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

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) \<13), or signs of intracranial hypertension.

4. Operability and Location:

   • Target Tumor is deemed operable by the neurosurgeon and is located in a non-eloquent area (e.g., excluding brainstem or regions associated with critical motor or speech function).
   • Tumor must be located in the cortical or subcortical regions, at least 20 mm beneath the inner skull surface to ensure accessibility to the TheraOne intervention.

5. In case of brain metastasis, extracerebral disease must be absent or at least controlled, defined as:

   • A Positron Emission Tomography (PET) scan performed within 6 weeks showing resolution of hyperintensity, or
   • Stable disease on two consecutive imaging assessments
   • And oligometastatic state, defined as ≤3 extracerebral lesions.
6. Blood Pressure Stability : Systolic ≤180 mmHg, Diastolic ≤100 mmHg at screening.

7. Coagulation Stability :

   • Platelets ≥80.10 9 /L
   • Prothrombin time (PT) ≤14 sec
   • Partial thromboplastin time (PTT) ≤36 sec
   • International Normalized Ratio (INR) ≤1.3

8. Prior and ongoing treatments

   • Prior systemic anticancer treatments are allowed provided that all the following conditions are met:

     • The patient has a clinically stable neurological status at inclusion.
     • There is no ongoing ≥ Grade 2 neurological toxicity attributable to prior or ongoing systemic treatment.
     • Corticosteroid dose is stable or decreasing for at least 7 days prior to inclusion.

   • The following minimum wash-out periods prior to sonication must be respected:

     • Immunotherapy (anti-PD-1, anti-PD-L1, anti-CTLA-4): ≥ 7 days before sonication.
     • Nitrosourea-containing chemotherapy (BCNU, CCNU): ≥ 6 weeks before sonication.
     • Targeted therapies - lung cancer (EGFR, ALK, ROS1, MET TKIs): Wash-out corresponding to 5 terminal half-lives, capped at a maximum of 7 days, provided neurological stability and absence of recent treatment initiation or dose escalation.
     • Targeted therapies - melanoma (BRAF and/or MEK inhibitors): A short pragmatic wash-out of approximately 5-7 days, not strictly based on pharmacokinetic half-life, may be applied provided neurological status is stable and no ≥ Grade 2 neurological toxicity is present.
     • Anti-angiogenic therapy (bevacizumab):

   A minimum interval of 7 days prior to sonication is required.

   • Antibody-drug conjugates (ADCs): A wash-out of 7 days prior to sonication is required. ADC treatment must be ongoing (not recently initiated), with no ≥ Grade 2 toxicity, particularly neurological or hematological.

   • Antiplatelet and anticoagulant agents: Must be discontinued according to the following minimum intervals prior to sonication:

     • antiplatelet agents: ≥ 7 days
     • vitamin K antagonists: ≥ 7 days
     • direct oral anticoagulants (NOACs): ≥ 72 hours

     • heparin-derived compounds: ≥ 48 hours

       • Prior brain radiotherapy is allowed provided it was completed ≥ 12 weeks before sonication
9. Renal Function: Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m².
10. MRI \& CT Compatibility: Patient must be able to complete high-density CT and MRI studies, including contrast-enhanced imaging.

11. Procedure Feasibility :

    • Willingness to undergo partial head shaving to allow proper ultrasound transmission
    • Ability to maintain stable seated position during procedure.
12. Negative Serum Pregnancy Test (within 7 days before first treatment) for women of childbearing potential.
13. Contraceptive Use: Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective (\<1% failure rate per year) approved contraceptive method during procedure and for 6 months post- procedure. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
14. Signed Informed Consent Form.
15. Patients must be affiliated or beneficiary to a social security system

Exclusion Criteria:

1. Tumor-Related Exclusions:

   • Tumor imaging features suggestive of:

     • Acute mass effect with ≥5 mm midline shift or basal cistern effacement.
     • Severe peritumoral edema causing acute intracranial hypertension or compression of critical structures.
     • Hemorrhagic transformation or necrosis with a high risk of rupture.

   • Tumor morphology or imaging findings that preclude the ability to sonicate the tumor volume, including:

     • Significant tumor volume outside the treatment envelope.
     • Tumor volume exceeding the maximum allowed sonication volume (currently 110 ccs at the treatment volume level).
     • Concerns about adequate tumor coverage by sonication based on tumor morphology should be discussed with the Sponsor.

2. Vascular \& Hemorrhagic Conditions:

   • Cerebrovascular disease history:

     • Untreated arteriovenous malformation (AVM).
     • Untreated or unstable cerebral aneurysm.

   • Acute hemorrhage or cystic lesions:

     • Evidence of acute intracranial hemorrhage.
     • Presence of a cyst within the region of interest (ROI).

   • MRI or clinical findings of:

     • Active or chronic infections/inflammatory processes.
     • Acute or chronic hemorrhages, lobar microbleeds, siderosis, amyloid angiopathy, or macro-hemorrhages.
     • Intracranial thrombosis, vascular malformation, cerebral aneurysm, or vasculitis.

3. Cardiovascular \& Systemic Conditions:

   • Unstable cardiac disease or hemodynamic status.
   • Uncontrolled severe hypertension (systolic >180 mmHg, diastolic >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 \<80,000 109/L, PT >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.