Nivolumab + Relatlimab for Glioblastoma

(GIANT Trial)

Overseen By Mustafa Khasraw

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: Immunotherapy, Anticoagulants, Immunosuppressants

Disqualifiers: CNS bleeding, Autoimmune disease, Active tuberculosis, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, nivolumab and relatlimab, to determine their safety and effectiveness in treating glioblastoma, a type of brain cancer. The trial examines the efficacy of these drugs when administered before and after surgery and compares different drug combinations. Individuals with newly diagnosed glioblastoma who require surgery and have not undergone previous radiation or chemotherapy may be suitable candidates for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients cannot be on certain treatments like immunosuppressive medications or anticoagulation therapy close to the trial start. 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 nivolumab is generally well-tolerated by patients with glioblastoma. Previous studies found that patients with recurring glioblastoma experienced few serious side effects from nivolumab, and they did not identify any major safety concerns.

For the combination of nivolumab and relatlimab, research suggests that this pair is safe and tolerable. One study found that this treatment did not present unusual safety issues compared to other treatments. The combination aids the immune system in fighting the tumor, and while it can cause some side effects, these are usually manageable.

Overall, both treatments have been studied in patients with similar conditions and have shown to be safe. However, like any treatment, side effects can occur, and discussing these with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about nivolumab and relatlimab for glioblastoma because these drugs target the immune system in a novel way. Unlike traditional chemotherapy and radiation, which directly attack cancer cells, these treatments work by enhancing the body's immune response. Nivolumab blocks PD-1, a protein that prevents T-cells from attacking cancer, while relatlimab targets LAG-3, another checkpoint inhibitor, to further unleash the immune system against the tumor. This dual approach could potentially result in more effective and sustained tumor control.

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

Research has shown that nivolumab has been tested in patients with glioblastoma, a type of brain cancer, but it did not significantly improve survival compared to treatments like bevacizumab. Despite this, nivolumab reached brain tumors and helped the immune system fight the cancer. In this trial, one group of participants will receive nivolumab alone, while another group will receive a combination of nivolumab and relatlimab. Studies in other cancers, such as melanoma, have shown promising results for this combination, with some patients experiencing long-lasting tumor shrinkage. This combination has also been found safe and effective for treating recurring glioblastoma compared to standard treatments. These findings are hopeful, but more research is needed to confirm its effectiveness specifically for glioblastoma. ^{3 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with a new diagnosis of glioblastoma, which is an aggressive type of brain cancer. Participants must have a specific genetic feature in their tumor (IDH wildtype). Details on who can't join are not provided here.

Inclusion Criteria

Life expectancy of at least 12 months

Negative human immunodeficiency virus (HIV) test at Screening

Negative hepatitis B surface antigen (HbsAg) test at Screening

Exclusion Criteria

Abnormal troponin levels

Known allergy or sensitivity to specific medications

My tumor cannot be completely removed by surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Patients receive a single dose of nivolumab with or without relatlimab followed by tumor resection

4 weeks

Part 1 Adjuvant Treatment

Patients receive nivolumab and relatlimab with concomitant radiation and TMZ for MGMT methylated patients

6 weeks

Part 2 Adjuvant Treatment

Continuation of nivolumab and relatlimab with TMZ for up to 6 cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Relatlimab

Trial Overview The GIANT study tests the combination of Nivolumab and Relatlimab immunotherapies with radiation and TMZ chemotherapy in patients with newly diagnosed glioblastoma. It's designed to see if this treatment is safe and how well it works.

How Is the Trial Designed?

Group I: Nivolumab and Relatlimab Experimental Treatment 4 Interventions

In Arm 2 and Safety Lead-In phase, patients will receive treatment in 4 stages as below: 1. Neoadjuvant Treatment: Patient will receive a single dose of 480 mg by IV infusion with 480 mg of relatimab on Day 1. 2. Resection 3. Part 1 Adjuvant Treatment: Patient will receive 480 mg of nivolumab and 480 mg of relatimab for up to 12 cycles with concomitant radiation 2Gy/day (60 Gy in total). All MGMT methylated patients under Part 1 Adjuvant Treatment setting will also receive 75 mg/m2 TMZ from Day 1 to Day 42 orally. 4. Part 2 Adjuvant Treatment: Part 1 Adjuvant Treatment will continue without concomitant radiation.

