Focused Ultrasound Blood-Brain Barrier Opening in Pontine Diffuse Midline Glioma to Enhance Temozolomide Therapy: Pilot Feasibility Study (FIDES)

Official title

Focused Ultrasound-mediated Blood-Brain Barrier Opening In Pontine Diffuse Midline Glioma (DMG) to Enhance Systemic Therapy With Temozolomide (FIDES) - an Exploratory Pilot and Feasibility Trial

Overview

This study is for people (children and adults) with a rare and aggressive brain tumor called H3K27-altered diffuse midline glioma (DMG) located in the pons, a deep part of the brainstem. These tumors are very difficult to treat because they grow into surrounding brain tissue and cannot be fully removed with surgery. Most patients currently survive less than one year after diagnosis, and treatment options are limited. Current standard treatment The usual treatment is radiotherapy, sometimes combined with a chemotherapy drug called temozolomide (TMZ). This combination may slightly improve outcomes, but it is often not very effective for tumors in the pons. One possible reason is that the blood-brain barrier (BBB)-a natural protective filter in the brain-may be especially strong in this area, making it harder for medicines to reach the tumor. What this study is testing This study is exploring a new approach to help chemotherapy reach the tumor more effectively. It uses MRI-guided focused ultrasound (with the Exablate system) to temporarily and safely open the blood-brain barrier in the tumor area. This may allow more temozolomide to enter the tumor. Study goal The main goal is to find out: * Whether this technique is safe * Whether it may help slow tumor growth or extend survival Who can join * Adults and children aged 4 years and older * Diagnosed with H3K27-altered pontine DMG * Eligible for temozolomide after completing radiation therapy The study will include 20 participants (about half children and half adults). What participants will do Participants will: * Receive 6 cycles of temozolomide chemotherapy * Undergo focused ultrasound blood-brain barrier opening on the first day of each cycle * Have regular MRI scans and check-ups to monitor safety and tumor response Each treatment cycle includes 5 days of chemotherapy followed by a rest period of 23 days. What the study is measuring Researchers will look at: * Safety of the procedure and device * How long patients live without tumor progression (progression-free survival) * Overall survival * Tumor response to treatment * Whether the procedure is practical to use in clinical care They will also compare results to data from previous patients in international brain tumor registries. Why this study matters This study is testing whether temporarily opening the brain's natural barrier can help chemotherapy work better in a type of brain tumor that currently has very limited treatment options.

Interventions

• Device Focused Ultrasound (FUS) Blood-Brain Barrier Opening
  FUS-BBB opening involves the application of acoustic energy at low frequencies from over 1000 individual transducers to induce localized and temporary blood-brain barrier disruption in patients. FUS-BBBO will be applied during each temozolomide cycle.
• Drug Temozolomide (TMZ)
  Patients will undergo six standard-of-care cycles of temozolomide maintenance therapy. Each cycle will be combined with FUS-BBBO.

Primary outcome measures

• Device and procedure related adverse events [Time frame: Up to 72 hours after each Exablate BBBO procedure]
• 6-month progression-free survival (PFS6) [Time frame: From date of diagnosis until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.]

Eligibility criteria

Inclusion criteria

• Age ≥ 4 years.
• Histologically/molecularly verified de novo pontine H3K27-altered diffuse midline glioma.
• Main localization ('center of mass') in the brainstem. NB: some degree of extension beyond the brainstem, e.g. cerebellar peduncles, is allowed.
• Karnofsky Performance Score (KPS) or Lansky Performance Score (LPS) of ≥ 70/ KPS or LPS 60 and WHO/ECOG performance status ≤ 2.
• ASA-score of I-III.
• Intention to treat with (TMZ chemo-) radiation and maintenance TMZ as per consensus of the local multidisciplinary tumor board.
• Feasible to schedule the first Exablate BBBO procedure preferably within 4-6 weeks, acceptably within 12 weeks, after successful completion of radiotherapy/ concomitant TMZ-chemoradiation, defined as completed treatment as planned without reported CTCAEv6.0 grade 3-4 toxicities or, in case of reported CTCAEv6.0 grade 3-4 toxicities, the toxicities must be resolved to grade 2 prior to inclusion.
• If on steroids, stable or decreasing dose for at least 7 days prior to inclusion.
• Able to attend all study visits.
• Able and willing to give informed consent or have a legal guardian who is able and willing to do so.

Exclusion criteria

• Previous or ongoing participation in other clinical trials with other than standard-of-care tumor-directed treatment(s) for H3K27-altered DMG.
• Multifocal or leptomeningeal metastasized disease. Multifocal disease is defined as multiple FLAIR-hyperintense lesions, separated by normal-appearing brain tissue, with or without gadolinium enhancement. Multiple enhancing regions within one continuous FLAIR lesion can be considered as unifocal disease.
• Signs/symptoms of elevated intracranial pressure (ICP) (e.g. headache, vomiting, impaired vision/papilledema, impaired consciousness), with corresponding radiographic findings on MRI at time of screening.
• Severe dysphagia with feeding tube dependency.
• Evidence of acute clinically significant intracranial hemorrhage. NB: minimal hemorrhagic foci without obvious related clinical symptoms will not serve as grounds for exclusion.
• Tumor not visible on any pre-therapy or post-radiation imaging.
• Presence of extracranial / intracranial structures (e.g. metal prostheses, implants, calcifications) on pre-treatment CT-scan/ MRI-scan, significantly interfering with acoustic impedance as per judgement of the researchers.
• Known co-occurring other malignancy that is progressing or has required active treatment within the past 3 years, with exception of: carcinomas in situ (CIS) and non-melanoma skin cancers.
• Patients with right-to-left, bi-directional or transient right-to-left cardiac shunts.
• Known LVEF < 40 or unstable hemodynamics.
• Severe hypertension, not adequately controlled with study compatible medication (Adults: RR systolic >180 and/ or RR diastolic >100; Children: >p95 + 12mmHg).
• History of bleeding disorder and/or coagulopathy.
• Treatment with anti-coagulant therapy.
• Severely impaired renal function; creatinine clearance <30 mL/ min.
• Subjects with significant liver dysfunction; Child Pugh classification C.
• Known diagnosis of active or untreated hepatitis B, hepatitis C, tuberculosis.
• Any other illness or medical condition that in the investigator's opinion precludes participation in this study.
• Pregnant or lactating women.
• Expected uncontrollable therapy non-compliance/ non-cooperation that is likely to interfere with the study procedure, as per judgement of the investigators.
• Head circumference ≤ 49 cm.
• Weight ≥ 135 kg.
• Patient ≥ 18 years old, who requires general anesthesia to undergo the Exablate BBBO procedure.
• Contra-indication for MRI procedures.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to the resonator agent (perflutren; Luminity®).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 2 centers

• Princess Maxima Center for pediatric oncology — Utrecht
• UMC Utrecht — Utrecht

Identifiers

NCT: NCT07562971 · UMC_Utrecht · 2025-520814-78-00 · NL-009201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