FIDES: Focused Ultrasound-mediated Blood-Brain Barrier Opening In Pontine Diffuse Midline Glioma (DMG) to Enhance Systemic Therapy with Temozolomide – an exploratory pilot and feasibility trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Utrecht

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-03-23

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Hersenstichting

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the safety of the Exablate-BBBO procedure and device in patients with H3K27-altered pontine DMG receiving TMZ.
To determine the 6-month progression-free survival (PFS6) in patients with H3K27-altered pontine DMG treated with Exablate BBBO to TMZ maintenance therapy.

Secondary objectives 5

1. To determine whether addition of Exablate BBBO to TMZ maintenance therapy results in an improved progression-free survival (PFS) in patients with H3K27-altered pontine DMG.
2. To determine whether addition of Exablate BBBO to TMZ maintenance therapy results in improved overall survival (OS) in patients with H3K27-altered pontine DMG.
3. To determine whether addition of Exablate BBBO to TMZ maintenance therapy results in improved radiological response rate according to the response assessment in neuro-oncology criteria (RANO and RAPNO criteria) in patients with H3K27-altered pontine DMG.
4. To assess feasibility of repeated Exablate BBBO, as evaluated by T1 weighted contrast-enhanced magnetic resonance (MR) imaging.
5. To evaluate the safety of the Exablate-BBBO procedure and device per cycle in patients with H3K27-altered pontine DMG receiving TMZ.

Conditions and MedDRA coding

Diffuse Midline Glioma, H3K27-altered

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age ≥ 4 years.
2. Able and willing to give informed consent or have a legal guardian who is able and willing to do so.
3. Histologically/molecularly verified de novo pontine H3K27-altered diffuse midline glioma.
4. Main localization (‘center of mass’) in the brainstem. NB: some degree of extension beyond the brainstem, e.g. cerebellar peduncles, is allowed.
5. Karnofsky Performance Score (KPS) or Lansky Performance Score (LPS) of ≥ 70/ KPS or LPS 60 and WHO/ECOG performance status ≤ 2.
6. ASA-score of I-III.
7. Intention to treat with (TMZ chemo-) radiation and maintenance TMZ as per consensus of the local multidisciplinary tumor board.
8. 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.
9. If on steroids, stable or decreasing dose for at least 7 days prior to inclusion.
10. Able to attend all study visits.

Exclusion criteria 25

1. Previous or ongoing participation in other clinical trials with other than standard-of-care tumor-directed treatment(s) for H3K27-altered DMG.
2. 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.
3. 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.
4. Severe dysphagia with feeding tube dependency.
5. Evidence of acute clinically significant intracranial hemorrhage. NB: minimal hemorrhagic foci without obvious related clinical symptoms will not serve as grounds for exclusion.
6. Tumor not visible on any pre-therapy or post-radiation imaging.
7. 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.
8. 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.
9. Patients with right-to-left, bi-directional or transient right-to-left cardiac shunts.
10. Known LVEF < 40 or unstable hemodynamics.
11. Severe hypertension, not adequately controlled with study compatible medication (Adults: RR systolic >180 and/ or RR diastolic >100; Children: >p95 + 12mmHg).
12. History of bleeding disorder and/or coagulopathy.
13. Treatment with anti-coagulant therapy.
14. Severely impaired renal function; creatinine clearance <30 mL/ min.
15. Subjects with significant liver dysfunction; Child Pugh classification C.
16. Known diagnosis of active or untreated hepatitis B, hepatitis C, tuberculosis.
17. Any other illness or medical condition that in the investigator's opinion precludes participation in this study.
18. Pregnant or lactating women.
19. Expected uncontrollable therapy non-compliance/ non-cooperation that is likely to interfere with the study procedure, as per judgement of the investigators.
20. Head circumference ≤ 49 cm.
21. Weight ≥ 135 kg.
22. Patient ≥ 18 years old, who requires general anesthesia to undergo the Exablate BBBO procedure.
23. Contra-indication for MRI procedures.
24. Known sensitivity to gadolinium-based contrast agents.
25. Known sensitivity to the resonator agent (perflutren; Luminity®).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Any serious adverse events (SAE) related to the Exablate BBBO device- and procedure, classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
2. Proportion of patients alive and progression-free at 6 months, based on standardized imaging criteria (e.g., RANO or RAPNO for DMG).

Secondary endpoints 5

1. Time from diagnosis to disease progression or death, measured by standardized criteria (e.g., RANO/RAPNO).
2. Time from diagnosis to death from any cause.
3. Radiological response rate according to the response assessment in neuro-oncology criteria (RANO and RAPNO criteria)
4. Extent and consistency of BBB opening as confirmed by T1-weighted contrast-enhanced MRI after each Exablate BBBO session.
5. Incidence of adverse events (AE) over time related to the Exablate BBBO device- and procedure, classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 12

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Utrecht

Sponsor organisation

Universitair Medisch Centrum Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Dr. T.J. Snijders

Public contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Dr. T.J. Snijders

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications