Nivolumab + Bevacizumab for Glioblastoma

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: David Peereboom

Must not be taking: Anticoagulants, Corticosteroids, Immunosuppressants, others

Disqualifiers: Autoimmune disease, Hypertension, Cardiovascular disease, others

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 3 years

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to test the effectiveness (how well the drug works), safety and tolerability of an investigational drug called nivolumab (also known as BMS-936558) in glioblastoma (a malignant tumor, or GBM), when added to bevacizumab. Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Opdivo (nivolumab ) is currently FDA approved in the United States for melanoma (a type of skin cancer), non-small cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not approved in glioblastoma. nivolumab may help your immune system detect and attack cancer cells. Bevacizumab is a drug which works on the blood vessel that supply the tumor and potentially can starve the tumor by cutting off the blood supply to these tumors. Bevacizumab is commercially available and FDA approved for individuals with recurrent glioblastoma. This study has two study groups. Arm 1 will receive the study drug nivolumab 240mg and bevacizumab 10 mg (standard dose) every 2 weeks and Arm 2 will receive the study drug nivolumab 240 mg and bevacizumab 3 mg (low dose) every 2 weeks. A process will be used to assign participants, by chance, to one of the study groups. Neither participants nor doctors can choose which group participants are in. This is done by chance because no one knows if one study group is better or worse than the other. 90 total participants are expected to participate in this study (45 participants in each arm). Your total participation in this study from the time you have signed the informed consent to your last visit, including follow-up visits, may be more than three years (depending on what effect the treatment has on your cancer, and how well you tolerate the treatment).

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not have ongoing safety issues from previous treatments and should not be on certain immunosuppressive treatments. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is the combination of Nivolumab and Bevacizumab safe for treating glioblastoma?

Bevacizumab, used for glioblastoma, can cause serious side effects like gastrointestinal perforation (a hole in the stomach or intestines), blood clots, and bleeding in the brain. It has also been linked to stroke and wound-healing issues. Patients receiving bevacizumab with chemotherapy reported more treatment-related side effects. ^{1 2 3 4 5}

How is the drug Nivolumab + Bevacizumab unique for treating glioblastoma?

Nivolumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells, while Bevacizumab reduces blood vessel growth in tumors. This combination is unique because it targets both the immune system and tumor blood supply, offering a novel approach for glioblastoma, which lacks standard second-line treatments. ^{3 6 7 8 9}

What data supports the effectiveness of the drug combination Nivolumab and Bevacizumab for glioblastoma?

Bevacizumab has been shown to reduce tumor growth and improve quality of life in glioblastoma patients by decreasing blood vessel formation in tumors. Additionally, combining similar drugs like pembrolizumab with bevacizumab has shown promise in treating recurrent glioblastoma, suggesting potential benefits for the combination of Nivolumab and Bevacizumab. ^{3 6 7 8 10}

Who Is on the Research Team?

David Peereboom, MD

Principal Investigator

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with a type of brain tumor called glioblastoma who have already undergone initial treatment like radiotherapy. They must expect to live more than 12 weeks, be able to follow the study plan and visits, and have a Karnofsky performance status of 70 or higher, indicating they can care for themselves.

Inclusion Criteria

I have received radiotherapy as my first treatment.

Written informed consent and HIPAA authorization obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations

Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by MRI.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab and bevacizumab every 2 weeks until disease progression or unacceptable toxicity

Up to 3 years

Bi-weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Nivolumab

Trial Overview The trial tests nivolumab's effectiveness in treating glioblastoma when combined with standard or low doses of bevacizumab. Participants are randomly assigned to one of two groups: one receives nivolumab with standard-dose bevacizumab and the other gets it with low-dose bevacizumab every two weeks.

How Is the Trial Designed?

Group I: Nivolumab + Low Dose Bevacizumab Experimental Treatment 2 Interventions

nivolumab 240 mg IV and low dose bevacizumab 3mg/kg every 2 weeks until disease progression or unacceptable toxicity Nivolumab is to be administered first. The second infusion will be bevacizumab, and will start no sooner than 10 minutes after completion of the nivolumab infusion

Group II: Nivolumab + Standard Dose Bevacizumab Active Control 2 Interventions

nivolumab 240 mg IV and standard dose bevacizumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Nivolumab is to be administered first. The second infusion will be bevacizumab, and will start no sooner than 10 minutes after completion of the nivolumab infusion

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

David Peereboom

Lead Sponsor

Trials

3

Recruited

160+

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

Bevacizumab, a monoclonal antibody that targets VEGF, has been shown to reduce tumor growth and associated brain swelling in glioblastoma patients, potentially improving their quality of life and survival rates.

Despite its benefits, the review highlights the importance of understanding the potential side effects and complications of bevacizumab, as well as exploring new drug combinations to enhance its efficacy in treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of bevacizumab therapy in the management of glioblastoma. Peak, SJ., Levin, VA.[2021]

In a study involving 15 patients with high-grade glioma, the combination of bevacizumab, radiation, and temozolomide was found to be feasible, with 86.6% of patients completing the treatment regimen.

The treatment resulted in a high radiographic response rate of 92.8%, and one-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively, indicating promising efficacy in managing this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. Narayana, A., Golfinos, JG., Fischer, I., et al.[2022]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

In a phase II study involving 80 patients with recurrent glioblastoma, pembrolizumab combined with bevacizumab showed a 6-month progression-free survival (PFS-6) of 26% and a median overall survival (OS) of 8.8 months, indicating limited efficacy despite being well tolerated.

Pembrolizumab alone had a much lower PFS-6 of 6.7% and no objective responses, suggesting that while the combination therapy had some durable responses, neither treatment was effective enough for significant clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Nayak, L., Molinaro, AM., Peters, 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, 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 296 patients with recurrent glioblastoma, continuing treatment with bevacizumab (BEV) after first-line therapy did not show a survival benefit compared to placebo, with median survival times of 6.4 months for BEV and 5.5 months for placebo.

The study found no new safety concerns with BEV treatment, as the incidence of severe treatment-related adverse events was similar between the BEV and placebo groups (19% vs. 15%), indicating that BEV can be safely administered through multiple lines of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. Brandes, AA., Gil-Gil, M., Saran, F., et al.[2020]

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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Ipilimumab and Bevacizumab in Glioblastoma. [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Role of bevacizumab therapy in the management of glioblastoma. [2021]

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

Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. [2022]

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

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]

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

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with 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. England pubmed.ncbi.nlm.nih.gov

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

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

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. [2020]

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

Bevacizumab combined with chemotherapy for glioblastoma: a meta-analysis of randomized controlled trials. [2022]

10. 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]