Nivolumab for Brain Cancer

Overseen By Jing Wu, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immune therapy, Corticosteroids

Disqualifiers: Autoimmune disease, HIV, Pregnancy, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 20

Duration: 64 weeks

61 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on a corticosteroid dose greater than dexamethasone 1 mg per day or its equivalent, and you cannot be receiving any other investigational agents.

What data supports the effectiveness of the drug Nivolumab for brain cancer?

Research shows that Nivolumab, used for lung cancer with brain metastases, has shown some positive effects in the brain, with one complete and one partial response in patients. This suggests it might help in treating brain cancer, but more research is needed to confirm its effectiveness specifically for brain cancer. ^{1 2 3 4 5}

Is Nivolumab safe for humans?

Nivolumab, also known as Opdivo, is generally safe for humans, but it can cause rare side effects like encephalitis (inflammation of the brain), which may lead to symptoms such as confusion or weakness. These side effects are treatable with steroids if recognized early. ^{6 7 8 9 10}

How is the drug Nivolumab unique for treating brain cancer?

Nivolumab is unique because it is an immune checkpoint inhibitor that helps the body's immune system attack cancer cells, and it has shown activity in brain metastases from other cancers, despite the challenge of penetrating the blood-brain barrier. ^{4 11 12 13 14}

What is the purpose of this trial?

Background: Gliomas are the most common malignant brain tumors. Some have certain changes (mutations) in the genes IDH1 or IDH2. If there are a high number of mutations in a tumor, it is called hypermutator phenotype (HMP). The drug nivolumab helps the immune system fight cancer. Researchers think it can be more effective in patients with IDH1 or IDH2 mutated gliomas with HMP. They will test gliomas with and without HMP. Objectives: To see if nivolumab stops tumor growth and prolongs the time that the tumor is controlled. Eligibility: Adults 18 years or older with IDH1 or IDH2 mutated gliomas Design: Participants will be screened with: Medical history Physical exam Heart, blood, and pregnancy tests Review of symptoms and activity levels Brain magnetic resonance imaging (MRI). Participants will lie in a cylinder that takes pictures in a strong magnetic field. Tumor samples Participants will get the study drug in 4-week cycles. They will get it through a small plastic tube in a vein (IV) on days 1 and 15 of cycles 1-4. For cycles 5-16, they will get it just on day 1. On days 1 and 15 of each cycle, participants will repeat some or all screening tests. After cycle 16, participants will have 3 follow-up visits over 100 days. They will answer health questions, have physical and neurological exams, and have blood tests. They may have a brain MRI. Participants whose disease did not get worse but who finished the study drug within 1 year of treatment may have imaging studies every 8 weeks for up to 1 year. Participants will be called or emailed every 6 months with questions about their health.

Research Team

Jing Wu, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with IDH1 or IDH2 mutated gliomas are eligible for this trial. They must have adequate organ function, be able to undergo MRI scans, and not be pregnant or breastfeeding. Participants should not have a history of severe allergies to monoclonal antibodies, active infections, certain autoimmune diseases, or other cancers within the last three years.

Inclusion Criteria

Patient must be able to tolerate an MRI study with intravenous gadolinium contrast

I can care for myself but may need occasional help.

My organs and bone marrow are working well.

Exclusion Criteria

Pregnant women or breastfeeding mothers

I do not have any uncontrolled illnesses.

History of severe hypersensitivity reaction to any monoclonal antibody

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nivolumab in 4-week cycles, with IV administration on days 1 and 15 for cycles 1-4, and on day 1 for cycles 5-16

64 weeks

16 visits (in-person)

Follow-up

Participants have 3 follow-up visits over 100 days, including health questions, physical and neurological exams, blood tests, and possibly a brain MRI

14 weeks

3 visits (in-person)

Long-term follow-up

Participants whose disease did not progress may have imaging studies every 8 weeks for up to 1 year, and will be contacted every 6 months for health updates

12 months

Treatment Details

Interventions

• Nivolumab

Trial Overview The trial is testing Nivolumab's effectiveness on brain tumors with specific genetic mutations (IDH1/IDH2). It aims to see if it can stop tumor growth in patients with these mutations both with and without a high number of additional mutations known as HMP.

Participant Groups

Group I: 1/Nivolumab Experimental Treatment 1 Intervention

IV nivolumab

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nivolumab, an anti-PD-1 immunotherapy, was associated with immune-related encephalitis in a 60-year-old woman with recurrent head and neck cancer, highlighting a potential serious side effect of this treatment.

Despite the occurrence of immune-related toxicities, including encephalitis and hypothyroidism, the patient achieved a complete radiologic response one year after stopping nivolumab, demonstrating the efficacy of immunotherapy in managing advanced cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoimmune-related encephalitis during treatment with nivolumab for advanced head and neck cancer: a case report. Guidi, A., Violati, M., Blasi, M., et al.[2022]

In a retrospective study of five patients with advanced non-small cell lung cancer (NSCLC) and new or progressing brain metastases, nivolumab showed promising intracranial activity, with one complete and one partial response observed, and stabilization of leptomeningeal carcinomatosis in another patient.

