In Situ Injection of Anti-angiogenics in Patients With Brain Arteriovenous Malformations Not Eligible for Exclusion Treatment

The main objective of this trial is to evaluate the tolerance of 3 escalating doses of an in situ intra-arterial injection of bevacizumab in patients with a brain arteriovenous malformation (bAVM) considered non-suitable for an exclusion treatment to determine the Maximum Tolerated Dose (MTD) using the Dose-Limiting Toxicity rate (DLT) at 30 days after the injection. The dose limiting toxicity (DLT) is defined as the occurrence within 30 days of the in-situ injection of bevacizumab of one of the following events: Symptomatic venous/arterial thromboembolic events (symptomatic pulmonary embolism, symptomatic deep venous thrombosis, symptomatic ischemic stroke related to an arterial occlusion); Severe cytopenia defined as follows: Anemia defined as hemoglobin (Hb) level less than 8.0 g/dL (grade ≥ III, according to the CTCAE v5.0, 2017) Thrombocytopenia < 50 G/L (grade ≥ III, according to the CTCAE v5.0, 2017), Neutropenia < 1000/μL (grade ≥ IV according to the CTCAE v5.0, 2017); hypertension grade ≥ III (CTCAE v5.0, 2017); symptomatic intracranial hemorrhage resulting in transcient or permanent neurological deficit; any bleeding requiring transfusion; leukoencephalopathy grade ≥ III (CTCAE v5.0, 2017); Onset of intractable seizures ≥ Grade III (CTCAE v5.0, 2017); thrombo-embolic complication during the endovascular procedure leading to permanent deficit or to death; Intracranial arterial perforation with the microcatheter or the microguide wire during the endovascular procedure resulting in severe symptomatic hemorrhage (disability or death); any other serious adverse reaction (any untoward medical occurrence in a subject, to whom the medicinal product is administered, and which have a causal relationship with this treatment) resulting in any disability or death.

The secondary objectives and endpoints are to evaluate 1) the tolerance of 3 escalating doses of an in situ intra-arterial injection of bevacizumab in patients with a bAVM considered non-suitable for an exclusion treatment up to 12 months of follow-up; 2) To evaluate the efficacy of an in situ intra-arterial injection of bevacizumab in patients with a bAVM considered non-suitable for an exclusion treatment in terms of :Nidus volume size reduction at 6 and 12 months, Occurrence of cerebral bleeding events up to 12 months, Occurrence of seizures up to 12 months

Inclusion criteria

• Age ≥18 and < 65 years at the time of inclusion
• bAVM (i.e.: located in the brain, brain stem or cerebellum)
• Spetzler-Martin grade IV - V on a brain MRI performed less than 2 months before inclusion
• History of rupture and/or with intractable symptoms related to the bAVM (i.e.: intractable seizure, steal phenomenon, compressive symptoms)
• bAVM deemed unsuitable for exclusion invasive treatment
• Adequate bone marrow function at inclusion :

• Hemoglobin (Hb) levels more than 13.5 g/dL in males and Hb levels more than 12.5 g/dL in females.
• Platelet count ≥ 150 G/L
• Leukocytes count ≥ 3000/μL
• Neutrophils count ≥ 1500/μL
• Normal liver function (alanine transaminase [ALT] < 56 UI/L and aspartate aminotransferase [AST] < 40 UI/L) at inclusion
• Normal renal function (creatinine clearance ≥ 30 ml/min calculated with the Cockcroft-Gault formula) at inclusion
• Complete COVID-19 vaccinal scheme, according to the French recommendations
• Affiliation to French Healthcare system (AME excluded)
• Signed informed consent

Exclusion criteria

• Diffuse bAVM (like proliferative angiopathy) that cannot be assessed in terms of volume by cross-sectional imaging on MRI
• Inability/contraindication to undergo MRI (Pacemaker, iron metallic items, cochlear implants, claustrophobia)
• Coagulation disorders (prothrombin time < 50% or Platelet count < 150 G/L)
• Any congenital predisposition to coagulation disorder
• Any disease requiring full anticoagulation
• History of cancer, except baso-cellular carcinoma
• Congestive cardiac failure
• Pre-existing coronary disease
• Unstable medical or psychiatric illness
• Any history of clinically significant thrombotic episode within the last 6 months
• Any history of atrial fibrillation
• Proteinuria (albumin excretion rate > 30 mg/day)
• Blood hypertension grade ≥ II (CTACE v5.0, 2017)
• Past history of a gastro-intestinal fistula
• Past history of a vaginal fistula
• Past history of open surgery within the last 28 days
• Infectious syndrome within the last month
• Any other contra-indication to bevacizumab administration
• Any contra-indication to general anesthesia
• Pregnancy or lactating woman
• Woman without efficacy contraception (combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence) all along study participation, and until 6 months after the bevacizumab administration, for woman of childbearing potential
• Seropositivity for HIV, HCV or HBV
• Severe and proven allergy to iodinated contrast material or Gadolinium
• Participation in another interventional clinical trial evaluating a health product or any randomized clinical trial
• Patients under legal protection (tutorship or curatorship) and patient deprived of freedom