Nivolumab + Temozolomide for Glioblastoma

(NUTMEG Trial)

Not currently recruiting at 19 trial locations

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Sydney

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Prior chemotherapy, Cranial radiation, Autoimmune, others

Stay on Your Current Meds You can continue your current medications while participating

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: 6

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining two treatments, nivolumab (an immunotherapy drug) and temozolomide (a chemotherapy drug), can extend survival in people with glioblastoma, a type of brain cancer, compared to using temozolomide alone. It targets individuals aged 65 or older who have recently been diagnosed with glioblastoma and have undergone surgery. Participants will receive either the combination of drugs or just temozolomide following their initial radiotherapy treatment and a break period. The goal is to determine which approach more effectively improves survival in this patient group. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it excludes those needing high doses of certain steroids or immunosuppressive drugs. It's best to discuss your specific medications with the trial team.

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

Research shows that the combination of nivolumab and temozolomide is generally well-tolerated. In one study, about 51.6% of patients experienced serious side effects when these drugs were combined with radiation, which is common for treatments in this field. Another study found that nivolumab, when used with radiation, had side effects similar to other glioblastoma treatments, indicating no unexpected issues.

Nivolumab has already been approved for other conditions, so its safety is well-known. Temozolomide is a standard treatment for glioblastoma and is widely used. Evidence suggests that using these treatments together is safe enough for further research in trials. However, discussing any concerns with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Nivolumab with Temozolomide for treating glioblastoma because it introduces a novel approach to tackling this aggressive brain cancer. Unlike the standard of care, which primarily relies on chemotherapy with Temozolomide, Nivolumab is an immunotherapy drug that helps the body's own immune system recognize and attack cancer cells. This combination aims to boost the effectiveness of the immune response while still leveraging the established benefits of Temozolomide, potentially leading to better outcomes for patients. By integrating these two mechanisms, there is hope for improved survival rates and quality of life for those battling glioblastoma.

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

Research has shown that adding temozolomide to radiotherapy can extend the lives of patients with glioblastoma, a type of brain cancer. Studies have found this combination more effective than radiotherapy alone. In this trial, one group of participants will receive the standard treatment of adjuvant temozolomide after radiotherapy. Another group will receive nivolumab, an immunotherapy drug, with temozolomide to determine if it can further improve survival rates. Early results suggest that nivolumab might enhance the immune system's ability to fight the cancer. While more research is needed, there is hope that adding nivolumab could lead to better outcomes for glioblastoma patients. ^{1 3 4 6 7}

Who Is on the Research Team?

Mustafa Khasraw

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

Elderly patients aged 65 or above with newly diagnosed glioblastoma (GBM) may qualify for this trial. They should have had surgery, a life expectancy over 12 weeks, and be able to undergo MRI scans. Excluded are those needing high doses of steroids, with certain autoimmune diseases or other serious health issues that could affect the study.

Inclusion Criteria

My liver tests are within normal limits.

I have tissue available for MGMT testing.

My blood tests show my bone marrow is working well.

Exclusion Criteria

I have been cancer-free for 2 years, except for certain skin or in-situ cancers.

I have an autoimmune disease but it's controlled or minor, like type 1 diabetes, mild hypothyroidism, or certain skin conditions.

I need more than 4 mg of dexamethasone or more than 20 mg of prednisone daily for my GBM symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy

Participants receive standard radiotherapy treatment (40 Gy administered in 15 fractions)

3 weeks

Treatment

Participants receive either Nivolumab with Temozolomide or Temozolomide alone after a 4-week break post-radiotherapy

24 weeks

6 cycles of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Temozolomide

Trial Overview The trial is testing if adding Nivolumab to Temozolomide improves survival in elderly GBM patients compared to using Temozolomide alone after surgery. It's designed to find better treatments for GBM by measuring how long patients live with each therapy.

How Is the Trial Designed?

Group I: Nivolumab and Temozolomide Experimental Treatment 2 Interventions

After radiotherapy and 4 week break, participants who are assigned to this arm will receive Nivolumab with concurrent adjuvant temozolomide treatment

Group II: Temozolomide Active Control 1 Intervention

After radiotherapy and 4 week break, participants who are assigned to this arm will receive the standard treatment of adjuvant temozolomide treatment

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

University of Sydney

Lead Sponsor

Trials

208

Recruited

417,000+

Cooperative Trials Group for Neuro-Oncology

Collaborator

Trials

2

Recruited

850+

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]

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]

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]

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 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]

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 phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Aspirin combined with temozolomide (TMZ) in coloaded microspheres showed enhanced antitumor effects against glioblastoma cells, leading to increased apoptosis and reduced cell proliferation compared to TMZ alone.

The combination therapy works by inhibiting β-catenin signaling, which is linked to tumor growth, and allows for a sustained release of TMZ, potentially reducing the required dosage while improving treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation. Shi, ZD., Qian, XM., Liu, CY., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9825306/

An international randomized phase III trial - PMC Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02617589

NCT02617589 | An Investigational Immuno-therapy Study ... The purpose of this study is to evaluate patients with glioblastoma that is MGMT-unmethylated (the MGMT gene is not altered by a chemical change).

3. nature.com nature.com/articles/s41423-024-01226-x

Immunotherapy for glioblastoma: current state, challenges ... The treatment outcomes have remained largely unchanged in recent decades, and most GBM patients experience tumor recurrence. The unique location ...

4. cancer.gov cancer.gov/clinicaltrials/NCI-2021-01939

Nivolumab and Temozolomide Versus ... The study aims to evaluate whether the combination of adjuvant nivolumab with temozolomide improves overall survival outcomes for this patient population. The ...

5. academic.oup.com academic.oup.com/noa/article/5/1/vdad124/7280593

A randomized phase II study of nivolumab and temozolomide ... A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8989388/

Nivolumab plus radiotherapy with or without temozolomide in ... NIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+ ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(20)37748-6/fulltext

Nivolumab (nivo) in combination with radiotherapy (RT) ± ... Conclusions: Nivo with RT ± TMZ was well tolerated, with the frequency of neurological AEs consistent with that in other reports in this disease. These data ...