Nivolumab + Radiation + Bevacizumab for Glioblastoma

Not currently recruiting at 12 trial locations

Overseen By Christian Grommes, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anti-CTLA-4, Anti-PD-1

Disqualifiers: Heart failure, Hypertension, Autoimmune, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding nivolumab (an immunotherapy drug) to radiation therapy and bevacizumab (also known as Avastin, an anti-angiogenic drug) can improve treatment for recurrent glioblastoma. Glioblastoma, a type of brain cancer, is challenging to treat, especially when it returns after initial treatment. The study includes two groups: one for those undergoing surgery and one for those not undergoing surgery. Individuals with glioblastoma who have previously had surgery and standard treatments, and whose cancer has returned, might be suitable candidates for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on high doses of corticosteroids or have been treated with certain immune therapies before, you may not be eligible to participate.

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

Research shows that combining nivolumab, bevacizumab, and radiation therapy for recurrent glioblastoma is generally safe. Previous studies on re-administering radiation treatment for glioblastoma have found it to be safe, with few serious side effects. Specifically, no major severe side effects were reported.

When used alone for recurrent glioblastoma, nivolumab did not improve survival compared to bevacizumab. However, it was safe, and patients tolerated the treatment well.

Overall, past research indicates that adding nivolumab and bevacizumab to radiation therapy is well-tolerated. While some patients may experience side effects, they are usually mild and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Nivolumab, Bevacizumab, and radiation for glioblastoma because this approach targets the tumor in novel ways. Unlike standard treatments that primarily involve surgery, chemotherapy, and radiation, Nivolumab enhances the immune system's ability to recognize and attack cancer cells by blocking the PD-1 pathway. Bevacizumab, on the other hand, inhibits blood vessel growth that tumors need to thrive. This combined strategy not only aims to directly attack the tumor but also to cut off its blood supply, offering a potentially more effective approach for recurrent glioblastoma compared to traditional treatments.

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

Research has shown that bevacizumab, one of the treatments in this trial, may help treat recurring glioblastoma, a type of brain cancer. Studies found that about 57% of patients experienced some tumor shrinkage after receiving this treatment, and some lived up to four years. Bevacizumab is approved for treating recurring glioblastoma and is often part of the usual care. In this trial, some participants will receive bevacizumab along with other treatments.

Conversely, nivolumab, another treatment option in this trial, helps the immune system fight tumors. Although it hasn't demonstrated a clear benefit in extending life for patients with recurring glioblastoma compared directly to bevacizumab, it does reach the brain tumor and boosts the activity of T-cells, which are important for fighting cancer. Participants in this trial may receive nivolumab as part of their treatment regimen. ^{6 7 8 9 10}

Who Is on the Research Team?

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with confirmed grade IV glioblastoma, IDH wildtype, MGMT hypermethylation, who've had surgery and chemo with temozolomide followed by radiation. They must show signs of recurrence but have a relatively small tumor (≤5cm), good performance status, and normal organ function. Excluded are those with multiple recurrences, certain heart conditions or infections, active autoimmune diseases requiring recent treatment, pregnancy/breastfeeding intentions within trial period, MRI incompatibility or prior treatments conflicting with the study drugs.

Inclusion Criteria

I have been treated with radiation and temozolomide.

My liver is working well.

Platelet count ≥ 100,000/mm3

Exclusion Criteria

Prior spontaneous CNS hemorrhage (as determined from clinical history, CT, or MRI)

I have had a blood clot in my lung or leg in the last 2 months.

Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab in combination with hypofractionated re-irradiation and bevacizumab

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Nivolumab
• Re-irradiation (RT)
• Re-resection

Trial Overview The trial tests if adding nivolumab to standard re-irradiation therapy and bevacizumab improves outcomes for recurrent glioblastoma patients. It's exploring whether this combination can better control tumor growth compared to current methods.

How Is the Trial Designed?

Group I: Recurrent Glioblastoma, Surgery Experimental Treatment 4 Interventions

The second cohort is for patients with recurrent GBM who are undergoing surgery as part of their treatment.

Group II: Recurrent Glioblastoma, No Surgery Experimental Treatment 3 Interventions

One cohort is for patients with recurrent GBM who are not undergoing surgical debulking as part of their treatment plan

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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 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 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 involving 25 patients with recurrent glioblastoma and anaplastic gliomas, the combination of bevacizumab and hypofractionated stereotactic radiotherapy (HFSRT) was found to be safe and well tolerated, with no cases of radiation necrosis reported.

The treatment showed promising efficacy, with a 50% overall response rate and a median overall survival of 12.5 months, indicating that this regimen could be an effective option for patients with recurrent malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Gutin, PH., Iwamoto, FM., Beal, K., et al.[2022]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4733960/

Efficacy and safety of bevacizumab for the treatment of ... In addition, 57% of the patients (95% CI, 39–74%) demonstrated at least a partial response (PR), and the 4-year survival rate was demonstrated to be 11% in this ...

2. avastin.com avastin.com/hcp/rgbm/efficacy-data.html

Avastin® (bevacizumab) Clinical Trials | rGBM Treatment Recurrent Glioblastoma: Avastin Efficacy Data. Recurrent glioblastoma (rGBM) Avastin is indicated for the treatment of recurrent glioblastoma in adults.

3. healthline.com healthline.com/health/drugs/avastin-for-glioblastoma

Avastin: How It's Used for Treating Glioblastoma In studies, about half the people receiving Avastin and chemotherapy for recurrent glioblastoma went 4.2 months without their tumor progressing.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01269853

Study Details | NCT01269853 | Repeated Super-selective ... The current standard of care for recurring GBM is for patients to receive Bevacizumab (Avastin) intravenously (IV) at 10mg/kg every two weeks until their tumor ...

5. academic.oup.com academic.oup.com/noa/article/6/1/vdad174/7585190

A systematic review and external pseudodata-based analysis Reassessing the efficacy of bevacizumab in newly diagnosed glioblastoma: A systematic review and external pseudodata-based analysis Open Access.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03743662

Nivolumab With Radiation Therapy and Bevacizumab for ... This study is being done to see if adding nivolumab to radiation therapy and bevacizumab can increase the effectiveness of the treatment for recurrent ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10689476/

Re-irradiation of recurrent IDH-wildtype glioblastoma in the ... Data is limited for glioblastoma re-irradiation with BEV, TMZ, and ICI. Re-irradiation with concurrent therapy is safe, with little acute ...

8. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2766213

Effect of Nivolumab vs Bevacizumab in Patients With ... In this randomized phase 3 clinical trial of 369 patients diagnosed with recurrent glioblastoma treated with nivolumab, an improved survival benefit was not ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12357250/

Reirradiation of recurrent glioblastoma: Results from a single ... Reirradiation for rGBM was safe with no grade 3–5 acute adverse events. Radiation necrosis (RN) occurred in 16.9% of patients, mostly grade ...

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

Immunotherapy for glioblastoma: current state, challenges ... This study enrolled 369 GBM patients at their first recurrence following RT and TMZ therapy and revealed that nivolumab treatment did not ...