Nivolumab +/− Relatlimab/Ipilimumab for Skin Cancer

Overseen By Alice Pons, R.N., B. S, B.S.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, CNS metastases, HIV, 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: 4

Duration: 48 weeks

57 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of nivolumab, an immune checkpoint inhibitor, both alone and in combination with other drugs, for treating advanced basal cell carcinoma that cannot be surgically removed or has spread. The study includes different groups: one for patients who haven't tried certain treatments before, and others for those whose cancer worsened after previous therapies. This trial might suit someone with basal cell carcinoma that has spread or cannot be removed and who hasn't yet taken specific immune-modulating drugs. As a Phase 2 trial, the 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 information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medications or corticosteroids, you may need to discuss this with the study investigator.

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

Research has shown that combining nivolumab with ipilimumab reveals certain safety patterns. In studies, serious side effects such as vomiting and pneumonia occurred in at least 2% of patients. The FDA has approved this combination for treating melanoma, a type of skin cancer, which provides some confidence in its safety, though side effects can still occur.

For the combination of nivolumab with relatlimab, studies conducted over four years have shown no new or unexpected safety issues. However, significant side effects appeared in about 43% of patients with advanced melanoma. This combination is also used for skin cancer that has spread or is difficult to remove.

In summary, both treatment combinations have safety data supporting their use in conditions like melanoma. However, like all treatments, they can cause side effects. Discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for skin cancer because they uniquely target immune checkpoints to enhance the body's immune response against cancer cells. Unlike traditional chemotherapy, which directly attacks cancer cells, nivolumab, ipilimumab, and relatlimab empower the immune system by blocking proteins like PD-1, CTLA-4, and LAG-3 that cancer cells use to hide from immune attacks. This combination approach is designed to improve the immune system's ability to detect and destroy cancer cells, potentially leading to more durable responses. The use of relatlimab, which targets LAG-3, represents a novel mechanism not commonly used in standard treatments, offering hope for those who have progressed on existing anti-PD-1 therapies.

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

Research has shown that using nivolumab with ipilimumab, one of the combinations tested in this trial, effectively treats advanced melanoma, reducing the risk of cancer progression by 58% compared to ipilimumab alone. This combination also achieves a five-year survival rate of 52%. Another combination in this trial, nivolumab with relatlimab, has reduced the risk of cancer growth by 25% compared to nivolumab alone, with about 43% of patients responding well to this treatment. These findings suggest that both combinations could offer promising results for treating skin cancer. ^{3 6 7 8 9}

Who Is on the Research Team?

Evan Lipson, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

Adults with advanced basal cell carcinoma (BCC) that can't be surgically removed or has spread, who haven't had systemic BCC treatment or have tried a specific immunotherapy without success. Participants need normal organ function and blood counts, not be pregnant or breastfeeding, agree to contraception use, and must not have HIV/AIDS, active hepatitis B/C, severe allergies to trial drugs, certain other cancers within the last 2 years, unstable brain metastases, or require high-dose steroids.

Inclusion Criteria

I have signed the consent form approved by the review board.

Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study

I have Basal Cell Carcinoma that cannot be removed by surgery or has spread.

Exclusion Criteria

Participants with HIV or AIDS

Participants with severe allergy or hypersensitivity to study drug components

Prisoners or participants who are incarcerated

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive treatment based on cohort assignment: Cohort A receives Nivolumab alone, Cohort B receives Nivolumab + Ipilimumab, and Cohort C receives Nivolumab + Relatlimab

48 weeks

Every 3-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Open-label extension (optional)

Participants may continue treatment if they demonstrate progressive disease after initial therapy, moving to another cohort if appropriate

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Relatlimab

Trial Overview The phase 2 trial is testing Nivolumab alone or combined with Relatlimab or Ipilimumab in treating unresectable/metastatic BCC. It aims to find out how well these treatments work for patients who either haven't received prior systemic therapy for BCC or whose disease didn’t respond to previous anti-PD-(L)1 monotherapy.

How Is the Trial Designed?

Group I: Progression after anti-PD-1 therapy (Cohort A) and Cohort C Experimental Treatment 2 Interventions

Cohort B: Nivolumab 240mg IV + ipilimumab 1mg/kg IV q3 weeks x 4 doses, then nivolumab 480mg IV q4 weeks x 7 doses for up to 48 total weeks of therapy.

Group II: Progression after anti-PD-1 therapy (Cohort A) Experimental Treatment 2 Interventions

Cohort C: Nivolumab 480 mg IV q4 weeks plus relatlimab 480 mg IV q4 weeks for up to 48 weeks.

Group III: Previous Systemic Therapy Patients Active Control 1 Intervention

Cohort A: Nivolumab 480mg IV q4weeks for up to 48 weeks (six 8-week cycles)

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

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]

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]

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]

Relatlimab, when used in combination with nivolumab, is an approved first-line treatment for metastatic or unresectable melanoma, enhancing the immune response against cancer cells.

The review highlights the mechanism of action and safety profile of this combination therapy, emphasizing its clinical efficacy based on recent studies and ongoing trials, making it a significant option for dermatologists treating melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relatlimab-nivolumab: A practical overview for dermatologists. Mullick, N., Nambudiri, VE.[2023]

Nivolumab monotherapy shows significantly better overall survival rates compared to both the combination of nivolumab with ipilimumab and chemotherapy after one year, indicating its effectiveness as a treatment for melanoma.

Nivolumab is associated with lower rates of adverse events compared to chemotherapy, suggesting it may be a safer option for patients with melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of nivolumab compared with other regimens in patients with melanoma: A network meta-analysis. Almohideb, M.[2022]

Over 40% of melanoma patients treated with anti-PD-1 therapy experience dermatologic immune-related adverse events (irAEs), but these are typically self-limiting and manageable, with common issues including rashes and itching.

Both anti-PD-1 and anti-PD-L1 antibodies show a similar dermatologic safety profile, and while these skin reactions are frequent, they rarely lead to severe complications or the need to stop treatment, highlighting the importance of early recognition and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Sibaud, V., Meyer, N., Lamant, L., 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]

This phase I/II clinical trial is investigating the safety and efficacy of a combination treatment involving selumetinib, tremelimumab, and durvalumab in 40 patients with previously treated, unresectable non-small-cell lung cancer (NSCLC).

The study aims to determine the maximum tolerated dose and progression-free survival, while also exploring biomarkers of response and resistance, which could help tailor future treatments for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. Gaudreau, PO., Lee, JJ., Heymach, JV., et al.[2021]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

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 the RELATIVITY-047 trial, the combination of nivolumab and relatlimab (NIVO + RELA) significantly improved progression-free survival in patients with advanced melanoma compared to nivolumab alone, with a median follow-up of 19.3 months.

Despite a higher incidence of severe treatment-related adverse events with the combination therapy, patients reported stable health-related quality of life, indicating that the benefits of NIVO + RELA outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial. Schadendorf, D., Tawbi, H., Lipson, EJ., et al.[2023]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

A patient with advanced melanoma experienced severe immune-related adverse events (irAEs) after receiving a single treatment of combined immunotherapy with ipilimumab and nivolumab, which are known to block PD-1 and CTLA-4 checkpoints.

Despite the severe irAEs leading to early discontinuation of therapy, the patient achieved a durable complete response, suggesting that irAEs may be associated with better long-term outcomes in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report. Matull, J., Livingstone, E., Wetter, A., et al.[2020]

Citations

1. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy-combination

Advanced Melanoma Skin Cancer | Clinical Trial Results In the clinical trial, people given OPDIVO + YERVOY had a 58% lower risk of their cancer spreading, growing, or getting worse than those given YERVOY alone.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910836

Five-Year Survival with Combined Nivolumab and ... Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

3. news.bms.com news.bms.com/news/details/2021/Six-and-a-Half-Year-Outcomes-for-Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-Continue-to-Demonstrate-Durable-Long-Term-Survival-Benefits-in-Patients-with-Advanced-Melanoma/default.aspx

Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in ... With a minimum follow-up of 6.5 years, median overall survival (OS) was 72.1 months with Opdivo plus Yervoy (95% CI: 38.2-NR), the longest ...

4. 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.

5. aimatmelanoma.org aimatmelanoma.org/long-term-results-continue-to-show-a-benefit-with-nivolumab-and-ipilimumab/

Long-term Results Continue to Show a Benefit with ... After ten years, the overall survival rate for the combination of nivolumab plus ipilimumab was 43%. This was higher than nivolumab alone (37%) and ipilimumab ...

6. opdivohcp.com opdivohcp.com/safety/melanoma/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety in ... The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia ( ...

7. opdivo.com opdivo.com/melanoma

Melanoma Skin Cancer Treatment OPDIVO® (nivolumab) is an FDA-approved immunotherapy that can be used alone, or in combination with YERVOY® (ipilimumab), to treat a type of skin cancer ...

8. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/yervoy

Yervoy | European Medicines Agency (EMA) Finally, two studies found the combination of Yervoy and nivolumab effective for treating advanced melanoma in adults who had not been treated previously, and ...

9. news.bms.com news.bms.com/news/details/2017/Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-and-Opdivo-Monotherapy-Significantly-Improved-Overall-Survival-Versus-Yervoy-Alone-in-Patients-with-Previously-Untreated-Advanced-Melanoma/default.aspx

Opdivo (nivolumab) in Combination with Yervoy ... Opdivo (nivolumab) in combination with Yervoy (ipilimumab) and Opdivo monotherapy significantly improved overall survival versus Yervoy alone.