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

Prior treatment

• Previous or ongoing participation in other clinical trials with other than standard-of-care tumor-directed treatment(s) for H3K27-altered DMG.
• Treatment with anti-coagulant therapy.
• Expected uncontrollable therapy non-compliance/ non-cooperation that is likely to interfere with the study procedure, as per judgement of the investigators.
• 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.

Other illness

• 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.
• 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.
• 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.
• Evidence of acute clinically significant intracranial hemorrhage. NB: minimal hemorrhagic foci without obvious related clinical symptoms will not serve as grounds for exclusion.
• 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.

Lab values

• Known LVEF < 40 or unstable hemodynamics.
• Severely impaired renal function; creatinine clearance <30 mL/ min.

Age

• Patient ≥ 18 years old, who requires general anesthesia to undergo the Exablate BBBO procedure.

Other

• Subjects with significant liver dysfunction; Child Pugh classification C.
• Pregnant or lactating women.
• Head circumference ≤ 49 cm.
• Weight ≥ 135 kg.
• Contra-indication for MRI procedures.
• Known sensitivity to gadolinium-based contrast agents.
• Known sensitivity to the resonator agent (perflutren; Luminity®/Definity®).
• 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.

• Age ≥ 4 years.
• 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.
• 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.