Immune Checkpoint Inhibitors + Temozolomide for Brain Cancer

Overseen By Eric C Burton, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Temozolomide

Must not be taking: Corticosteroids, Investigational agents

Disqualifiers: Autoimmune disease, Active infection, 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: 3

Duration: 24 weeks

47 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Glioblastoma (GBM) is a type of malignant glioma. These cancers are nearly always fatal. People who develop these cancers get aggressive treatments. But the tumors almost always recur. Researchers want to study people with newly diagnosed disease to learn more. Objective: To study people with newly diagnosed GBM or gliosarcoma to look at the changes in immune cells in the blood of those who take ipilimumab and nivolumab, along with temozolomide. Eligibility: Adults ages 18 and older with newly diagnosed GBM or gliosarcoma, who have had surgical removal of their tumor and have completed standard initial chemotherapy and radiation therapy. Design: Participants will be screened with the following: Medical record review Medical history Physical exam Tests to assess their nervous system and their ability to do typical activities Blood tests Tumor assessment. For this, they will have magnetic resonance imaging (MRI). They may get a contrast dye through an intravenous (IV) catheter. The MRI scanner makes noise. They will get earplugs. Electrocardiogram. It measures heart rate and rhythm. They will lie still. Sticky pads will be placed on their chest, arms, and legs. Screening tests will be repeated during the study. Treatment will be given in cycles. Each cycle lasts 4 weeks. Participants will get nivolumab and ipilimumab via IV. They will take temozolomide by mouth. They will keep a pill diary. Participants will fill out surveys about their symptoms. Participants will have follow-up visits about 60 days and 100 days after treatment ends. Then they will be contacted every 6 months for the rest of their life.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on a corticosteroid dose greater than 30 mg of cortisone per day, and you must stop any higher doses at least 7 days before starting the study treatment.

What data supports the effectiveness of the drug combination of immune checkpoint inhibitors and temozolomide for brain cancer?

Research shows that temozolomide, a drug used in brain cancer treatment, is being studied in combination with other therapies, including immune checkpoint inhibitors, for its potential to treat various cancers. In a study with mice, combining temozolomide with an anti-PD-1 antibody showed potential benefits for treating gliomas, a type of brain tumor. ^{1 2 3 4 5}

Is the combination of immune checkpoint inhibitors and temozolomide generally safe for humans?

Temozolomide is generally safe and well-tolerated, with common side effects like fatigue, nausea, and low blood cell counts. Severe blood-related side effects are rare. Nivolumab, an immune checkpoint inhibitor, has been studied with temozolomide and radiotherapy, showing a good safety profile in brain cancer patients. ^{3 6 7 8 9}

How is the drug combination of Ipilimumab, Nivolumab, and Temozolomide unique for brain cancer treatment?

This drug combination is unique because it combines immune checkpoint inhibitors (Ipilimumab and Nivolumab) with Temozolomide, a chemotherapy drug, to potentially enhance the immune system's ability to fight brain cancer, which is different from using Temozolomide alone. ^{1 3 10 11 12}

Research Team

Eric C Burton, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with newly diagnosed GBM or gliosarcoma who've had surgery to remove their tumor and completed initial chemo and radiation. They must be in good health, have a Karnofsky score of at least 70%, agree to use two forms of contraception, and not be pregnant or breastfeeding.

Inclusion Criteria

- The patient must be able to understand and be willing to sign a written informed consent document

I am mostly able to care for myself.

You have an intrauterine device (IUD) inserted.

Exclusion Criteria

I have had immune therapy, like a vaccine or dendritic cell vaccine.

History of allergic reactions attributed to gadolinium contrast

You have had a serious allergic reaction to any type of antibody treatment in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nivolumab and ipilimumab via IV and take temozolomide by mouth in cycles of 4 weeks

24 weeks

Weekly visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits at 60 days and 100 days post-treatment, then contacted every 6 months for life

Long-term

2 visits (in-person), then biannual contact

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Temozolomide

Trial Overview The trial is testing the combination of nivolumab and ipilimumab immunotherapies with temozolomide chemotherapy in patients with brain tumors. It aims to understand how these treatments affect immune cells in the blood. Treatment cycles last four weeks, including IV infusions and oral medication.

