Preliminary Clinical Feasibility Study of a Medical Device Enabling Brain Access Using Microbubble-Enhanced Sonication

CAMPSIS is a preliminary feasibility study of the TheraOne medical device (IIb). TheraOne is an active, non-invasive medical device intended to deliver transcranial FUS in combination with intravenous microbubbles in order to transiently and locally induce the BBB permeability. This study aims to evaluate the safety of cerebral sonication (TheraOne) in the management of patients with recurrent grade 4 glioma (wild-type IDH, technically resectable) or brain metastases originating from an extracranial solid tumor. Patients enrolled in the study will undergo a single sonication session during a protocol visit and will be monitored for up to 30 days after the sonication through the various scheduled protocol visits. Blood samples will be collected at the start of the study, during the sonication, and during the post-sonication follow-up visit for all patients enrolled in the study.

Inclusion Criteria: 1. Age: ≥18 years old. 2. Performance Status: Karnofsky Performance Score (KPS) ≥ 70%. 3. Tumor Characteristics: 1. Patient with an expansive intra-cerebral tumor showing enhancement after gadolinium injection on MRI (T1-weighted images, with and without gadolinium contrast). 2. Tumor radiologically classified as: * Recurrent High-Grade glioma (excluding prosthetic material), or a brain metastasis from extracranial solid primary. * Measuring at least 25-30 mm in the longest axis. * In both cases, Surgery is not required as a first-line option. However, the target lesion must be considered technically operable (non-eloquent location) 3. In the case of brain metastases, multifocal disease is allowed, provided that additional metastases are smaller to 20 mm, not neurologically threatening, and do not require surgery. Cases of leptomeningeal invasion are not allowed. 4. Tumor should not exhibit signs of rapid progression or acute neurological compromise requiring urgent intervention. Rapid progression is defined as a ≥25% increase in contrast-enhancing tumor volume within 4 weeks, associated with mass effect or new edema. Acute neurological compromise includes any newly developed or worsening neurological deficit (e.g., motor weakness, aphasia), seizures refractory to antiepileptics, decreased level of consciousness (Glasgow Coma Scale (GCS) \100 mmHg). 4. Anticoagulation \& Bleeding Risks: * Use of medications that increase bleeding risk: * Antiplatelet agents (e.g., aspirin, clopidogrel) within 7 days prior to treatment. * Anticoagulants (e.g., warfarin, dabigatran, apixaban, heparin) within specified washout periods: * Oral vitamin K inhibitors: 7 days * Non-Vitamin K antagonist oral anticoagulants (NOACs) (e.g., rivaroxaban, apixaban): 72 hours * Heparin-derived compounds: 48 hours * Abnormal coagulation profile: Platelets \14, PTT \>36, INR \>1.3. * History of bleeding disorder, coagulopathy, or spontaneous hemorrhage. 5. Neurological \& Psychiatric Conditions: * Active seizures (\>1 per week) despite medication, as BBB opening could worsen seizures. * Active drug/alcohol disorder, increasing seizure, infection, or compliance risks. * Known positive Human Immunodeficiency Virus (HIV) status, which may increase BBB permeability and lead to encephalitis. * Potential blood-borne infections that could increase risk of meningitis or brain abscess. 6. Prior treatments incompatible with study participation * Any immunotherapy administered within 7 days prior to sonication. * Any nitrosourea-containing chemotherapy administered within 6 weeks prior to sonication. * Any targeted therapy not meeting the wash-out and stability criteria described above. * Any antibody-drug conjugate administered within 7 days prior to sonication or associated with ongoing ≥ Grade 2 toxicity. * Any experimental therapy or investigational medicinal product not discontinued ≥ 30 days prior to sonication. * Brain radiotherapy completed \< 12 weeks prior to sonication 7. Imaging \& Gadolinium Contraindications: * Severe claustrophobia or inability to remain supine for 2 hours. * Body habitus incompatible with CT or MRI scanner limits * Known allergy(ies) or hypersensitivity to gadolinium contrast agents. * MRI-incompatible implanted device (e.g., pacemaker, defibrillatore, cochlear implant) * Ferromagnetic foreign body 8. Contraindications to Microbubble Use: * Hypersensitivity to sulfur hexafluoride microbubbles or any excipient * History of severe allergic reactions (anaphylaxis) to contrast agents. * Right-to-left cardiac shunt or embolization risk. * Severe pulmonary hypertension or unstable cardiac conditions (e.g. unstable ischemic heart disease, acute coronary syndrome within the previous 30 days). * Uncontrolled systemic hypertension, * Adult respiratory distress syndrome (ARDS) * Any SmPC-listed contraindication 9. Contraindications/ constraints from associated non-experimental devices : * Ultrasound gel : * Known hypersensitivity to any component of the ultrasound gel used during the procedure * Cervical collar (PATRIOT) , contraindications per IFU * Compromised airway, * Known severe spinal deformity (e.g., ankylosing spondylitis), * Penetrating trauma injuries (cervical). * Positionning chair : * Inability to maintain a stable seated position for the duration of the procedure. 10. Other Procedure-Related Exclusions: * Presence of metallic implants (e.g., clips in skull/brain) interfering with sonication. * Scalp infection at target site 11. Psychological, Social \& Legal Factors: * Mental health disorders or social/geographical barriers that could affect CI compliance. * Patients under legal protection, guardianship, or deprived of liberty. 12. Pregnancy \& Breastfeeding: * Pregnant or breastfeeding women, or those planning pregnancy during the CI and 6 months after.