Nivolumab + Opdualag for Skin Cancer

(ClearMe Trial)

Overseen By Anna Spreafico, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Uveal melanoma, Metastatic disease, Autoimmune disorders, 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: 1

Duration: 6 cycles (each cycle is 28 days)

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for high-risk melanoma, a serious type of skin cancer. The researchers aim to determine if combining two drugs, Nivolumab and Opdualag (a combination of Nivolumab and Relatlimab), is more effective than using Nivolumab alone in preventing cancer recurrence after surgery. Individuals who have undergone surgery for high-risk melanoma and show no signs of disease on scans might be suitable candidates for this trial. Participants will be randomly assigned to receive either the combination treatment or the single drug 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 must stop taking your current medications. However, you cannot participate if you have used immunosuppressive medication within 14 days before the first dose, except for certain types like inhaled or topical steroids, or low-dose systemic corticosteroids.

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

Research has shown that Opdualag, a combination of the drugs nivolumab and relatlimab, maintains a safety record similar to each drug individually. In studies lasting up to four years, researchers have not found any new or unexpected side effects. Common side effects include muscle pain, tiredness, and skin problems.

Nivolumab alone also has a well-established safety record. The FDA has approved it for treating several types of cancer, indicating it is generally well-tolerated by patients.

Overall, both treatments have demonstrated consistent safety in previous studies, making them promising options for clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Nivolumab and Opdualag for skin cancer because these treatments offer a novel approach to tackling the disease. Nivolumab is an anti-PD-1 therapy that enhances the immune system's ability to detect and destroy cancer cells, providing an alternative to traditional chemotherapy. Meanwhile, Opdualag combines anti-PD-1 and anti-LAG-3 actions, potentially offering a more comprehensive immune response by targeting two different pathways that cancer cells use to evade the immune system. This dual targeting is particularly promising because it could lead to more effective and longer-lasting responses in patients.

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

Research shows that Opdualag, a combination of nivolumab and relatlimab, holds promise for treating melanoma, a type of skin cancer. In earlier studies, patients taking Opdualag experienced cancer progression at half the rate compared to those on standard treatments. On average, patients went 10.1 months without their cancer worsening, which is longer than with other treatments. This combination therapy enhances the body's immune response against cancer cells. In this trial, some participants will receive Opdualag, while others will receive nivolumab alone. Studies have shown that nivolumab alone can improve survival rates in melanoma treatment. This trial tests whether combining these treatments offers even better results for patients with high-risk melanoma. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for patients with high-risk melanoma who have had surgery to remove their cancer. They must have detectable circulating tumor DNA (ctDNA) after the surgery. The study is open to various stages of melanoma, from Stage 2A up to Stage 4.

Inclusion Criteria

Written informed consent and any locally required authorization obtained from the subject prior to performing any protocol-related procedures

My melanoma is at a high risk stage where immunotherapy could help prevent relapse.

I am eligible for surgery and immune-boosting therapy, with or without radiation, for my condition.

Exclusion Criteria

History of allogeneic organ transplantation

Judgment by the investigator that the participant should not participate in the study if unlikely to comply with study procedures

Subjects who are unable to willingly provide consent or comply with the protocol procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either anti-PD-1/LAG-3 (Opdualag/BMS-986213) or anti-PD-1 (Nivolumab) based on randomization

6 cycles (each cycle is 28 days)

Visits at pre-dose cycle 1 and 6, and end of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Opdualag

Trial Overview

The Clear-Me trial compares two treatments: Opdualag, a combination therapy targeting LAG3 and PD-1 proteins on immune cells, versus Nivolumab alone, which targets only PD-1. Patients are randomly assigned to one of these treatments post-surgery.

How Is the Trial Designed?

Group I: Anti-PD-1/LAG-3 (Opdualag/BMS-986213) Experimental Treatment 2 Interventions

Group II: Anti-PD-1 ( Nivolumab) Active Control 1 Intervention

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union 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 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?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

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]

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]

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 retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

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, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

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, 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, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Citations

1.

opdualag.com

opdualag.com/about/results

Advanced Melanoma Clinical Trial Results

Half the patients on Opdualag went 2X longer without advanced melanoma worsening than those on a standard treatment. In a clinical trial of 714 patients ...

2.

opdualaghcp.com

opdualaghcp.com/efficacy/melanoma/relativity-047

Efficacy | Opdualag® (nivolumab and relatlimab-rmbw) for HCPs

*Based on the 13.2-month median final analysis, the primary endpoint of PFS was statistically significant; mPFS† was 10.1 months (95% CI: 6.4–15.7) with ...

3.

ncbi.nlm.nih.gov

ncbi.nlm.nih.gov/books/NBK604840/

Clinical Review - Nivolumab and Relatlimab (Opdualag) - NCBI

... efficacy and safety outcomes. For efficacy outcomes (OS and PFS), data from the CheckMate 067 trial were truncated, with patients without events before ...

4.

evidence.nejm.org

evidence.nejm.org/doi/full/10.1056/EVIDoa2200239

Overall Survival and Response with Nivolumab and ...

The fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up.

5.

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 ...

Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise ...

6.

opdualaghcp.com

opdualaghcp.com/safety/melanoma/relativity-047

Safety Profile - Opdualag® (nivolumab and relatlimab-rmbw)

No new or unexpected safety events with 4-year data ; Musculoskeletal and Connective Tissue Musculoskeletal pain · General Fatigue · Skin and Subcutaneous Tissue