Bevacizumab for Brain Cancer

Overseen By John Boockvar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Northwell Health

Must not be taking: Bevacizumab

Disqualifiers: Pregnancy, Lactation, Significant medical conditions

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: Unknown

Duration: 6 months

54 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. Please consult with the trial coordinators for more details.

What data supports the idea that Bevacizumab for Brain Cancer (also known as: Bevacizumab, Avastin) is an effective drug?

The available research shows that Bevacizumab may improve the quality of life for patients with glioblastoma, a type of brain cancer, but it does not necessarily extend overall survival. Some studies suggest that it helps in delaying the progression of the disease when combined with other treatments like radiotherapy and temozolomide, especially in certain patient subgroups. However, there are concerns that it might reduce the effectiveness of standard treatments and increase the risk of the cancer spreading by using normal blood vessels. Overall, while Bevacizumab can be beneficial in some ways, its effectiveness compared to other treatments is mixed. ^{1 2 3 4 5}

What safety data is available for Bevacizumab in brain cancer treatment?

Bevacizumab, also known as Avastin, has a unique toxicity profile due to its antiangiogenic effects. In glioblastoma patients, there is a slightly higher risk of adverse events such as gastrointestinal perforation, venous thromboembolism, and intracranial hemorrhages compared to other tumor types. Safety concerns include stroke, bleeding events, and wound-healing complications, especially when combined with radiotherapy/temozolomide. A meta-analysis showed an increased risk of cerebrovascular events, including CNS ischemic events and CNS hemorrhage, with a relative risk of 3.28 compared to controls. The risk varies with dose and tumor type, with higher risks observed in metastatic colorectal cancer. Preventive and therapeutic measures are recommended to manage these risks. ^{2 6 7 8 9}

Is the drug Bevacizumab a promising treatment for brain cancer?

Bevacizumab, also known as Avastin, is a drug that has shown promise in treating brain cancer, specifically glioblastoma. It has been approved in the USA for recurrent cases because it can improve the quality of life and has a higher response rate compared to other treatments. It works by targeting blood vessels that help tumors grow, which can slow down the progression of the disease. ^{1 2 10 11 12}

What is the purpose of this trial?

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). The investigators have shown in a previous phase I trial that a single Super-selective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that the investigators seek to test the hypothesis that repeated dosing of intraarterial Bevacizumab is safe and effective in the treatment of recurrent malignant glioma. By achieving the aims of this study the investigators will also determine if IV therapy with Bevacizumab should be combined with repeated selected intraarterial Bevacizumab to improve progression free and overall survival. The investigators expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to the patients in the near future.

Research Team

John Boockvar, MD

Principal Investigator

Feinstein Institute for Medical Research

Eligibility Criteria

Adults with relapsed or refractory high-grade brain tumors like GBM and AA, who have not had more than two cycles of Bevacizumab treatment. Participants must be able to perform daily activities (Karnofsky performance status ≥70%), have at least one confirmed tumor site, and agree to use contraception during the study.

Inclusion Criteria

I have a confirmed diagnosis of a specific type of brain tumor that has returned or is not responding to treatment.

I am mostly independent and can care for myself.

I have at least one tumor confirmed by biopsy.

Exclusion Criteria

Patients with significant inter-current medical or psychiatric conditions that would place them at increased risk or affect their ability to receive or comply with treatment or post-treatment clinical monitoring

I have received more than 2 cycles of Bevacizumab at 10mg/kg.

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive repeated intraarterial delivery (SIACI) of Bevacizumab, with one arm also receiving biweekly IV Bevacizumab. IA therapy is repeated upon MRI progression.

6 months

Biweekly visits for IV therapy, additional visits for IA therapy as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival assessments.

6 months

Treatment Details

Interventions

• Bevacizumab

Trial Overview The trial is testing repeated doses of intraarterial Bevacizumab for safety and effectiveness in treating recurrent malignant glioma. It aims to see if this method improves survival compared to standard intravenous therapy by delivering the drug directly into arteries supplying the tumor.

Participant Groups

Group I: Arm 2 Experimental Treatment 1 Intervention

Group II: Arm 1 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Feinstein Institute for Medical Research

Collaborator

Trials

22

Recruited

5,700+

Findings from Research

Inhibiting vascular endothelial growth factor (VEGF) with agents like bevacizumab is intended to normalize tumor blood vessels, potentially improving drug delivery and radiotherapy effectiveness for primary CNS tumors.

However, concerns have emerged that these agents may restore the blood-brain barrier's low permeability too quickly, which could reduce the effectiveness of standard treatments like radiochemotherapy and increase tumor infiltration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The paradoxical effect of bevacizumab in the therapy of malignant gliomas. Thompson, EM., Frenkel, EP., Neuwelt, EA.[2021]

A study of 310 glioblastoma patients from 2010 to 2014 found that the use of bevacizumab did not improve overall survival compared to patients treated before its approval, with median survival remaining similar at 13.5 months for IDH wild-type tumors.

However, patients receiving bevacizumab experienced a significant reduction in corticosteroid use during second-line treatment, suggesting a potential clinical benefit in managing treatment side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study. Gramatzki, D., Roth, P., Rushing, EJ., et al.[2020]

In a retrospective analysis of the AVAglio trial involving 921 glioblastoma patients, those with IDH1 wild-type proneural tumors showed a significant overall survival (OS) benefit from bevacizumab treatment compared to placebo, with an OS of 17.1 months versus 12.8 months.

While patients with mesenchymal and proneural tumors experienced progression-free survival (PFS) benefits from bevacizumab, only the proneural subtype demonstrated a corresponding OS advantage, highlighting the importance of molecular subtypes in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. Sandmann, T., Bourgon, R., Garcia, J., et al.[2022]

In a study of 12 patients with relapsed/refractory brain tumors treated with a combination of bevacizumab and irinotecan, the treatment showed promising results with two complete responses and two partial responses after three months, along with a median progression-free survival of 11 months.

The treatment was well tolerated, with low toxicity reported, and 42% of patients remained progression-free at two years, indicating that this regimen could be a viable option for managing difficult-to-treat brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab-containing regimen in relapsed/progressed brain tumors: a single-institution experience. Schiavetti, A., Varrasso, G., Mollace, MG., et al.[2020]

In a study of 48 patients with recurrent glioblastoma, single-agent bevacizumab demonstrated significant biological activity, with 71% of patients achieving a radiographic response and a median progression-free survival of 16 weeks.

However, the combination of bevacizumab with irinotecan showed no objective responses, highlighting that while bevacizumab is effective as a standalone treatment, its efficacy may not extend when combined with certain other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Kreisl, TN., Kim, L., Moore, K., 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 significantly increases the risk of cerebrovascular events, including CNS ischemic events and CNS hemorrhage, with a relative risk of 3.28 based on a meta-analysis of 17 randomized controlled trials involving 12,917 patients.

The risk of cerebrovascular events varies with the dose of bevacizumab and is particularly high in patients with metastatic colorectal cancer, indicating that careful monitoring is needed for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: a meta-analysis. Zuo, PY., Chen, XL., Liu, YW., et al.[2021]

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 II trial involving 115 patients with non-small-cell lung cancer (NSCLC) and treated brain metastases, the addition of bevacizumab to chemotherapy or erlotinib showed a low incidence of serious CNS hemorrhage, with no cases of grade 2 or higher reported among 106 safety-evaluable patients.

The study suggests that bevacizumab is safe for use in this patient population, as it was well-tolerated with a median treatment duration of 6.3 months and only a small percentage of patients (24.5%) discontinuing due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. Socinski, MA., Langer, CJ., Huang, JE., et al.[2022]

Bevacizumab (BEV) has shown a median radiographic response rate of 25% and a 6-month progression-free survival (PFS6) rate of 40% in patients with recurrent glioblastoma, leading to its accelerated approval in the USA for this indication.

Despite improvements in treatment options, glioblastoma remains a challenging and incurable condition, with current therapies yielding low response rates and variable survival outcomes, highlighting the need for ongoing research into effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for the treatment of glioblastoma. Chowdhary, S., Chamberlain, M.[2022]

Bevacizumab, an anti-VEGF therapy, may not be effective against brain metastases from non-small cell lung carcinoma (NSCLC) due to their significantly higher proportion of mature blood vessels compared to primary tumors, which suggests resistance to this treatment.

The study found that while hypoxia markers were similar between primary tumors and brain metastases, other factors like VEGF expression and microvessel density differed, indicating that brain metastases may not respond to anti-angiogenic therapies in the same way as the original tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Jubb, AM., Cesario, A., Ferguson, M., et al.[2021]

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]

References

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

The paradoxical effect of bevacizumab in the therapy of malignant gliomas. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study. [2020]

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

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Bevacizumab-containing regimen in relapsed/progressed brain tumors: a single-institution experience. [2020]

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

Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. [2022]

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

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

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

Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: a meta-analysis. [2021]

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

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

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

Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Bevacizumab for the treatment of glioblastoma. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. [2021]

12. England pubmed.ncbi.nlm.nih.gov

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