or 4 weeks for 3 cycles of 28 days; Drug: Lumason; Lumason is a sulfur hexafluoride microsphere ultrasound contrast agent which will be used as a mechanical resonator. Lumason will be given in combination with NgFUS every 2 or 4 weeks for 3 cycles of 28 days.; Drug: Nivolumab; Nivolumab is a monoclonal antibody targeting the immune checkpoint axis PD-1/PD-L1. Nivolumab will be given prior to NgFUS with microbubbles (Lumason) every 2 or 4 weeks for 3 cycles of 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLT) as assessed by CTCAE v6.0.	Safety will be evaluated by the incidence of DLTs. DLT is defined as toxicities which are at least possibly related to treatment and meeting protocol-specified criteria for grade, duration, severity, and/or delay of subsequent treatment cycles. If the overall toxicity rate exceeds protocol-specified criteria, enrollment will be halted and the study will be amended to modify the treatment plan.	First treatment through 28 days post-first treatment.
Percentage of patients completing at least two cycles of planned therapy	Treatment will be determined feasible if at least 80% of enrolled patients complete at least 2 cycles of planned therapy. Feasibility will be assessed separately for each cohort.	Enrollment through end of Cycle 2 (each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response assessment per RAPNO.	Overall response assessment: complete response (CR), partial response (PR), minor response (MR), stable disease (SD), or progressive disease (PD) following treatment, will be assessed based on the Response Assessment in Pediatric Neuro-Oncology (RAPNO) scale.	From screening through 1 year post-final treatment.
Progression-free survival (PFS)	PFS is defined as the interval of time between the date of protocol treatment initiation and the earliest date of documentation of progressive disease, or second malignancy or death (for any reason) for patients who fail, or to date of last contact or initiation of other therapy for patients who remain at risk of failure.	From enrollment through up to 2 years post-final treatment.
Overall survival (OS)	OS post nivolumab infusion will be analyzed by the Kaplan-Meier method.	From enrollment through up to 2 years post-final treatment.

Other Outcome Measures

Outcome Measure	Time Frame
Tissue expression of PD-1 and PD-L1	From enrollment through immediately after surgery.
Lymphocyte counts according to FUS area treated	From enrollment through 3 months post-final treatment.
Immunologic correlates	Pre- and post-procedure starting from enrollment through immediately after the final treatment (Cycle 3 Day 0 for Q4Week Group A and Group B, or Cycle 3 Day 14 for Q2Week Group A).
Immunohistochemistry for PD1/PDL1	From enrollment through immediately after surgery.
Immunostaining for lymphocytes	From enrollment through immediately after surgery.
Increase of areas (measured in percentage) of contrast enhancement on T1-gadolinium MRI sequences obtained immediately following BBB disruption.	From enrollment through 36 hours after the final treatment (Cycle 3 Day 0 for Q4Week Group A and Group B, or Cycle 3 Day 14 for Q2Week Group A).

Collaborators and Investigators

• Sponsor: Children's National Research Institute

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: May 20, 2026
• First Submitted That Met QC Criteria: June 17, 2026
• First Posted (Actual): June 24, 2026

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Nivolumab; High Grade Glioma; HGG; Pediatrics; DIPG; Focused Ultrasound; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; DMG
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms, Complex and Mixed; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioma; Brain Neoplasms; Rhabdoid Tumor; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab
• Other Study ID Numbers: STUDY00001735

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes