Relatlimab + Nivolumab for Recurrent Glioblastoma

Recruiting at 124 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: National Cancer Institute (NCI)

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II trial compares the safety, side effects and effectiveness of anti-lag-3 (relatlimab) and anti-PD-1 blockade (nivolumab) to standard of care lomustine for the treatment of patients with glioblastoma that has come back after a period of improvement (recurrent). Relatlimab and nivolumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. Lomustine is a chemotherapy drug and in a class of medications called alkylating agents. It damages the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Relatlimab and nivolumab may be safe, tolerable, and/or effective compared to standard of care lomustine in treating patients with recurrent glioblastoma.

Do I have to stop taking my current medications for the trial?

The protocol does not specify if you need to stop taking your current medications. However, you must be off corticosteroids for at least 5 days before joining the trial.

What data supports the idea that Relatlimab + Nivolumab for Recurrent Glioblastoma is an effective treatment?

The available research does not provide specific data supporting the effectiveness of Relatlimab + Nivolumab for Recurrent Glioblastoma. The studies mentioned focus on other treatments or conditions, such as the limited benefit of PD-1 inhibitors like nivolumab for recurrent high-grade gliomas and the effectiveness of nivolumab + relatlimab in melanoma, not glioblastoma. Therefore, there is no direct evidence from the provided information to support the effectiveness of Relatlimab + Nivolumab for Recurrent Glioblastoma. ^{1 2 3 4 5}

What safety data is available for Relatlimab and Nivolumab in treating recurrent glioblastoma?

The safety of Nivolumab, with or without Ipilimumab, has been evaluated in patients with recurrent glioblastoma in the CheckMate 143 study, focusing on safety/tolerability and immune-mediated effects. Additionally, a systematic review and meta-analysis assessed the safety of Nivolumab for newly diagnosed and recurrent glioblastoma multiforme. Intracerebral administration of Nivolumab combined with Ipilimumab was also investigated in a phase I trial, providing further safety data. However, specific safety data for the combination of Relatlimab and Nivolumab in recurrent glioblastoma is not directly mentioned in the provided research. ^{1 2 6 7 8}

Is the drug Nivolumab, Relatlimab a promising treatment for recurrent glioblastoma?

The combination of Nivolumab and Relatlimab shows promise in treating certain cancers, like melanoma, by working better together than Nivolumab alone. However, the research doesn't specifically highlight its effectiveness for recurrent glioblastoma, so more studies are needed to confirm its potential for this condition. ^{1 2 3 4 7}

Research Team

Michael Lim

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for adults over 18 with recurrent glioblastoma, confirmed by WHO criteria and RANO criteria. Participants must have stable neurological status without steroids for 5 days, a Karnofsky Performance Status of at least 60%, an ALC of ≥1000/mm^3, no IDH mutation, and are in their first recurrence post radiation therapy and temozolomide. Prior treatments should be completed within specific time frames before joining.

Inclusion Criteria

I haven't taken corticosteroids for 5 days before signing up.

Absolute lymphocyte count (ALC): ≥ 1000/mm^3

Platelet count: ≥ 100,000/mm^3

Exclusion Criteria

I do not have any lung problems causing symptoms.

I do not have any autoimmune diseases needing treatment, except possibly thyroid issues or diabetes.

Treatment Details

Interventions

• Lomustine (Alkylating agents)
• Nivolumab (Monoclonal Antibodies)
• Relatlimab (Monoclonal Antibodies)

Trial Overview The trial compares the safety and effectiveness of two monoclonal antibodies (Relatlimab & Nivolumab) against standard chemotherapy drug Lomustine in patients with recurrent glioblastoma. It aims to see if these antibodies can better inhibit tumor growth compared to traditional treatment.

Participant Groups

Group I: Arm I (nivolumab, relatlimab) Experimental Treatment 6 Interventions

Patients receive nivolumab IV over 30 minutes followed by relatlimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo surgery or biopsy, MRI, and blood sample collection throughout study.

