Fianlimab + Cemiplimab + Ipilimumab for Melanoma

Recruiting at 10 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

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, you cannot be on high-dose systemic steroids or other immunosuppressive medications within 14 days of starting the trial treatment.

What data supports the effectiveness of the drug combination Fianlimab, Cemiplimab, and Ipilimumab for treating melanoma?

Research shows that combining drugs like nivolumab and ipilimumab can significantly improve survival and response rates in advanced melanoma patients compared to using ipilimumab alone. This suggests that combining similar drugs, like Fianlimab, Cemiplimab, and Ipilimumab, might also enhance treatment effectiveness. ^{1 2 3 4 5}

What safety information is available for the combination of Fianlimab, Cemiplimab, and Ipilimumab in treating melanoma?

Ipilimumab, an immune checkpoint inhibitor, can cause immune-related side effects, which are often mild but can sometimes be severe and life-threatening. These side effects are generally manageable with early recognition and treatment, such as using corticosteroids. Combining ipilimumab with other treatments like anti-PD1 agents has shown increased efficacy but also potential for greater toxicity. ^{6 7 8 9 10}

What makes the drug combination of Fianlimab, Cemiplimab, and Ipilimumab unique for treating melanoma?

The combination of Fianlimab, Cemiplimab, and Ipilimumab is unique because it targets multiple immune checkpoints to enhance the body's immune response against melanoma, potentially offering a more comprehensive approach compared to treatments using fewer drugs. This combination may provide a novel strategy by incorporating Fianlimab, which is not commonly used in existing melanoma treatments. ^{1 11 12 13 14}

What is the purpose of this trial?

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 side effects for locally advanced or metastatic, unresectable, refractory melanoma.

Research Team

James Smithy, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

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 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 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]

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]

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]

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 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]

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]

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 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]

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]

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]

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]

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

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma. [2021]

3. 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]

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

A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Vemurafenib for the treatment of melanoma. [2018]

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

Full Spectrum: Efficacy and Toxicity of Immunotherapy in Metastatic Melanoma [2019]

7. Switzerland 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. [2021]

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

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. [2021]

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

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Combined effect of ipilimumab and nivolumab improves oncology endpoints in metastatic melanoma patients. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. [2021]