Ipilimumab + Nivolumab + Radiation for Glioblastoma

Recruiting at 339 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

159 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the usual treatment with radiation therapy and temozolomide to radiation therapy in combination with immunotherapy with ipilimumab and nivolumab in treating patients with newly diagnosed MGMT unmethylated glioblastoma. Radiation therapy uses high energy photons to kill tumor and shrink tumors. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temozolomide, may not work as well for the treatment of tumors that have the unmethylated MGMT. Immunotherapy with monoclonal antibodies called immune checkpoint inhibitors, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is possible that immune checkpoint inhibitors may work better at time of first diagnosis as opposed to when tumor comes back. Giving radiation therapy with ipilimumab and nivolumab may lengthen the time without brain tumor returning or growing and may extend patients' life compared to usual treatment with radiation therapy and temozolomide.

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.

What data supports the effectiveness of the treatment Ipilimumab + Nivolumab + Radiation for Glioblastoma?

Research shows that combining ipilimumab with radiation therapy improved survival in patients with melanoma brain metastases, suggesting that this combination might also be effective for glioblastoma. Additionally, studies indicate that radiation therapy can enhance the effects of immune checkpoint inhibitors like ipilimumab and nivolumab, potentially leading to better outcomes. ^{1 2 3 4 5}

Is the combination of Ipilimumab, Nivolumab, and Radiation Therapy generally safe for humans?

Studies have shown that combining Ipilimumab and Nivolumab with radiation therapy has been used safely in patients with melanoma, including those with brain metastases. However, these treatments can have side effects, and the safety profile may vary depending on the specific condition and treatment combination. ^{1 3 4 6 7}

How is the treatment of Ipilimumab, Nivolumab, and Radiation Therapy for Glioblastoma different from other treatments?

This treatment combines immune checkpoint inhibitors (Ipilimumab and Nivolumab) with radiation therapy, which may enhance the immune system's ability to attack tumor cells, a strategy that has shown promise in other cancers like melanoma. This combination is unique because it leverages both the direct tumor-killing effects of radiation and the immune-boosting effects of the drugs, potentially leading to better outcomes than using these treatments separately. ^{1 3 4 5 8}

Research Team

Andrew B Lassman

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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]

References

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

A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]

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

Ipilimumab and radiation therapy for melanoma brain metastases. [2022]

4. England 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. [2018]

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

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. [2020]

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

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. [2021]

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

Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. [2022]