SIACI Bevacizumab + Temozolomide and Radiation for Glioblastoma

Overseen by John Boockvar, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Northwell Health

Disqualifiers: Other malignancy, Active infection, HIV, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for aggressive brain cancer by using Mannitol to open the brain's barrier and then delivering Bevacizumab directly into the brain's arteries. It aims to improve survival rates for patients with newly diagnosed Glioblastoma Multiforme. Bevacizumab, typically administered intravenously, has shown superior outcomes when delivered directly into the brain's arteries in patients with recurrent Glioblastoma Multiforme.

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

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 treatment Bevacizumab, Temozolomide, and Radiation Therapy for glioblastoma?

Research shows that adding bevacizumab to radiotherapy and temozolomide can prolong the time before glioblastoma worsens, although it may not extend overall survival for all patients. Some studies suggest certain subgroups might benefit more from this combination. ^{1 2 3 4 5}

Is the combination of Bevacizumab, Temozolomide, and Radiation Therapy safe for humans?

The combination of Bevacizumab, Temozolomide, and Radiation Therapy for glioblastoma has shown some safety concerns, including risks of stroke, bleeding, and blood clots. Bevacizumab, in particular, is associated with these risks, and its interaction with the other treatments is still being studied. ^{2 3 6 7 8}

What makes the SIACI Bevacizumab + Temozolomide and Radiation treatment unique for glioblastoma?

This treatment combines bevacizumab, which reduces blood vessel leakage, with temozolomide, a drug that kills cancer cells by causing mutations, and a specialized form of radiation therapy. This combination aims to enhance the effectiveness of radiation by making the tumor more sensitive to it, potentially offering better control of the tumor compared to standard treatments. ^{3 4 9 10 11}

Research Team

John Boockvar, MD

Principal Investigator

Feinstein Institute for Medical Research/Lenox Hill Hospital

Eligibility Criteria

This trial is for adults over 18 with newly diagnosed GBM brain cancer, expected to live at least 6 months. They must be able to have an MRI, use birth control if of reproductive potential, and sign consent. Participants need normal blood counts and organ function, a specific diagnosis of GBM per WHO criteria, and a Karnofsky Performance Status of 70% or higher.

Inclusion Criteria

I am not pregnant and agree to use birth control.

I am mostly able to care for myself and carry out daily activities.

Subject must be able to undergo MRI evaluation

Exclusion Criteria

I am currently pregnant or breastfeeding.

Subject has a known positive test for human immunodeficiency virus infection, or active hepatitis B or hepatitis C infection

I have started treatment for glioblastoma.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Subjects receive Mannitol followed by repeated IA BV infusion and chemoradiation. IA BV is repeated every three months for a total of 3 infusions.

9 months

3 visits (in-person) for IA BV infusions

Follow-up

Participants are monitored for overall survival and progression-free survival, with assessments for adverse events and quality of life.

62 months

Treatment Details

Interventions

• Bevacizumab (Monoclonal Antibodies)
• Radiation Therapy (Radiation)
• Temozolomide (Alkylating agents)

Trial Overview The study compares two treatments for GBM: one group receives standard Temozolomide with Radiation; the other gets an additional treatment called SIACI Bevacizumab (Avastin) alongside Temozolomide and Radiation. The goal is to see if SIACI increases survival without disease progression or overall lifespan compared to the standard therapy.

Participant Groups

Group I: SIACI of Bevacizumab (Avastin) with Temozolomide and Radiation Experimental Treatment 1 Intervention

Repeated Superselective Intraarterial Cerebral infusion (SIACI) of Bevacizumab (Avastin) with Temozolomide and Radiation

Group II: Standard of care Temozolomide and Radiation Active Control 1 Intervention

Standard of care Temozolomide and Radiation

Bevacizumab is already approved in Japan, Canada for the following indications:

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?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Michael Dowling

Northwell Health

Chief Executive Officer since 2002

Bachelor's and Master's degrees from University College Cork, Ireland

Dr. David Battinelli

Northwell Health

Chief Medical Officer since 2022

MD from Georgetown University School of Medicine

Findings from Research

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 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]

In a study of 70 patients with newly diagnosed glioblastoma, combining bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) resulted in improved progression-free survival (PFS) of 13.6 months compared to 7.6 months in a control group, although overall survival (OS) was similar between groups.

