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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effects of nivolumab, BMS-986205, and standard radiation therapy with or without temozolomide in treating patients with new diagnosed glioblastoma. Immunotherapy with nivolumab, may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. BMS-986205 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, 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. Giving nivolumab and BMS-986205 may work better compared to radiation therapy and temozolomide alone in treating patients with newly diagnosed glioblastoma.

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 the combination of immunotherapy, targeted therapy, and radiation generally safe for humans?

The combination of nivolumab (a type of immunotherapy) and radiation therapy, with or without temozolomide (a chemotherapy drug), has been studied for safety in glioblastoma patients. Temozolomide is generally considered safe but can cause severe blood-related side effects in some cases. Nausea and constipation are also common side effects when using temozolomide with radiation therapy. ^{1 2 3 4 5}

What makes the treatment with BMS-986205, Nivolumab, Radiation Therapy, and Temozolomide unique for glioblastoma?

This treatment combines immunotherapy (using drugs like Nivolumab) with targeted therapy and radiation, aiming to enhance the immune system's ability to fight glioblastoma, a type of brain cancer. The combination of these therapies is designed to improve survival by using the body's own defenses alongside traditional cancer treatments. ^{1 6 7 8 9}

What data supports the effectiveness of the treatment involving immunotherapy, targeted therapy, and radiation for glioblastoma?

Research shows that combining temozolomide (a chemotherapy drug) with radiotherapy can improve overall survival in glioblastoma patients, especially when the MGMT promoter is methylated. Additionally, nivolumab (an immune checkpoint inhibitor) combined with radiotherapy is being explored for its potential benefits in glioblastoma treatment. ^{1 8 10 11 12}

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

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]

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 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 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 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]

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]

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]

Citations

1. England 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. [2023]

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

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. [2023]

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

Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma. [2022]

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

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. [2018]

6. United States 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. [2018]

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

Phase II trial of hypofractionated IMRT with temozolomide for patients with newly diagnosed glioblastoma multiforme. [2018]

8. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

9. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

10. England pubmed.ncbi.nlm.nih.gov

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

11. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

12. India pubmed.ncbi.nlm.nih.gov

Prognostic factors effective on survival of patients with glioblastoma: Anadolu Medical Center experience. [2018]