Bevacizumab Injection for Subdural Hematoma

(CHAI Trial)

Overseen By Thuy Cao

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: The Cooper Health System

Disqualifiers: Pregnancy, Intracranial pathology, Coagulation abnormalities, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

140 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test whether infusing bevacizumab into the middle meningeal arteries can be used to treat chronic subdural hematomas (cSDH). The main questions it aims to answer are: * Is bevacizumab infusion safe in cSDH patients? * Is bevacizumab infusion effective in treating cSDH?

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Bevacizumab for treating subdural hematoma?

Bevacizumab, a drug that blocks a protein called VEGF, has shown potential in treating chronic subdural hematoma (a type of brain bleed) because high levels of VEGF are found in these hematomas. In one case, a patient's chronic subdural hematoma improved after receiving Bevacizumab for another condition, suggesting it might help reduce the hematoma by affecting VEGF. ^{1 2 3 4 5}

Is bevacizumab safe for use in humans?

Bevacizumab, also known as Avastin, has been used in humans for various conditions, but it can cause serious side effects like bleeding, high blood pressure, and wound-healing problems. In studies, some patients experienced headaches, fatigue, and infections, and there were cases of bleeding in the brain and other areas. It's important to weigh these risks with a healthcare provider before starting treatment. ^{1 6 7 8 9}

How does the drug bevacizumab differ from other treatments for subdural hematoma?

Bevacizumab is unique because it targets vascular endothelial growth factor (VEGF), which is involved in the formation of new blood vessels and may play a role in the development of subdural hematomas. This mechanism is different from traditional surgical approaches, as it potentially addresses the underlying cause of hematoma formation rather than just removing the accumulated blood. ^{1 2 3 4 10}

Research Team

Jane Khalife, MD

Principal Investigator

Cooper Neurological Institute

Ajith Thomas, MD

Principal Investigator

Cooper Neurological Institute

Eligibility Criteria

This trial is for individuals with chronic subdural hematomas, a type of blood clot under the skull. Participants should be suitable candidates for arterial infusion procedures.

Inclusion Criteria

Can obtain informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.

I have a chronic bleeding in my brain from an injury that happened over 10 days ago.

Exclusion Criteria

Patients with known hypersensitivity to bevacizumab

I need emergency surgery.

I have specific symptoms due to bleeding in my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive intra-arterial bevacizumab infusion to treat cSDH, with doses varying based on unilateral or bilateral condition

2 weeks

2 visits (in-person)

Treatment Phase 2

Continuation of bevacizumab infusion treatment with similar dosing as Phase 1

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of hematoma resolution and neurological symptoms

1 year

Multiple visits (in-person and virtual) at 3 months, 6 months, and 1 year

Treatment Details

Interventions

• Bevacizumab

Trial Overview The study tests two doses (2 mg/kg and 4 mg/kg) of Bevacizumab infused into arteries to treat chronic subdural hematomas. It aims to determine the safety and effectiveness of this treatment.

Participant Groups

Group I: Phase 2 Unilateral cSDH/ 2mg/kg Arm Experimental Treatment 1 Intervention

During phase 2, single 2mg/kg dose of bevacizumab to treat unilateral cSDH

Group II: Phase 2 Bilateral cSDH/ 4mg/kg Arm Experimental Treatment 1 Intervention

During phase 2, two 2mg/kg doses (cumulatively 4mg/kg) of bevacizumab to treat bilateral cSDH

Group III: Phase 1 Unilateral cSDH/ 2mg/kg Arm Experimental Treatment 1 Intervention

During phase 1, single 2mg/kg dose of bevacizumab to treat unilateral cSDH

Group IV: Phase 1 Bilateral cSDH/ 4mg/kg Arm Experimental Treatment 1 Intervention

During phase 1, two 2mg/kg doses (cumulatively 4mg/kg) of bevacizumab to treat bilateral cSDH

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

The Cooper Health System

Lead Sponsor

Trials

82

Recruited

35,600+

Findings from Research

Bevacizumab, a monoclonal antibody targeting VEGF, has shown efficacy in treating malignant tumors and was successfully used in a case of chronic subdural hematoma (CSDH) associated with recurrent glioblastoma, suggesting a potential therapeutic role for CSDH.

The presence of high levels of VEGF in the outer membrane of CSDH indicates that VEGF may play a significant role in the development and recurrence of CSDH, warranting further investigation into its mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of complete clearance of chronic subdural hematoma accompanied by recurrent glioblastoma multiforme after administration of bevacizumab. Suzuki, K., Kawataki, T., Kanemaru, K., et al.[2018]

Bevacizumab therapy, used for treating colon cancer, may be linked to the development and fluctuation of chronic subdural hematoma (CSDH) in patients, as seen in this 78-year-old man.

Neuroendoscope-assisted craniotomy proved to be an effective surgical method for the complete removal of organized CSDH, highlighting its utility in cases where simpler drainage methods are insufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroendoscope-assisted removal of an organized chronic subdural hematoma in a patient on bevacizumab therapy--case report. Takahashi, S., Yazaki, T., Nitori, N., et al.[2019]

A patient with glioblastoma multiforme experienced a traumatic subarachnoid hemorrhage (SAH) while being treated with bevacizumab, but showed no signs of vasoconstriction, a potential complication associated with the drug.

