Fianlimab + Cemiplimab + Ipilimumab for Melanoma

Recruiting at 11 trial locations

Overseen By Michael Postow, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Uveal melanoma, Untreated CNS metastases, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

88 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new treatment combination for individuals with advanced melanoma that cannot be surgically removed and has stopped responding to current treatments. Researchers are testing whether the drugs fianlimab (an experimental treatment), cemiplimab, and ipilimumab can work together safely and effectively with minimal side effects. The study includes two groups: one for those whose melanoma worsened after PD-1 treatment, and another for those whose condition advanced after PD-1 and LAG-3 treatments. Eligible participants should have melanoma that progressed after these specific therapies. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering early access to potentially effective therapies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on high-dose systemic steroids or other immunosuppressive medications within 14 days of starting the trial treatment.

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

Research has shown that the combination of fianlimab and cemiplimab has undergone safety testing in patients with various cancers, including advanced melanoma. Early studies found this combination to be generally well-tolerated, with most side effects being mild to moderate, such as fatigue and skin reactions.

Ipilimumab has been used for some time in treating melanoma and is known for causing more intense side effects, including inflammation in various parts of the body. However, doctors have experience managing these effects.

Since this trial is in phase 2, the treatment has passed initial safety tests. This suggests the combination is considered safe enough for further study, but more information is needed on patient responses. Prospective participants should know that the safety data so far is promising, but all treatments can have side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Fianlimab, Cemiplimab, and Ipilimumab for melanoma because it offers a fresh approach to tackling the disease. Unlike current standard treatments, which often focus on single pathways, this combo targets multiple immune checkpoints, specifically PD-1 and LAG-3, which may enhance the body's ability to fight cancer more effectively. By integrating these mechanisms, the treatment has the potential to overcome resistance seen in patients who have not responded to previous therapies. This multi-pronged strategy could significantly improve outcomes for those with refractory melanoma.

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

In this trial, all participants will receive a combination of three drugs—fianlimab, cemiplimab, and ipilimumab—to treat advanced melanoma. Research has shown that this combination may be effective, with studies indicating it worked well and had lasting effects in patients with advanced melanoma, even when other treatments failed. Each drug blocks different proteins that aid tumor growth, potentially increasing their effectiveness when used together. These findings suggest that this treatment could be a strong option for individuals whose melanoma hasn't responded to other therapies. ^{4 6 7 8 9}

Who Is on the Research Team?

James Smithy, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with advanced melanoma that can't be removed by surgery or has spread, and who haven't responded to other treatments. Participants should meet certain health standards but specific inclusion and exclusion criteria are not listed.

Inclusion Criteria

I do not have any symptoms of heart problems.

My kidneys are functioning well enough, with a creatinine clearance rate of at least 30 mL/min.

Patient/legal authorized representative (LAR) must be able to provide informed consent

Exclusion Criteria

History of severe hypersensitivity reactions to any unknown allergens or study drug components

Patients who are breastfeeding or pregnant

I haven't taken antibiotics for a serious infection in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous Fianlimab and Cemiplimab every three weeks and Ipilimumab every six weeks continuously

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cemiplimab
• Fianlimab
• Ipilimumab

Trial Overview The study is examining the safety and effectiveness of combining three drugs: fianlimab, cemiplimab, and ipilimumab in treating melanoma. It aims to determine if this combination leads to fewer or milder side effects while being effective.

How Is the Trial Designed?

Group I: Refractory melanoma after combined PD-1 and LAG-3 blockade (Cohort B) Experimental Treatment 3 Interventions

All patients will receive intravenous Fianlimab and Cemiplimab every three weeks continuously. Ipilimumab will be given every 6 weeks continuously.

Group II: Refractory melanoma after PD-1 monotherapy (Cohort A) Experimental Treatment 3 Interventions

All patients will receive intravenous Fianlimab and Cemiplimab every three weeks continuously. Ipilimumab will be given every 6 weeks continuously.

Cemiplimab is already approved in European Union, United States, Canada, Brazil for the following indications:

Approved in European Union as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in United States as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Basal cell carcinoma (BCC)
• Non-small cell lung cancer (NSCLC)

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Regeneron Pharmaceuticals

Industry Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Published Research Related to This Trial

In a study of 249 melanoma patients, immune-related adverse events (irAEs) were observed in 74.6% of patients, with a notable correlation between the occurrence of irAEs and improved treatment outcomes in the non-adjuvant setting.

The frequency of irAEs was high in both treatment settings, but in the adjuvant setting, they did not correlate with disease relapse, suggesting that while irAEs may indicate better efficacy in some cases, they do not universally predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis. Dimitriou, F., Staeger, R., Ak, M., et al.[2021]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

Ipilimumab, an anti-CTLA-4 antibody, has been shown to improve survival in patients with unresectable or metastatic melanoma, with a standard dosing of 3 mg/kg every 3 weeks for a total of 4 doses.

While ipilimumab can cause immune-related adverse events in 15% of patients, most are mild and manageable; however, high-grade events can be serious and require careful monitoring and treatment with corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. Trinh, VA., Hagen, B.[2021]

In a retrospective analysis of 40 advanced melanoma patients, a treatment regimen combining short-term CTLA-4 blockade (ipilimumab) followed by PD-1 blockade (nivolumab or pembrolizumab) achieved a best overall response rate of 55% and a disease control rate of 75%, indicating promising efficacy.

The combination therapy resulted in grade 3 and 4 adverse events in 38% of patients, suggesting that this approach may offer similar effectiveness to concurrent therapies but with potentially lower toxicity, warranting further investigation in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. Meerveld-Eggink, A., Rozeman, EA., Lalezari, F., et al.[2020]

In a phase Ib study involving 31 patients with advanced melanoma, the combination of ipilimumab and peginterferon alfa-2b showed a maximum tolerated dose of ipilimumab at 3 mg/kg and peginterferon at 2 μg/kg/week, with a 40% overall response rate.

The treatment had a manageable safety profile, with 45.2% of patients experiencing grade 3 drug-related adverse events, but no severe (grade 4/5) adverse events, indicating that this combination therapy could be a promising option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma. Brohl, AS., Khushalani, NI., Eroglu, Z., et al.[2021]

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

The combination of nivolumab and ipilimumab significantly improves median progression-free survival and overall survival rates in patients with metastatic melanoma compared to using either drug alone.

This combination therapy works by targeting different immune checkpoints (CTLA-4 and PD-L1), leading to a greater reduction in tumor size and disease progression, with a 66.7% increase in progression-free survival compared to nivolumab and a 296.6% increase compared to ipilimumab monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effect of ipilimumab and nivolumab improves oncology endpoints in metastatic melanoma patients. Wahid, M., Mandal, RK., Jawed, A., et al.[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]

Regorafenib and NU7441 were identified as promising therapies that can enhance T-cell immunotherapy for melanoma by modifying immunomodulatory proteins and increasing melanoma antigens, which may improve treatment outcomes.

In mouse models, regorafenib not only suppressed melanoma progression but also positively influenced T-cell behavior, leading to increased proliferation and cytokine production, suggesting a synergistic effect when combined with other immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies. Tsai, AK., Khan, AY., Worgo, CE., et al.[2018]

Ipilimumab, an immune checkpoint inhibitor approved in 2011, has shown the potential to induce deep and durable remissions in up to 20% of metastatic melanoma patients by enhancing T-cell activation against tumors.

While ipilimumab can cause significant immune-related adverse events (irAEs), such as uveitis and nephritis, these can be effectively managed, and patients can still achieve remarkable outcomes, as demonstrated by a case where a patient had a complete response after treatment despite experiencing severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full Spectrum: Efficacy and Toxicity of Immunotherapy in Metastatic Melanoma Zibelman, M., Olszanski, AJ.[2019]

In a study of 59 patients with advanced melanoma, combining immune checkpoint inhibitors (ICI) with targeted therapies (TT) was found to be a safe treatment option, with only 12% experiencing severe adverse events.

For patients with BRAF wild-type melanoma, the combination of MEK inhibitors and anti-PD1 showed a high tumor control rate of 83% and a median progression-free survival of 7.1 months, suggesting potential effectiveness that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study. Huynh, S., Mortier, L., Dutriaux, C., et al.[2020]

In a study of 47 patients with advanced melanoma who experienced acquired resistance to initial combination immunotherapy, reinduction with ipilimumab (with or without anti-PD-1) resulted in a modest response rate of 26% and a disease control rate of 45%.

While reinduction therapy showed some clinical activity, it also carried a significant risk of immune-related adverse events (irAEs), with 58% of patients experiencing them, including severe cases, and many patients experiencing recurrence of previously observed irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. Hepner, A., Atkinson, VG., Larkin, J., 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]

Vemurafenib is an effective oral treatment for patients with inoperable and metastatic melanoma that have the BRAF V600E mutation, showing improved survival rates in clinical trials.

While vemurafenib is generally effective, it can cause significant side effects, including skin cancers, joint pain, fatigue, and heart rhythm changes, necessitating regular monitoring for these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib for the treatment of melanoma. Jordan, EJ., Kelly, CM.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06594991

NCT06594991 | A Study of Fianlimab, Cemiplimab, and ... The purpose of this study is to test whether the combination of fianlimab, cemiplimab, and ipilimumab is a safe and effective treatment that causes few or ...

2. cancer.gov cancer.gov/clinicaltrials/NCI-2024-07955

A Study of Fianlimab, Cemiplimab, and Ipilimumab in ... Giving fianlimab, cemiplimab and ipilimumab may be an effective treatment for patients with refractory, locally advanced, unresectable or metastatic melanoma.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10452647/

Immunotherapy in Melanoma: Recent Advancements and ... Progress in the treatment of malignant melanoma, particularly with the use of immunotherapy, has markedly improved outcomes.

4. onclive.com onclive.com/view/fianlimab-cemiplimab-demonstrates-persistent-activity-in-advanced-melanoma-independent-of-lag-3-and-pd-l1-status

Fianlimab/Cemiplimab Demonstrates Persistent Activity in ... Fianlimab plus cemiplimab demonstrated persistent and significant clinical activity in patients with advanced melanoma.

5. mskcc.org mskcc.org/cancer-care/clinical-trials/24-166

A Phase 2 Study of Fianlimab, Cemiplimab, and ... Combining fianlimab, cemiplimab, and ipilimumab may work well against melanoma because each drug blocks different proteins that make tumors grow.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06594991

NCT06594991 | A Study of Fianlimab, Cemiplimab, and ... The purpose of this study is to test whether the combination of fianlimab, cemiplimab, and ipilimumab is a safe and effective treatment that causes few or mild ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02172

Phase I Study of Fianlimab, a Human Lymphocyte ... We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

8. yalemedicine.org yalemedicine.org/clinical-trials/a-study-with-combinations-of-anti-lag-3-and-anti-pd-1-antibodies-in-adult-participants-with-advanced

R3767-ONC-22122: A Phase 3 Study of Fixed Dose ... The aim of the study is to see how safe and effective the combination of fianlimab and cemiplimab is in treating melanoma, in comparison with ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11647203/

First-in-Human Dose-Escalation Study of Fianlimab, an ... Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti–PD-1) enhances antitumor activity.