SIACI Bevacizumab + Temozolomide and Radiation for Glioblastoma

Overseen By John Boockvar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Northwell Health

Disqualifiers: Other malignancy, Active infection, HIV, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 3

Duration: 9 months

432 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating glioblastoma (GBM), a common and aggressive brain cancer. Researchers aim to determine if Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (Avastin, an anti-cancer drug), combined with standard treatments of Temozolomide (a chemotherapy drug) and radiation therapy, can extend the time patients live without cancer progression. One group of participants will receive the experimental treatment, while the other will receive standard care. The trial seeks individuals with newly diagnosed GBM who have not yet started other treatments. Participants must have a confirmed GBM diagnosis and be able to undergo MRI scans. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using Superselective Intraarterial Cerebral Infusion (SIACI) to deliver Bevacizumab, along with Temozolomide and Radiation, appears safe. In a previous study, patients who received Bevacizumab through SIACI at doses up to 15mg/kg found the treatment safe. This approach has also shown potential to improve survival in patients with newly diagnosed glioblastoma, a type of brain cancer.

However, some safety concerns exist. This combination treatment has been associated with risks of stroke and bleeding. While these are serious issues, they do not affect everyone. Many patients tolerate the treatment well and experience positive outcomes.

Overall, the treatment has shown potential benefits, but participants should discuss these risks with their healthcare team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for glioblastoma?

Researchers are excited about the combination of Bevacizumab with Temozolomide and Radiation for glioblastoma because it uses a unique delivery method called Superselective Intraarterial Cerebral Infusion (SIACI). Unlike the standard treatments, which typically involve systemic administration, SIACI delivers Bevacizumab directly to the brain's blood vessels. This targeted approach allows for higher concentrations of the drug to reach the tumor while potentially reducing systemic side effects. By enhancing the effectiveness of the existing chemotherapy and radiation, this method could improve outcomes for patients with this aggressive brain cancer.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

This trial will compare two treatment approaches for glioblastoma. One arm will use the SIACI method to deliver Bevacizumab, along with Temozolomide and radiation. Research has shown that this approach is promising, as it increased the time patients lived without their cancer worsening from 4-6 months to 11.5 months in previous studies. It also extended overall survival from 12-15 months to 23 months in newly diagnosed patients. Bevacizumab has proven effective in helping patients with recurring glioblastoma live longer. This method involves delivering the drug directly to the brain's blood vessels, which may enhance its effectiveness. Early findings suggest that this treatment could significantly extend the time patients live without their cancer getting worse. The other arm will receive the standard of care with Temozolomide and radiation. ^{1 4 6 7 8}

Who Is on the Research Team?

John Boockvar, MD

Principal Investigator

Feinstein Institute for Medical Research/Lenox Hill Hospital

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Radiation Therapy
• Temozolomide

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.

How Is the Trial Designed?

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 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?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Published Research Related to This Trial

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 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]

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 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]

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, 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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01269853

Study Details | NCT01269853 | Repeated Super-selective ... A single Super-selective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05271240

Study Details | NCT05271240 | Repeated Superselective ... The investigators have completed a Phase I clinical trial that has shown that Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (BV) is safe ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34601657/

Repeated superselective intraarterial bevacizumab after ... This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood-brain ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1878875019320431

Rechallenging Recurrent Glioblastoma with Intra-Arterial ... A single-institution retrospective database review determined that bevacizumab was well tolerated and improved outcomes as a third-line treatment of recurrent ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20192120/

Superselective intraarterial cerebral infusion of bevacizumab Recent monoclonal antibody therapies such as Bevacizumab (Avastin) have been shown to be active in GBM and to prolong survival in patients with recurrent ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3058273/

Phase II Study of Bevacizumab Plus Temozolomide During ... Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.

7. withpower.com withpower.com/trial/phase-3-gliomas-malignant-3-2022-8e5ac

SIACI Bevacizumab + Temozolomide and Radiation for ... The combination of Bevacizumab, Temozolomide, and Radiation Therapy for glioblastoma has shown some safety concerns, including risks of stroke, bleeding, and ...

8. app.trialscreen.org app.trialscreen.org/trials/phase-3-glioblastoma-repeated-superselective-intraarterial-cerebral-infusion-trial-nct05271240

Repeated Superselective Intraarterial Cerebral Infusion ... A Phase 2 study of Repeated Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab in Newly Diagnosed Glioblastoma. Evaluating the Effectiveness ...