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

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, 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.

What data supports the effectiveness of the drug Relatlimab + Nivolumab + Ipilimumab for Melanoma?

Research shows that combining nivolumab and ipilimumab significantly improves survival and response rates in advanced melanoma compared to using ipilimumab alone. Additionally, nivolumab combined with relatlimab has shown better results than nivolumab alone in treating melanoma. ^{1 2 3 4 5}

Is the combination of Relatlimab, Nivolumab, and Ipilimumab safe for humans?

The combination of Nivolumab and Relatlimab has a manageable safety profile in patients with advanced melanoma. However, combining Nivolumab with Ipilimumab can increase the risk of immune-related side effects, which are reactions where the immune system attacks healthy cells. More studies are needed to fully understand the safety of these combinations. ^{6 7 8 9 10}

What makes the drug combination of relatlimab, nivolumab, and ipilimumab unique for treating melanoma?

This drug combination is unique because it includes relatlimab, a first-in-class drug targeting the LAG-3 protein, which is combined with nivolumab and ipilimumab to enhance the immune response against melanoma. This combination has shown to more than double progression-free survival compared to nivolumab alone, offering a promising new option for patients with advanced melanoma. ^{1 3 6 11 12}

What is the purpose of this trial?

This is a multicenter, phase II trial of relatlimab (rela), nivolumab (nivo), and ipilimumab (ipi) in patients with asymptomatic and symptomatic melanoma brain metastases.

Research Team

Allison B Warner, MD, PhD

Principal Investigator

Stanford University

Eligibility Criteria

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.

Participants with known HIV-infection must meet specific criteria

I am following strict birth control measures.

Exclusion Criteria

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

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

I am not pregnant or breastfeeding.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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]

References

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

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

2. Georgia (Republic) 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)]. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]

4. England 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. [2022]

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

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma. [2023]

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

Nivolumab Plus Relatlimab: First Approval. [2022]

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

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

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

Novel melanoma therapies and their side effects. [2018]

10. Greece pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. [2021]

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

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

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

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