Nivolumab was well-tolerated, with no severe treatment-related adverse events reported, suggesting a favorable safety profile for patients with CNS metastases from NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Dudnik, E., Yust-Katz, S., Nechushtan, H., et al.[2022]

In a phase III trial, nivolumab significantly improved health-related quality of life (HRQoL) and disease-related symptoms compared to docetaxel in patients with advanced non-squamous non-small cell lung cancer, with improvements noted at multiple time points (weeks 12, 24, 30, and 42).

Patients receiving nivolumab experienced a longer time to first deterioration in HRQoL compared to those treated with docetaxel, indicating a more favorable safety profile and sustained symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Reck, M., Brahmer, J., Bennett, B., et al.[2019]

Nivolumab plus ipilimumab significantly improved overall survival in patients with metastatic non-small cell lung cancer (NSCLC), including those with baseline brain metastases, compared to chemotherapy, with a hazard ratio of 0.63 for those with brain metastases and 0.76 for those without.

At 5 years, patients with baseline brain metastases treated with nivolumab plus ipilimumab had higher rates of systemic (12%) and intracranial (16%) progression-free survival compared to chemotherapy (0% and 6%, respectively), and fewer developed new brain lesions (4% vs. 20%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1. Reck, M., Ciuleanu, TE., Lee, JS., et al.[2023]

In a study of 66 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab, those with a poor performance status (PS ≥2) had a significantly shorter median overall survival of 3.04 months compared to 10.23 months for those with better performance status (PS ≤1).

Despite similar rates of treatment-related adverse events between the two groups, the findings suggest that performance status is a crucial factor in predicting survival outcomes and should be considered when selecting immunotherapy treatments for lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of nivolumab in the treatment of poor performance status patients with advanced non-small cell lung cancer. Abbas, MN., Klevansky, M., Koczwara, B., et al.[2022]

Nivolumab, an immune checkpoint inhibitor approved for non-small cell lung cancer, can cause rare but serious side effects like immune-related encephalitis in 1% to 3% of patients, highlighting the need for awareness among healthcare providers.

In a case study of a 74-year-old male with stage 4 lung cancer, early recognition and treatment with intravenous steroids led to significant recovery from nivolumab-induced encephalitis, emphasizing the importance of prompt management to reduce risks of severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case Report of Steroid Responsive Nivolumab-Induced Encephalitis. Richard, K., Weslow, J., Porcella, SL., et al.[2018]

In a review of 3,763 patients with advanced melanoma treated with nivolumab and ipilimumab, 0.93% experienced serious neurologic immune-related adverse events (irAEs), including encephalitis, with a median onset time of 45 days.

Most neurologic irAEs resolved (75% of cases), but awareness and prompt management of these rare but serious events are crucial for oncologists and neurologists to prevent complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. Larkin, J., Chmielowski, B., Lao, CD., et al.[2018]

A case study of a 59-year-old woman with treatment-resistant laryngeal cancer revealed that nivolumab, an immunotherapy drug, can cause severe central nervous system (CNS) toxicities, specifically acute demyelinating encephalitis, which is rarely reported in the literature.

The patient's symptoms improved significantly after discontinuing nivolumab and receiving high-dose steroids and immunoglobulin therapy, suggesting that CNS toxicity from immune checkpoint inhibitors may be reversible with prompt treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-Associated Acute Demyelinating Encephalitis: A Case Report and Literature Review. Zafar, Z., Vogler, C., Hudali, T., et al.[2020]

In a study of 47 patients with metastatic renal cell carcinoma treated with nivolumab, 48.9% experienced immune-related adverse events (irAEs), with rash being the most common.

Patients who developed irAEs had significantly longer progression-free survival (13.1 months vs. 4.87 months) and overall survival (26.0 months vs. not reached) compared to those without irAEs, indicating that the presence of irAEs may be a positive prognostic factor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Ishihara, H., Takagi, T., Kondo, T., et al.[2020]

Nivolumab, a widely used chemotherapy drug for various cancers, has well-documented common side effects, but this study highlights the extremely rare occurrence of encephalitis as a side effect.

Reporting rare side effects like encephalitis is crucial as the field of cancer treatment evolves and more chemotherapeutic agents are introduced, ensuring better patient safety and awareness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-Induced Encephalitis in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome. Chaucer, B., Stone, A., Demanes, A., et al.[2020]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

Nivolumab and ipilimumab show significant intracranial activity in patients with melanoma brain metastases, with response rates of 46% and 57% in two phase II studies, respectively.

Nivolumab can penetrate the cerebrospinal fluid (CSF), achieving concentrations that are effective for therapeutic action, challenging the belief that large molecules like monoclonal antibodies cannot affect the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. van Bussel, MTJ., Beijnen, JH., Brandsma, D.[2020]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

References

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

Autoimmune-related encephalitis during treatment with nivolumab for advanced head and neck cancer: a case report. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. [2022]

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

Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. [2019]

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

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1. [2023]

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

Real-world experience of nivolumab in the treatment of poor performance status patients with advanced non-small cell lung cancer. [2022]

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

A Case Report of Steroid Responsive Nivolumab-Induced Encephalitis. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. [2018]

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

Nivolumab-Associated Acute Demyelinating Encephalitis: A Case Report and Literature Review. [2020]

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

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. [2020]

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

Nivolumab-Induced Encephalitis in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome. [2020]

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

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. [2020]

14. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. [2022]