Group II: Nivolumab Experimental Treatment 3 Interventions

4 stages of treatment on Arm 1 are: 1. Neoadjuvant Treatment: Patient will receive a single dose of 480 mg by IV infusion on Day 1. 2. Resection 3. Part 1 Adjuvant Treatment: Patient will receive 480 mg of nivolumab and 380 mg of relatimab for up to 12 cycles with concomitant radiation 2Gy/day (60 Gy in total). All MGMT methylated patients under Part 1 Adjuvant Treatment setting will also receive 75 mg/m2 TMZ from Day 1 to Day 42 orally. 4. Part 2 Adjuvant Treatment: Part 1 Adjuvant Treatment will continue without concomitant radiation.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Published Research Related to This Trial

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]

Immune checkpoint inhibitors like nivolumab have revolutionized cancer treatment but can lead to serious autoimmune-like side effects known as immune-related adverse events (irAEs).

This study highlights a specific case of severe liver injury linked to nivolumab in a glioblastoma patient, emphasizing the need for better understanding and management of these potential toxicities to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Simonelli, M., Di Tommaso, L., Baretti, M., et al.[2018]

The combination of nivolumab and relatlimab shows a manageable safety profile for patients with advanced melanoma who have already undergone treatment.

This combination therapy may offer a new option for patients with pretreated melanoma, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

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 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]

Nivolumab, an immune checkpoint inhibitor, is being investigated as a treatment for pediatric glioblastoma multiforme, a rare and aggressive brain cancer, to improve patient survival.

This report highlights a significant adverse effect of nivolumab, specifically bilateral optic neuritis, in a patient with grade 4 glioblastoma multiforme, indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. Kartal, Ö., Ataş, E.[2019]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5892140/

Nivolumab with or without ipilimumab in patients with ... Exploratory efficacy results indicated that ~20% of patients achieved stable disease ≥12 weeks, and 5 (12.5%) survived >25 months. Pathologically assessed ...

2. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2766213

Effect of Nivolumab vs Bevacizumab in Patients With ... In this randomized phase 3 clinical trial of 369 patients diagnosed with recurrent glioblastoma treated with nivolumab, an improved survival benefit was not ...

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

Immunotherapy for glioblastoma: current state, challenges ... Despite these aggressive treatments, the median overall survival (mOS) of GBM patients remains dismally low, typically ranging from 12–18 months ...

4. aacrjournals.org aacrjournals.org/cancerimmunolres/article/12/9/1202/747081/Nivolumab-Reaches-Brain-Lesions-in-Patients-with

Nivolumab Reaches Brain Lesions in Patients with Recurrent ... Our study demonstrates that nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02017717

NCT02017717 | A Study of the Effectiveness and Safety ... A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients (CheckMate 143).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4638899/

SAFETY AND ACTIVITY OF NIVOLUMAB MONOTHERAPY ... Preliminary results from the study were previously presented and showed nivolumab monotherapy 3 mg/kg was well tolerated in patients with recurrent GBM, with no ...

7. ascopubs.org ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.3010

Preliminary safety and activity of nivolumab and its ... This study evaluates the safety/tolerability of the checkpoint inhibitors nivolumab (NIVO) and ipilimumab (IPI) in patients (pts) with a first recurrence of ...

8. news.bms.com news.bms.com/news/details/2017/Bristol-Myers-Squibb-Announces-Results-from-CheckMate--143-a-Phase-3-Study-of-Opdivo-nivolumab-in-Patients-with-Glioblastoma-Multiforme/default.aspx

143, a Phase 3 Study of Opdivo (nivolumab) in Patients ... A randomized Phase 3 clinical trial evaluating the efficacy and safety of Opdivo in patients with first recurrence of glioblastoma multiforme (GBM), did not ...