The presence of MGMT promoter methylation in tumor tissue was associated with better OS and PFS, suggesting that this biomarker may help identify patients who could benefit more from the treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. Lai, A., Tran, A., Nghiemphu, PL., et al.[2022]

In a phase II trial involving 40 patients with newly diagnosed glioblastoma, the combination of hypofractionated stereotactic radiotherapy (HFSRT), temozolomide, and bevacizumab resulted in a remarkable 1-year overall survival rate of 93%, indicating high efficacy of this treatment approach.

The study also identified that advanced neuroimaging parameters, such as baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism on FDG-PET, could serve as potential biomarkers for predicting poor overall survival, while the proneural transcriptional subclass was associated with worse outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Omuro, A., Beal, K., Gutin, P., et al.[2022]

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

Bevacizumab, an antibody used to treat recurrent glioblastoma, has been associated with serious side effects like increased risk of blood clots and bleeding, which raises concerns about its safety in patients with primary brain tumors.

This study reports a rare case of dural venous sinus thrombosis in a patient with primary glioma who was treated with a combination of temozolomide, radiation, and bevacizumab, highlighting the potential risks of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab. Vargo, JA., Snelling, BM., Ghareeb, ER., et al.[2021]

In a Phase II pilot study involving 10 patients with newly diagnosed glioblastoma, the combination of bevacizumab (BV), temozolomide (TMZ), and regional radiation therapy (RT) showed acceptable safety and tolerability, with some patients experiencing serious toxicities like presumed radiation-induced optic neuropathy and high rates of fatigue and myelotoxicity.

Preliminary results indicated encouraging mean progression-free survival, but further research with more patients and longer follow-up is needed before considering routine use of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Lai, A., Filka, E., McGibbon, B., et al.[2022]

In a study of 11 patients with newly diagnosed glioblastoma, treatment with radiation, temozolomide (TMZ), and bevacizumab (BEV) significantly reduced the number of regulatory T cells (Tregs) in peripheral blood, which may enhance anti-tumor immunity.

The treatment also led to increased levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in the plasma, suggesting that these changes in immune cell populations and growth factors could influence the tumor microenvironment and inform future immunotherapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma. Thomas, AA., Fisher, JL., Hampton, TH., et al.[2018]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a phase II trial involving 75 elderly patients with newly diagnosed glioblastoma, the addition of bevacizumab to hypofractionated radiotherapy improved progression-free survival (PFS) but did not significantly extend overall survival (OS), which remained similar between the treatment and control groups (12.1 vs. 12.2 months).

The prolonged PFS benefit from bevacizumab was primarily observed in patients with specific molecular subtypes of tumors, suggesting that certain biomarkers may help identify individuals who could benefit more from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial. Wirsching, HG., Tabatabai, G., Roelcke, U., et al.[2020]

In a phase 3 study involving 921 patients with newly diagnosed glioblastoma, the addition of bevacizumab to standard treatment (radiotherapy plus temozolomide) significantly improved progression-free survival (10.6 months vs. 6.2 months) but did not lead to a significant increase in overall survival.

While bevacizumab helped maintain quality of life and reduced glucocorticoid use, it was associated with a higher rate of severe adverse events (66.8% vs. 51.3% in the placebo group), indicating a trade-off between benefits and risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. Chinot, OL., Wick, W., Mason, W., et al.[2022]

References

1. 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]

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

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

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

Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. [2022]

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

Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. [2018]

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

Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab. [2021]

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

Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma. [2018]

9. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

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

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial. [2020]

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

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. [2022]