Relatlimab + Nivolumab + Ipilimumab for Melanoma

Overseen By Allison Zhang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Immunosuppressants, Investigational drugs

Disqualifiers: Active infections, Autoimmune disease, Cardiac disease, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three medications—relatlimab (an experimental treatment), nivolumab, and ipilimumab—to determine their effectiveness for people with melanoma that has spread to the brain. The study includes two groups: one for those without symptoms and another for those with symptoms related to their brain metastases. Suitable candidates for this trial have melanoma that has reached the brain and have not received certain prior therapies. Participants should not have active infections or other major medical conditions that could complicate treatment. 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 need to stop taking your current medications. However, if you are taking steroids, the dose must be no higher than 4 mg of dexamethasone per day or equivalent, and it should be stable or tapering within 10 days before treatment.

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

Research has shown that the combination of relatlimab, nivolumab, and ipilimumab is generally well-tolerated, though some risks exist. Studies have found that nivolumab and ipilimumab together can cause side effects where the immune system might attack healthy cells. Common issues include skin problems, fatigue, and stomach troubles.

Adding relatlimab to nivolumab has been linked to specific heart-related risks. While some side effects are similar, each combination presents unique risks. Another study found that the safety of the nivolumab and relatlimab combo aligns with known effects of these drugs when used separately.

If these treatments are already FDA-approved for other uses, they have passed safety checks for those conditions. However, this trial remains in the early phase and is part of ongoing research to better understand these combinations. Always consult a doctor about potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of relatlimab, nivolumab, and ipilimumab for melanoma because it brings a fresh approach to how we tackle this cancer. Most treatments for melanoma, like traditional immune checkpoint inhibitors, target individual proteins such as PD-1 or CTLA-4. This combination, however, adds a new layer by including relatlimab, which targets LAG-3, a different immune checkpoint. By simultaneously blocking multiple pathways that tumors use to hide from the immune system, this treatment has the potential to enhance the body's ability to fight melanoma more effectively than current options.

What evidence suggests that this trial's treatments could be effective for melanoma brain metastases?

This trial will evaluate the effectiveness of combining relatlimab, nivolumab, and ipilimumab for treating melanoma. Studies have shown that using these drugs together can effectively treat melanoma, a type of skin cancer. For example, combining nivolumab with ipilimumab has proven more effective for advanced melanoma than using each drug alone. Adding relatlimab to nivolumab has shown similar results to the nivolumab and ipilimumab combination. In some cases, these drug combinations have led to tumor shrinkage or disappearance in up to 56% of patients with melanoma that has spread to the brain, meaning more than half of these patients saw their tumors get smaller or go away. Current research suggests that this combination could be a promising treatment for melanoma. Participants in this trial will be assigned to different cohorts based on symptom presentation to further explore these findings. ^{3 4 6 7 8}

Who Is on the Research Team?

Allison B Warner, MD, PhD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals with melanoma that has spread to the brain, whether or not they have symptoms. Specific eligibility details are not provided, but typically participants must meet certain health standards and may be excluded based on factors like other medical conditions or treatments.

Inclusion Criteria

I am fully active or have some restrictions but can still care for myself.

I have received radiation for cancer outside of my brain.

Participants with known HIV-infection must meet specific criteria

Exclusion Criteria

Specific criteria related to Troponin T (TnT) or I (TnI) levels

Implanted device that precludes the use of MRI

I have not had another type of cancer in the last 3 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive relatlimab, nivolumab, and ipilimumab for melanoma brain metastases

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Relatlimab

Trial Overview The study is testing a combination of three drugs: Relatlimab (rela), Nivolumab (nivo), and Ipilimumab (ipi) in patients with melanoma brain metastases. It's a phase II trial, which means it focuses on the effectiveness of this drug combo and further evaluates its safety.

How Is the Trial Designed?

Group I: Cohort B: Symptomatic Experimental Treatment 2 Interventions

Group II: Cohort A: Asymptomatic Experimental Treatment 2 Interventions

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

In a study of 53 patients with metastatic renal cell carcinoma treated with nivolumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival compared to those without irAEs, indicating a potential link between irAEs and treatment efficacy.

The study found that a lower platelet-to-lymphocyte ratio before treatment was a risk factor associated with the development of irAEs, suggesting that this ratio could be a useful predictor for monitoring patient responses to nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. Kobayashi, K., Iikura, Y., Hiraide, M., et al.[2021]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

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]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

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]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

In a phase III trial, the combination of the LAG3 immune checkpoint inhibitor relatlimab with the PD-1 inhibitor nivolumab significantly improved progression-free survival for melanoma patients, more than doubling the time without disease progression.

The combination therapy was associated with relatively manageable side effects, suggesting it could be a safe and effective addition to current melanoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LAG3-PD-1 Combo Impresses in Melanoma. [2021]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

Nivolumab plus relatlimab is a combination immunotherapy that targets immune checkpoints, specifically PD-1 and LAG-3, and has been approved for treating unresectable or metastatic melanoma in adults and adolescents weighing at least 40 kg.

This combination therapy represents a significant advancement in cancer treatment, as it utilizes two different mechanisms to enhance the immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. Paik, J.[2022]

Citations

1. cancernetwork.com cancernetwork.com/view/relatlimab-shows-comparable-efficacy-to-ipilimumab-in-advanced-melanoma

Relatlimab Shows Comparable Efficacy to Ipilimumab in ... The addition of relatlimab (Opdualag) to nivolumab (Opdivo) exhibited comparable efficacy outcomes vs ipilimumab (Yervoy) and nivolumab in patients with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164023/

The Latest Option: Nivolumab and Relatlimab in Advanced ... Based on the results of two phase 2 trials the combination therapy with ipilimumab and nivolumab lead to an ORR of up to 56% intracranially in patients with ...

3. opdualaghcp.com opdualaghcp.com/efficacy/melanoma/relativity-047

Efficacy | Opdualag® (nivolumab and relatlimab-rmbw) for HCPs View efficacy data for Opdualag (nivolumab and relatlimab-rmbw) in unresectable or metastatic melanoma. Please see Indications and Important Safety ...

4. news.bms.com news.bms.com/news/details/2025/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-RELATIVITY-098-Trial/default.aspx

Bristol Myers Squibb Provides Update on Phase 3 ... RELATIVITY-098 is a randomized Phase 3, double-blind study evaluating adjuvant immunotherapy with Opdualag, the fixed-dose combination of nivolumab and ...

5. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/nivolumab-opdivo-ipilimumab-yervoy

Nivolumab (Opdivo) + Ipilimumab (Yervoy) When used together, nivolumab and ipilimumab can treat advanced melanoma more effectively than each drug on its own.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9554

Efficacy and safety of first-line (1L) nivolumab plus ... This updated ITC with longer follow-up from RELA-047 suggests that 1L treatment with NIVO + RELA may have comparable efficacy to NIVO + IPI in pts with ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40684089/

Comparative safety of nivolumab plus ipilimumab versus ... NIVO-IPI is linked with a broader range of immune-related toxicities, whereas NIVO-RELA presents higher cardiac-specific risks.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925003296

Nivolumab plus relatlimab in advanced melanoma With 4 years of follow-up, nivolumab plus relatlimab demonstrated durable improvement in outcomes versus nivolumab monotherapy for patients with previously ...