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

Official title

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

Overview

Brain arteriovenous malformations (bAVMs) are rare aggressive vascular malformations affecting mostly young and healthy adults. The most frequent revealing condition (in almost 50% of cases) is an intra-cerebral hemorrhage, which is a considerable source of disability and mortality. The only way to prevent a bleeding or a rebleeding is to perform an exclusion treatment (endovascular embolization, microsurgery, stereotactic radiosurgery, or a combination of these techniques). The major drawback of these treatments is the risk of severe complications, which can reach 20%, especially in patients presenting a bAVM with complex angio-architecture (i.e., grade IV to V in the Spetzler Martin grading scale). There is a growing evidence about the strong implication of angiogenesis (mainly mediated by the type A vascular endothelial growth factor \[VEGF-A\]) on the size and growth of the bAVM and even in the occurrence of bleeding events. Our hypothesis is that an in situ injection of bevacizumab, a monoclonal antibody inhibiting VEGF-A, in patients with bAVM deemed not suitable for exclusion treatment may be safe and help to reduce the nidus volume.

Detailed description

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

Interventions

• Drug Single in situ intra-arterial injection of bevacizumab
  3 Escalating doses of an in situ intra-arterial injection of Bevacizumab (5 mg/kg, 7.5 mg/kg, 10 mg/kg)

Primary outcome measures

• Dose limiting toxicity [Time frame: Days 0 (day of the injection) to day 30]

Secondary outcome measures (4)

• Tolerance of escalating doses (3+3) of an in situ intra-arterial injection of bevacizumab [Time frame: Days 0 (day of the injection) to 12 months]
• Reduction of the nidus volume [Time frame: at 6 and 12 months]
• Occurrence of an intra-cerebral bleeding event [Time frame: Days 0 (day of the injection) to 12 months]
• Occurrence of at least one seizure [Time frame: Days 0 (day of the injection) to 12 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 5 centers

• CHU de Limoges, Hôpital Dupuytren — Limoges
• CHU de Nancy, Hôpital Central — Nancy
• APHP, Hôpital Pitié-Salpêtrière — Paris
• Centre Hospitalier Sainte-Anne — Paris
• CHU de Rouen, Hôpital Charles-Nicolle — Rouen

Identifiers

NCT: NCT07075757 · APHP211033 · 2023-506991-28-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