Participant Groups

Group I: Arm 2 Experimental Treatment 3 Interventions

Nivolumab + Ipilimumab 3mg/kg + TMZ

Group II: Arm 1 Experimental Treatment 3 Interventions

Nivolumab + Ipilimumab 1mg/kg + TMZ

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+

Findings from Research

In a mouse model of glioma, combining temozolomide (TMZ) with anti-PD-1 antibody therapy significantly improved overall survival compared to either treatment alone, indicating a potential synergistic effect.

The combination therapy also resulted in a notable reduction in tumor size and an increase in the infiltration of immune cells (CD4 and CD8 T cells) within the tumor, suggesting enhanced immune response against the glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model. Dai, B., Qi, N., Li, J., et al.[2018]

In a study of 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a study of 32 patients with brain metastases from solid tumors, the combination of temozolomide (TMZ) and cisplatin (CDDP) showed promising efficacy, with a 28.1% partial response rate and a median overall survival of 5.5 months.

The treatment was generally well-tolerated, although some patients experienced grade III-IV toxicities, including anemia and leukopenia, indicating that while the regimen is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. Christodoulou, C., Bafaloukos, D., Linardou, H., et al.[2018]

In a randomized trial involving 447 patients with recurrent high-grade glioma, temozolomide (TMZ) did not show a clear survival advantage over procarbazine, lomustine, and vincristine (PCV), with a hazard ratio of 0.91, indicating similar effectiveness.

However, within the TMZ treatment groups, the 5-day regimen demonstrated better overall progression-free survival and quality of life compared to the 21-day regimen, suggesting that shorter treatment schedules may be more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. Brada, M., Stenning, S., Gabe, R., et al.[2022]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[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 is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

A low-dose metronomic regimen of temozolomide (TMZ) significantly reduced the ratio of regulatory T cells (Tregs) to CD4+ T cells in the spleens of tumor-bearing rats, suggesting a potential strategy to enhance immune response against glioblastoma.

In contrast, standard high-dose TMZ regimens did not significantly affect Treg levels, indicating that lower doses may be more effective in modulating the immune environment for potential therapeutic benefits in glioblastoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Banissi, C., Ghiringhelli, F., Chen, L., et al.[2021]

In a phase I study involving 19 patients with advanced solid tumors, the maximum tolerated dose (MTD) of cyclical oral temozolomide (TMZ) was determined to be 100 mg/m² when combined with pegylated interferon alpha-2b (PEG-IFN-alpha-2b) at 1.5 mcg/kg/week.

The combination treatment did not alter the pharmacokinetics of PEG-IFN-alpha-2b, suggesting that it can be safely administered alongside TMZ without affecting its absorption or effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation study of cyclical weekly oral temozolomide and weekly PEG-interferon alpha-2b in patients with refractory or advanced solid tumours. Coker, SA., Dandamudi, UB., Beelen, AP., et al.[2020]

Naringenin (NGEN) significantly reduces the migration and invasion of drug-resistant glioma cells, suggesting it can enhance the effectiveness of temozolomide (TMZ) treatment.

The study provides evidence that NGEN can overcome TMZ resistance by modifying protein levels related to cell migration and invasion, making it a promising adjunct therapy for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. J, J., Vanisree, AJ.[2022]

References

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

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model. [2018]

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

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

Future directions for temozolomide therapy. [2019]

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

Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. [2018]

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

Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

7. 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]

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

Temozolomide for treating brain metastases. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. [2021]

11. England pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation study of cyclical weekly oral temozolomide and weekly PEG-interferon alpha-2b in patients with refractory or advanced solid tumours. [2020]

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

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. [2022]