Group II: Arm II (lomustine) Active Control 5 Interventions

Patients receive lomustine PO on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo surgery or biopsy, MRI, and blood sample collection throughout study.

Nivolumab is already approved in Canada, Switzerland for the following indications:

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

Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) after maximal safe resection of recurrent glioblastoma (rGB) was found to be feasible and safe, with mild immune-related adverse events and no significant central nervous system toxicity observed.

The treatment resulted in a median overall survival of 38 weeks, which is favorable compared to historical data, suggesting that this approach may improve outcomes for patients with rGB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. Duerinck, J., Schwarze, JK., Awada, G., et al.[2022]

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]

In a study of 31 adult patients with recurrent high-grade gliomas, salvage therapy using PD-1-blocking antibodies nivolumab or pembrolizumab, with or without bevacizumab, showed a median progression-free survival of only 3.2 months, indicating limited efficacy.

The study found no significant survival benefit from these treatments in this patient population, suggesting that PD-1-blocking antibodies should be used cautiously and only in selected cases until further clinical trial results are available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 inhibition has only limited clinical benefit in patients with recurrent high-grade glioma. Kurz, SC., Cabrera, LP., Hastie, D., et al.[2019]

In a study of 129 patients with advanced melanoma treated with nivolumab and relatlimab, those without diabetes had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients with type 2 diabetes, indicating that diabetes negatively impacts treatment efficacy.

Interestingly, patients who developed immune checkpoint inhibitor-induced diabetes (ICI-DM) during treatment had the best outcomes, suggesting that this condition may enhance the effectiveness of the therapy, possibly due to changes in LAG3 expression in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. Mallardo, D., Woodford, R., Menzies, AM., et al.[2023]

A systematic review of 48 randomized trials for recurrent glioblastoma (rGBM) found that there is no single systemic therapy that shows a clear survival advantage, with median overall survival ranging from 3 to 17.6 months across studies.

The inconsistency in outcome reporting among studies made it difficult to perform a network meta-analysis, highlighting the need for standardized measures in future research on rGBM treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current landscape of systemic therapy for recurrent glioblastoma: A systematic review of randomized-controlled trials. Fazzari, FGT., Rose, F., Pauls, M., et al.[2022]

Nivolumab alone was better tolerated than when combined with ipilimumab, with treatment-related adverse events like fatigue and diarrhea being more common in the combination therapy group.

Despite the safety concerns, some patients showed promising responses, with three achieving partial responses and eight maintaining stable disease for at least 12 weeks, indicating potential efficacy of nivolumab in treating recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Vlahovic, G., Lim, M., et al.[2023]

In a study of 26 patients with recurrent glioblastoma, pembrolizumab showed an overall response rate of 8%, with two patients experiencing partial responses lasting up to 22.8 months, indicating some durable antitumor activity.

While 73% of patients experienced treatment-related adverse events, most were manageable, suggesting that pembrolizumab has a safety profile that allows for further exploration in combination therapies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. Reardon, DA., Kim, TM., Frenel, JS., et al.[2021]

Nivolumab treatment showed improved overall survival outcomes in patients with newly diagnosed glioblastoma multiforme (GBM), indicating potential efficacy for this group.

However, Nivolumab did not demonstrate significant benefits in progression-free survival or in patients with recurrent GBM, suggesting that its effectiveness may be limited to newly diagnosed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for newly and recurrent glioblastoma multiforme treatment: A systematic review and meta-analysis. Araujo Moura, AW., da Silva Rodrigues, S., de Oliveira, TF., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. [2022]

2. 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]

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

PD-1 inhibition has only limited clinical benefit in patients with recurrent high-grade glioma. [2019]

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

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The current landscape of systemic therapy for recurrent glioblastoma: A systematic review of randomized-controlled trials. [2022]

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

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. [2023]

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

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Nivolumab for newly and recurrent glioblastoma multiforme treatment: A systematic review and meta-analysis. [2023]