Ipilimumab + Nivolumab + Radiation for Glioblastoma

Not currently recruiting at 348 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Warfarin

Disqualifiers: Metastatic disease, Autoimmune 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

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for people with glioblastoma, a type of brain cancer. Researchers aim to determine if adding two immunotherapy drugs, ipilimumab (Yervoy) and nivolumab (Opdivo), to radiation therapy is more effective than the standard treatment of radiation with the chemotherapy drug temozolomide. The new approach seeks to harness the immune system to attack cancer cells and potentially prevent tumor recurrence. The trial seeks participants recently diagnosed with glioblastoma that does not respond well to standard chemotherapy. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to advancing cancer treatment.

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

The trial does not specify if you need to stop taking your current medications, but you cannot be on any systemically administered corticosteroids within 3 days before registration. Inhaled, topical, and ocular corticosteroids are allowed.

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

Research has shown that combining the drugs ipilimumab and nivolumab with radiation therapy is safe for patients newly diagnosed with glioblastoma. In earlier studies, most patients tolerated this treatment well. About 16% experienced serious side effects, but none were life-threatening. Some patients required treatment adjustments to prevent harm, known as dose-limiting toxicity. Overall, the treatment did not cause unexpectedly high levels of side effects, suggesting it is a relatively safe option for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining ipilimumab and nivolumab with radiation therapy for glioblastoma because these treatments work differently than traditional options. Unlike standard treatments like temozolomide, which directly targets and damages DNA in cancer cells, ipilimumab and nivolumab are immunotherapy drugs that enhance the body's immune response to attack cancer cells. Ipilimumab blocks CTLA-4, a protein that downregulates the immune system, while nivolumab inhibits PD-1, another protein that prevents T-cells from attacking tumors. This dual immunotherapy approach, combined with radiation, offers a promising strategy to improve the effectiveness of glioblastoma treatment by harnessing the power of the immune system.

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

This trial will compare two treatment approaches for glioblastoma. In one arm, participants will receive radiation therapy combined with ipilimumab and nivolumab. Research suggests that combining ipilimumab and nivolumab with radiation therapy might be promising for treating glioblastoma, a type of brain cancer. Studies have shown that this combination can be safely administered before the usual radiation treatment in patients with newly diagnosed brain tumors. However, one analysis found that this approach did not significantly extend the period during which the tumor does not grow in patients with a specific type of glioblastoma called MGMT unmethylated. Another study found that a small group of patients tolerated this treatment well, but it did not clearly show major improvements in survival. Overall, while there is potential, more evidence is needed to confirm the treatment's effectiveness. ^{4 5 6 7 8}

Who Is on the Research Team?

Andrew B Lassman

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

Adults with newly diagnosed MGMT unmethylated glioblastoma who've had surgery can join. They need a good performance status, no prior tumor treatments except resection, and no history of severe allergies to the drugs being tested or other cancers in the last 2 years. Women must not be pregnant and participants should use contraception.

Inclusion Criteria

History/physical examination within 28 days prior to step 2 registration

Negative pregnancy test for women of childbearing potential

My cancer's MGMT gene is not methylated as confirmed by a specialized lab.

Exclusion Criteria

I have not had any other cancer besides this one in the last 2 years.

I am currently taking or will start taking warfarin.

I have or had an autoimmune disease that could come back.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation and Chemotherapy

Patients undergo radiation therapy for 5 days per week for 6 weeks and receive temozolomide daily for 6 weeks

6 weeks

5 visits per week (in-person)

Immunotherapy

Patients receive ipilimumab every 4 weeks for 4 doses and nivolumab every 2 weeks until disease progression

Until disease progression

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

19.3 months

Every 3 months for year 1, then every 4 months for year 2, and every 6 months thereafter

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview

The trial is testing if combining radiation therapy with immunotherapy drugs Ipilimumab and Nivolumab improves outcomes compared to the usual treatment of radiation therapy plus Temozolomide for this type of brain cancer. It's looking at whether these new drugs help patients live longer without their tumor growing back.

How Is the Trial Designed?

Group I: Arm II (radiation therapy, ipilimumab, nivolumab) Experimental Treatment 6 Interventions

Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks. Starting on the first day of radiation, patients also receive ipilimumab IV over 90 minutes Q4W for 4 doses and nivolumab IV over 30 minutes every 2 weeks until disease progression. Patients also undergo contrast-enhanced brain MRI throughout the trial.

Group II: Arm I (radiation therapy, temozolomide) Active Control 6 Interventions

Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks and simultaneously receive temozolomide PO daily for 6 weeks. After radiation, patients may wear the Optune device at the discretion of the patient and their treating physician. Beginning 1 month after radiation therapy, patients receive temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 cycles at the discretion of the treating investigator in the absence of disease progression or unacceptable toxicity. Patients also undergo contrast-enhanced brain MRI throughout the trial.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

In a study of 70 melanoma patients with brain metastases, those treated with ipilimumab had a significantly longer median survival of 18.3 months compared to 5.3 months for those who did not receive the treatment, indicating ipilimumab enhances overall survival.

