Nivolumab + Temozolomide for Glioblastoma

(NUTMEG Trial)

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

103 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Nivolumab and Temozolomide for treating glioblastoma?

Research shows that Temozolomide is effective in treating various types of brain tumors, including glioblastoma, and is often used in combination with other treatments to improve outcomes. Additionally, Nivolumab has been studied in combination with radiotherapy and Temozolomide, showing potential benefits in newly diagnosed glioblastoma patients. ^{1 2 3 4 5}

What safety information is available for the combination of Nivolumab and Temozolomide in humans?

Temozolomide, used for brain cancers like glioblastoma, commonly causes mild to moderate side effects such as fatigue, nausea, and low blood cell counts. Severe blood-related side effects are rare but can include conditions like aplastic anemia. Safety data for Nivolumab in combination with Temozolomide specifically is limited, but Temozolomide alone has been generally well-tolerated in humans. ^{1 2 3 6 7}

How is the drug Nivolumab + Temozolomide unique for treating glioblastoma?

Nivolumab + Temozolomide is unique because it combines an immune checkpoint inhibitor (Nivolumab) with a chemotherapy drug (Temozolomide) to potentially enhance the immune system's ability to fight glioblastoma, a type of brain cancer. This combination aims to improve outcomes compared to standard treatments, which often involve only Temozolomide and radiotherapy. ^{2 5 8 9 10}

What is the purpose of this trial?

This study aims to investigate effect of Nivolumab and Temozolomide vs Temozolomide alone on overall survival in newly diagnosed elderly patients with glioblastoma. Who is it for? You may be eligible to join this study if you are aged 65 years or above, with newly diagnosed histologically confirmed GBM (WHO grade IV glioma including gliosarcoma) following surgery. The study aims to evaluate whether the combination of adjuvant nivolumab with temozolomide improves overall survival outcomes for this patient population. The outcome of the study will help determine the most effective treatment for patients with glioblastoma in the future.

Research Team

Mustafa Khasraw

Principal Investigator

Duke University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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) 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 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 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]

References

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

Future directions for temozolomide therapy. [2019]

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

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation. [2022]

5. 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]

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

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

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The safety of the temozolomide in patients with malignant glioma. [2019]

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

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

9. Greece pubmed.ncbi.nlm.nih.gov

Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line. [2021]

10. 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]