Bevacizumab was safely resumed five weeks after the SAH without any recurrence of bleeding or vasoconstriction, marking the first documented case of continuing this treatment post-SAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for glioblastoma multiforme after traumatic subarachnoid hemorrhage. Lukas, RV., Goldenberg, F., Nicholas, MK.[2018]

A 55-year-old woman with metastatic colorectal cancer developed a subarachnoid hemorrhage after treatment with bevacizumab, a drug that inhibits vascular endothelial growth factor, suggesting a possible link between the medication and the hemorrhage.

The patient's neurological symptoms and increased blood flow velocities in the brain resolved with medical treatment within 10 days, indicating that while bevacizumab may have contributed to the hemorrhage, effective management can lead to recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretruncal subarachnoid hemorrhage and high cerebral blood flow velocities with bevacizumab therapy. Baizabal-Carvallo, JF., Alonso-Juárez, M., Salas, I.[2016]

In a study of 115 patients with chronic subdural hematoma (CSDH), higher concentrations of vascular endothelial growth factor (VEGF) in hematoma fluid were significantly associated with specific MRI types, indicating a potential biomarker for assessing CSDH severity.

Patients with type 1 CSDH, which had the highest VEGF levels, showed a higher recurrence rate compared to those with type 4, suggesting that VEGF concentration could help predict the likelihood of CSDH recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of vascular endothelial growth factor with magnetic resonance imaging in chronic subdural hematomas. Li, F., Hua, C., Feng, Y., et al.[2018]

Bevacizumab, used to treat glioblastoma and other tumors, has a unique toxicity profile that can lead to serious side effects like gastrointestinal perforation and intracranial hemorrhages, particularly in glioblastoma patients.

The study systematically reviewed these adverse events, identifying risk factors and suggesting preventive and therapeutic measures to reduce treatment-related complications, emphasizing the need for careful monitoring in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. Brandes, AA., Bartolotti, M., Tosoni, A., et al.[2022]

In a phase III trial involving 911 patients with newly diagnosed glioblastoma, those treated with bevacizumab had a longer safety follow-up (12.3 months) and a higher completion rate of maintenance temozolomide (64.6%) compared to placebo (36.9%).

While bevacizumab was associated with a higher incidence of adverse events such as arterial thromboembolic events (5.9% vs 1.6%) and wound-healing complications (6.9% vs 4.7%), these did not hinder patients' ability to receive standard treatment or undergo subsequent surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. Saran, F., Chinot, OL., Henriksson, R., et al.[2022]

Bevacizumab (Avastin) received accelerated FDA approval for treating glioblastoma multiforme (GBM) based on its ability to produce partial responses in 25.9% of patients in one trial and 19.6% in another, with median response durations of approximately 4.2 and 3.9 months, respectively.

While bevacizumab shows efficacy in GBM treatment, it is associated with significant adverse events, including serious risks like CNS hemorrhage and thromboembolic events, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Cohen, MH., Shen, YL., Keegan, P., et al.[2022]

In a study of 21 patients treated with bevacizumab and anticoagulation for a median of 72 days, there were no major lobar hemorrhages, indicating that anticoagulation may be safe in this context.

While some patients experienced small, asymptomatic hemorrhages, the study suggests that anticoagulation does not increase the risk of significant bleeding when using bevacizumab, contrasting with cases of symptomatic hemorrhages in patients not on anticoagulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of anticoagulation use and bevacizumab in patients with glioma. Nghiemphu, PL., Green, RM., Pope, WB., et al.[2022]

In a study involving 18 rabbits, the VEGF inhibitor bevacizumab (BVZ) significantly prevented vasospasm in the basilar artery after inducing subarachnoid hemorrhage (SAH), as confirmed by magnetic resonance angiography (MRA).

BVZ also reduced apoptosis in the artery wall, suggesting that it may help protect against damage following SAH, highlighting its potential therapeutic role in managing vascular complications after such events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the restorative effect of VEGF inhibitor bevacuzimab against subarachnoid hemorrhage in an experimental model? Demirci, AY., Güvenç, Y., Özeren, E., et al.[2023]

References

1. Germany pubmed.ncbi.nlm.nih.gov

A case of complete clearance of chronic subdural hematoma accompanied by recurrent glioblastoma multiforme after administration of bevacizumab. [2018]

2. Japan pubmed.ncbi.nlm.nih.gov

Neuroendoscope-assisted removal of an organized chronic subdural hematoma in a patient on bevacizumab therapy--case report. [2019]

3. Scotland pubmed.ncbi.nlm.nih.gov

Bevacizumab for glioblastoma multiforme after traumatic subarachnoid hemorrhage. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Pretruncal subarachnoid hemorrhage and high cerebral blood flow velocities with bevacizumab therapy. [2016]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Correlation of vascular endothelial growth factor with magnetic resonance imaging in chronic subdural hematomas. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Practical management of bevacizumab-related toxicities in glioblastoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. [2022]

8. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Safety of anticoagulation use and bevacizumab in patients with glioma. [2022]

10. Turkey pubmed.ncbi.nlm.nih.gov

What is the restorative effect of VEGF inhibitor bevacuzimab against subarachnoid hemorrhage in an experimental model? [2023]