Immunotherapy + Targeted Therapy + Radiation for Glioblastoma

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must not be taking: Corticosteroids, Immunosuppressants, Investigational agents, others

Disqualifiers: Chemotherapy, Brain radiation, Autoimmune, others

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

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for glioblastoma, an aggressive brain cancer. It tests the effectiveness of immunotherapy drugs (nivolumab, also known as Opdivo, and BMS-986205, an experimental treatment) combined with radiation therapy, and sometimes with an additional chemotherapy drug (temozolomide), in stopping tumor growth. The goal is to determine if these combined treatments outperform the usual approach. Ideal participants are those newly diagnosed with glioblastoma who have not undergone chemotherapy or radiation therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you must be off all steroids at the start of the study treatment. Additionally, you cannot be on any investigational agents or certain medications that affect the immune system.

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

Research shows that nivolumab is usually well-tolerated by patients with glioblastoma. In studies, patients treated with nivolumab demonstrated that it could reach brain tumors and trigger immune responses without causing serious side effects.

Temozolomide, a chemotherapy drug approved by the FDA for treating certain brain cancers like glioblastoma, is generally safe. However, some patients, especially older adults, may experience low blood cell counts or tiredness.

Less information is available about BMS-986205, which is currently in a phase 1 trial. These trials are small studies that focus on determining the safety of a new treatment before testing it in larger groups. Therefore, safety information is still being collected, and its tolerability is not fully known yet.

Overall, while nivolumab and temozolomide have established safety records, BMS-986205 remains in the early stages of research. Participants should consider these factors when thinking about joining the clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for glioblastoma because it combines immunotherapy, targeted therapy, and radiation, which is a novel approach compared to the current standard of care. The standard treatments typically include surgery, radiation, and the chemotherapy drug temozolomide alone. This new treatment regimen includes BMS-986205, an IDO1 inhibitor that may enhance the immune system's ability to fight cancer, and nivolumab, a drug that helps the immune system recognize and attack cancer cells more effectively. By integrating these therapies, there's hope for a more robust attack on tumor cells, potentially improving outcomes for patients with this aggressive brain cancer.

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

This trial will evaluate the combination of nivolumab and BMS-986205 with radiation therapy for individuals newly diagnosed with glioblastoma. Research suggests that nivolumab, which participants in this trial may receive, enhances the immune system's ability to fight the tumor and has improved survival in glioblastoma patients. BMS-986205, another treatment option in this trial, blocks certain enzymes that aid tumor cell growth. Studies have shown that combining these treatments can lead to better survival outcomes than using them separately. In one of the trial arms, temozolomide, a chemotherapy drug, is combined with radiation therapy, which has been proven to improve survival rates. Together, these treatments aim to attack the cancer in different ways, potentially improving outcomes for patients with glioblastoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Rimas V. Lukas, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed glioblastoma who have stable or decreasing steroid use, adequate blood counts and organ function, and a performance score of >=70%. They must not have had recent brain radiation or chemotherapy, certain genetic deficiencies or lung diseases, other cancers within 2 years, known allergies to the drugs tested, be pregnant/nursing, HIV/AIDS positive, drug/alcohol dependent or on immunosuppressants.

Inclusion Criteria

I had my diagnostic surgery or biopsy less than 5 weeks ago.

My organs and bone marrow are working well.

I had specific MRI scans before and within 3 days after my surgery or biopsy.

Exclusion Criteria

I do not have any unmanaged ongoing illnesses.

I or my family have a history of conditions that increase the risk of methemoglobinemia.

Blood methemoglobin > upper limit of normal (ULN)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Patients undergo radiation therapy 5 days per week for up to 6 weeks, with concurrent administration of nivolumab and BMS-986205, and temozolomide for the methylated cohort.

6 weeks

5 visits per week (in-person)

Maintenance Therapy

Patients receive BMS-986205 and nivolumab, with temozolomide for the methylated cohort, in 28-day cycles for up to 2 years.

Up to 2 years

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and every 3 months thereafter.

3 years

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• BMS-986205
• Nivolumab
• Radiation Therapy
• Temozolomide

Trial Overview The study tests if nivolumab (an immune system modulator), BMS-986205 (an enzyme blocker), combined with standard radiation therapy are more effective when temozolomide (a chemotherapy drug) is added. It aims to see which combination better stops tumor growth in patients with glioblastoma.

How Is the Trial Designed?

Group I: Unmethylated Cohort (radiation, BMS-986205 50mg QD, nivolumab) Experimental Treatment 3 Interventions

RADIATION THERAPY: Patients with MGMT unmethylated promoter undergo radiation therapy 5 days per week (Monday-Friday) for up to 6 weeks. Patients also receive IDO1 inhibitor BMS-986205 PO QD and nivolumab IV over 30 minutes every 2 weeks for up to 6 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-5 and on day 1 of subsequent cycles. Cycles repeats every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity, withdrawal of consent, the study ends, or until Q4W dosing begins.

Group II: Unmethylated Cohort (radiation, BMS-986205 100mg QD, nivolumab) Experimental Treatment 3 Interventions

RADIATION THERAPY: Patients with MGMT unmethylated promoter undergo radiation therapy 5 days per week (Monday-Friday) for up to 6 weeks. Patients also receive IDO1 inhibitor BMS-986205 PO QD and nivolumab IV over 30 minutes every 2 weeks for up to 6 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-5 and on day 1 of subsequent cycles. Cycles repeats every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity, withdrawal of consent, the study ends, or until Q4W dosing begins.

Group III: Methylated Cohort (radiation, temozolomide, BMS-986205 25mg QD, nivolumab) Experimental Treatment 4 Interventions

RADIATION THERAPY: Patients with MGMT methylated promoter undergo radiation therapy 5 days per week (Monday-Friday) for up to 6 weeks. Patients also receive temozolomide PO QD, IDO1 inhibitor BMS-986205 PO QD, and nivolumab IV over 30 minutes every 2 weeks for up to 6 weeks in the absence of disease progression, unacceptable toxicity, withdrawal of consent, the study ends, or until Q4W dosing begins. MAINTENANCE THERAPY: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-5 and on day 1 of subsequent cycles. Within 4 weeks of radiation therapy completion, patients also receive temozolomide PO QD on days 1-5 of cycles 2-6. Cycles repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a study of 87 newly diagnosed glioblastoma patients, only 5% experienced severe myelotoxicity during treatment with temozolomide (TMZ) and radiation therapy, indicating that while the risk exists, it is relatively low.

Factors such as female sex, low pretreatment platelet counts, and specific genetic markers were identified as potential predictors of severe myelotoxicity, suggesting that personalized treatment approaches could help mitigate risks in vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Lombardi, G., Rumiato, E., Bertorelle, R., et al.[2018]

In a study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

In a phase III study involving 716 patients with newly diagnosed glioblastoma, the addition of the immune checkpoint inhibitor nivolumab (NIVO) to standard radiotherapy (RT) and temozolomide (TMZ) did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to placebo, with median OS of 28.9 months for NIVO versus 32.1 months for placebo.

The study found a higher rate of grade 3/4 treatment-related adverse events in the NIVO group (52.4%) compared to the placebo group (33.6%), indicating that while NIVO did not enhance efficacy, it was associated with increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Lim, M., Weller, M., Idbaih, A., et al.[2023]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

Citations

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Both IDO1 and TDO contribute to the malignancy of ... Our results showed that the IDO1/TDO–Kyn–AhR–AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas.