Nivolumab + Bevacizumab for Glioblastoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining nivolumab and bevacizumab against glioblastoma, an aggressive brain tumor. Nivolumab helps the immune system target cancer cells, while bevacizumab cuts off the tumor's blood supply. Participants will be randomly assigned to one of two groups, receiving either a standard or low dose of bevacizumab alongside nivolumab every two weeks. This trial may suit those whose glioblastoma has returned after initial treatment, such as radiotherapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

Previous studies have generally shown that patients with glioblastoma tolerate the combination of nivolumab and bevacizumab well. One study found that patients managed the treatments without major issues. Another study demonstrated that both standard and low doses of bevacizumab with nivolumab had similar safety levels, with side effects being about the same for both doses.

The FDA has already approved nivolumab for other cancers, such as melanoma and lung cancer, indicating its safety for those conditions. Bevacizumab is also FDA-approved for use in recurrent glioblastoma, confirming its safety record for this specific cancer.

While any treatment carries risks, existing research suggests that patients have managed the combination of nivolumab and bevacizumab well in past studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for glioblastoma, which often include surgery, radiation, and chemotherapy, nivolumab and bevacizumab offer a novel approach. Nivolumab is an immunotherapy that works by blocking the PD-1 protein on immune cells, boosting the body's ability to fight cancer. Bevacizumab, an angiogenesis inhibitor, prevents the growth of new blood vessels that tumors need to grow. Researchers are particularly excited about the combination of these two drugs because it not only harnesses the immune system but also starves the tumor, potentially leading to more effective treatment outcomes. Additionally, the trial is exploring different dosing strategies for bevacizumab, which could further enhance treatment effectiveness and safety.

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

Research suggests that combining nivolumab with bevacizumab may help treat glioblastoma, a type of brain cancer. In this trial, participants will receive either nivolumab with a standard dose of bevacizumab or nivolumab with a low dose of bevacizumab. One study showed that 37.8% of patients experienced tumor reduction or disappearance with the combination treatment, compared to 28.2% with bevacizumab alone. Another study found that about 40% of patients survived for at least 12 months with either treatment. Nivolumab aids the immune system in attacking the cancer, while bevacizumab cuts off the tumor's blood supply. This combination shows promise in improving outcomes for patients with glioblastoma. ^{1 4 6 7 8}

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

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]

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 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 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 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, 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 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 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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7243167/

Effect of Nivolumab vs Bevacizumab in Patients With ... Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our ...

2. targetedonc.com targetedonc.com/view/unveiling-the-potential-of-combined-therapies-for-glioblastoma

Unveiling the Potential of Combined Therapies for ... The overall survival at 12 months was close to 40% in both the arms, which was comparable to what we have seen with either bevacizumab alone or ...

3. onclive.com onclive.com/view/eo2401-plus-nivolumab-and-bevacizumab-shows-activity-in-progressive-recurrent-glioblastoma

EO2401 Plus Nivolumab and Bevacizumab Shows Activity ... The 12- and 18-month OS rates were 57.4% and 43.1%, respectively. EO2401 plus nivolumab and bevacizumab was also found to be well tolerated.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03452579

Study Details | NCT03452579 | Nivolumab Plus Standard ... 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 ...

5. mdpi.com mdpi.com/2072-6694/15/17/4279

Recurrent Glioblastoma: A Review of the Treatment Options Objective response rates (ORR) for the bevacizumab-alone arm was 28.2% and for the combination arm 37.8%. Six-month PFS rates were 42.6% and 50.3%, respectively ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2072

A randomized, controlled, phase 2 trial of nivolumab plus ... Conclusions: Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02017717

NCT02017717 | A Study of the Effectiveness and Safety ... The purpose of the study is to compare the efficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent ...

8. nature.com nature.com/articles/s41423-024-01226-x

Immunotherapy for glioblastoma: current state, challenges ... In a phase I/II study (NCT01260506), combined treatment with VB-111 and bevacizumab significantly improved survival in recurrent GBM patients ...