Patients who received ipilimumab before radiotherapy showed a higher partial response rate (40%) to treatment compared to those who did not receive ipilimumab (9.1%), suggesting that the sequence of treatments may influence disease control in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and radiation therapy for melanoma brain metastases. Silk, AW., Bassetti, MF., West, BT., et al.[2022]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

In a phase 1 study involving 16 patients with brain metastases from melanoma, ipilimumab combined with stereotactic radiosurgery (SRS) was found to be safe at a maximum dose of 10 mg/kg, with no dose-limiting toxicities reported.

The study showed that while the median progression-free survival was similar for both treatment arms (2.1 months for SRS and 2.5 months for whole brain radiation therapy), the overall survival was not reached for the SRS group, indicating potential benefits of this combination therapy that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. Williams, NL., Wuthrick, EJ., Kim, H., et al.[2022]

In a phase 1 study involving 20 patients with stage IV melanoma, combining radiotherapy with nivolumab and ipilimumab was found to be safe, with treatment-related severe adverse events occurring in 40% of patients in one cohort and 30% in another, but no severe events linked to radiotherapy itself.

Patients showed positive responses to treatment outside the irradiated areas, indicating potential systemic immunologic effects, as evidenced by increased T-cell receptor diversity in some responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma. Postow, MA., Knox, SJ., Goldman, DA., et al.[2021]

Patients with melanoma brain metastases who received ipilimumab alongside stereotactic radiosurgery (SRS) had a significantly improved overall survival (OS) of 15.1 months compared to 7.8 months for those who did not receive ipilimumab, indicating its efficacy in enhancing treatment outcomes.

While ipilimumab did not increase the risk of acute toxicity, 5% of patients experienced radiation necrosis, primarily among those treated with ipilimumab, suggesting a need for careful monitoring in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. Diao, K., Bian, SX., Routman, DM., et al.[2020]

In a review of 16 melanoma patients treated with ipilimumab and cranial radiation, the combination was found to be well tolerated and associated with a median survival of 14 months, suggesting potential benefits for patients with brain metastases.

There was a notable trend indicating that administering ipilimumab within three months of radiation may enhance the likelihood of improved responses in extra-cranial lesions, warranting further investigation into the timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. Schoenfeld, JD., Mahadevan, A., Floyd, SR., et al.[2022]

Combining palliative radiotherapy (pRT) with immune checkpoint inhibitors (ICI) in melanoma treatment significantly improved objective response rates, complete response rates, and one-year local control, indicating enhanced efficacy of the treatment.

The combination treatment did not lead to a significant increase in adverse events or immune-related adverse events compared to ICI alone, suggesting that it is a safe option for patients with advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. Ben Shimol, J., Guzman-Prado, Y., Karlinskaya, M., et al.[2021]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11587836/

Pre-radiation Nivolumab plus ipilimumab in patients with ...

We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11376446/

NRG-BN002: Phase I study of ipilimumab, nivolumab, and the ...

The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04606316

Surgical Nivolumab And Ipilimumab For Recurrent GBM

This research trial is studying the safety and effectiveness of nivolumab in combination with ipilimumab and surgery when used in the treatment of recurrent ...

4.

ecancer.org

ecancer.org/en/news/26884-dual-immune-checkpoint-inhibition-with-radiotherapy-does-not-improve-progression-free-survival-for-patients-with-newly-diagnosed-mgmt-unmethylated-glioblastoma

Dual immune checkpoint inhibition with radiotherapy does ...

A pre-planned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipilimumab ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.2057

Results of nivolumab plus ipilimumab treatment arm.

Results: Fifteen patients were treated with nivolumab plus ipilimumab. 27% (4/15) of patients were receiving dexamethasone at treatment ...

6.

nrgoncology.org

nrgoncology.org/Home/News/Post/dual-immune-checkpoint-inhibition-with-radiotherapy-does-not-improve-progression-free-survival-for-patients-with-newly-diagnosed-mgmt-unmethylated-glioblastoma

News Post Template

... ipilimumab and nivolumab with radiation therapy was safe for patients with newly diagnosed glioblastoma. Glioblastoma is the most common ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04396860

Study Details | NCT04396860 | Testing the Use of the ...

Giving radiation therapy with ipilimumab and nivolumab may lengthen the time without brain tumor returning or growing and may extend patients' life compared ...

8.

ascopost.com

ascopost.com/news/august-2025/glioblastoma-dual-immunotherapy-plus-radiotherapy-in-newly-diagnosed-mgmt-unmethylated-disease/

Glioblastoma: Dual Immunotherapy Plus Radiotherapy in ...

The combination of ipilimumab and nivolumab plus radiation therapy did not lead to an improvement in progression-free survival compared with ...