Nivolumab + Relatlimab + Ipilimumab for Melanoma

Overseen By Hussein Tawbi, MD,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives, Herbal supplements, others

Disqualifiers: Ocular melanoma, Autoimmune disease, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, the use of corticosteroids is not allowed for 14 days before starting the trial, except for certain cases like physiological replacement. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Nivolumab, Relatlimab, and Ipilimumab for treating melanoma?

Research shows that combining nivolumab and ipilimumab improves survival and response rates in advanced melanoma compared to using ipilimumab alone. Additionally, nivolumab combined with relatlimab has been found to be more effective than nivolumab alone in certain melanoma patients. ^{1 2 3 4 5}

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

The combination of Nivolumab and Relatlimab has a manageable safety profile in patients with advanced melanoma, but combining Nivolumab with Ipilimumab can increase the risk of immune-related side effects. These side effects are specific to each drug and can combine when used together, so it's important to monitor for these reactions. ^{6 7 8 9 10}

What makes the drug combination of Nivolumab, Relatlimab, and Ipilimumab unique for treating melanoma?

This drug combination is unique because it combines three immunotherapy agents that target different immune checkpoints, enhancing the body's immune response against melanoma. Nivolumab targets PD-1, Relatlimab targets LAG-3, and Ipilimumab targets CTLA-4, making it a comprehensive approach to boost the immune system's ability to fight cancer. ^{1 2 6 11 12}

What is the purpose of this trial?

To determine the recommended Phase IIa dose (RP2D) of the triplet combination. To determine the safety and efficacy of the combination at the RP2D.

Research Team

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for individuals with metastatic melanoma, which means their skin cancer has spread to other parts of the body. They should be receiving this treatment as their first line of therapy. Specific details about who can or cannot participate are not provided here.

Inclusion Criteria

I know my BRAF V600 mutation status or agree to be tested.

I am fully active or can carry out light work.

I have signed the consent form for this study.

Exclusion Criteria

I have been diagnosed with eye melanoma.

The use of herbal supplements within 7 days

Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Determine the recommended Phase IIa dose (RP2D) of ipilimumab in combination with nivolumab and relatlimab

12 weeks

Phase IIa Treatment

Determine the preliminary clinical efficacy of ipilimumab at the RP2D in combination with nivolumab and relatlimab

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Relatlimab

Trial Overview The study is testing a combination of three drugs: Nivolumab, Relatlimab, and Ipilimumab in patients with metastatic melanoma. The goal is to find the safest and most effective dose for Phase IIa of the trial.

Participant Groups

Group I: Phase I + IIa: Nivolumab + Relatlimab + Ipilimumab Experimental Treatment 3 Interventions

Participants particiapting on study will be randomized

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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 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]

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]

The CheckMate 511 study found that using nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) resulted in a significantly lower incidence of severe treatment-related adverse events (34%) compared to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) which had a 48% incidence (P = .006).

While the efficacy outcomes such as objective response rate (45.6% for NIVO3+IPI1 vs. 50.6% for NIVO1+IPI3) and median progression-free survival (9.9 months vs. 8.9 months) were similar between the two groups, the NIVO3+IPI1 regimen showed a better safety profile without compromising effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. Lebbé, C., Meyer, N., Mortier, L., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

4. 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]

5. 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]

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. England pubmed.ncbi.nlm.nih.gov

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. [2023]

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

Novel melanoma therapies and their side effects. [2018]

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

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study). [2023]

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

Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. [2020]