Nivolumab + Ipilimumab + Sargramostim for Advanced Melanoma

Recruiting at 713 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Anticoagulants

Disqualifiers: CNS metastases, HIV, Hepatitis, 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: 8

600 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial studies the side effects of nivolumab and ipilimumab when given together with or without sargramostim and to see how well they work in treating patients with stage III-IV melanoma that cannot be removed by surgery (unresectable) and that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must stop any chemotherapy, immunotherapy, or investigational agents at least 4 weeks before joining the trial and recover from any side effects. If you are on steroids or other immunosuppressants, you need to stop them at least 2 weeks before joining, unless they are replacement doses for adrenal insufficiency.

What data supports the effectiveness of the drug combination of Nivolumab, Ipilimumab, and Sargramostim for advanced melanoma?

Research shows that combining Nivolumab and Ipilimumab significantly improves survival rates and response in advanced melanoma compared to Ipilimumab alone. This combination is considered a standard first-line treatment for advanced melanoma, offering better outcomes for certain patient groups. ^{1 2 3 4 5}

Is the combination of Nivolumab, Ipilimumab, and Sargramostim safe for humans?

The combination of Nivolumab and Ipilimumab is associated with a high rate of immune-related side effects, which can be severe and require hospital admission for some patients. Most side effects are mild to moderate, but serious ones can occur, and close monitoring is necessary. Sargramostim's safety profile is not detailed in the provided studies, but it is generally used to boost the immune system. ^{3 6 7 8 9}

How is the drug combination of nivolumab, ipilimumab, and sargramostim unique for advanced melanoma?

This drug combination is unique because it combines nivolumab and ipilimumab, which are immune checkpoint inhibitors that help the immune system attack cancer cells, with sargramostim, which may enhance the immune response. This combination has shown improved survival outcomes compared to using ipilimumab alone. ^{1 2 3 10 11}

Research Team

Frank S Hodi

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

Adults with advanced melanoma that can't be surgically removed, who haven't had certain treatments recently or have recovered from them. They must not be pregnant, breastfeeding, or have HIV/HBV/HCV infections. No prior ipilimumab/anti-PD-1/PD-L1 in the metastatic setting and no live vaccines close to trial start. Stable brain metastases treated are okay.

Inclusion Criteria

My melanoma is at stage III or IV and cannot be surgically removed.

I've had previous cancer treatments but it's been over a year since my last dose.

I stopped my previous cancer treatments at least 4 weeks ago and have recovered from any side effects.

Exclusion Criteria

I haven't had any cancer except for skin cancer in the last 5 years.

Patients with human immunodeficiency virus (HIV) infection are ineligible

You have an active hepatitis B or hepatitis C virus infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Therapy

Patients receive nivolumab and ipilimumab, with or without sargramostim, every 21 days for 4 cycles

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients with partial response, stable disease, or complete response at 24 weeks may continue maintenance therapy for up to 2 years

Up to 2 years

Regular visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

Every 3 months for 2 years, then every 6 months for 3 years

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Sargramostim

Trial Overview The trial is testing the effectiveness and side effects of nivolumab and ipilimumab with or without sargramostim in patients with stage III-IV melanoma. It aims to see if these immunotherapies help the immune system fight cancer better alone or combined.

Participant Groups

Group I: Arm B (nivolumab, ipilimumab) Experimental Treatment 7 Interventions

INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab as in Induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT scan, and blood sample collection throughout the study. Patients may also undergo a MUGA during screening, as well as an ECHO throughout the trial as clinically indicated.

Group II: Arm A (nivolumab, ipilimumab, sargramostim) Experimental Treatment 8 Interventions

INDUCTION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle, ipilimumab IV over 30 minutes on day 1 of each cycle, and sargramostim SC on days 1-14 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in Induction therapy. Patients with PR, SC, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT scan, and blood sample collection throughout the study. Patients may also undergo a MUGA during screening, as well as an ECHO throughout the trial as clinically indicated.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 combined with ipilimumab has been established as a first-line treatment for advanced melanoma, showing significant efficacy based on results from the phase III CheckMate 067 trial.

While this combination therapy is effective, it is also associated with severe immune-related toxicities, highlighting the need to identify patient subgroups, such as those with BRAF mutations or asymptomatic brain metastases, who may benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations. Vázquez-Montero, L., de la Gala, MDCÁ., de la Cruz-Merino, L.[2023]

In a study of 142 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a significantly higher objective response rate of 61% compared to 11% for ipilimumab alone, indicating that the combination therapy is much more effective for treating this type of cancer.

While the combination therapy showed promising efficacy, it also had a higher incidence of severe adverse events (54% vs. 24% for monotherapy), but most of these side effects were manageable with immune-modulating medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Postow, MA., Chesney, J., Pavlick, AC., et al.[2022]

In a study of 84 advanced melanoma patients who had previously failed anti-PD-1 therapy, ipilimumab alone showed a 16% overall response rate, while the combination of ipilimumab and nivolumab had a slightly higher response rate of 21%.

Despite the combination therapy showing a higher response rate, both treatments had similar one-year overall survival rates of around 54-55%, suggesting that ipilimumab alone remains a viable option for patients who did not respond to prior anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. Zimmer, L., Apuri, S., Eroglu, Z., et al.[2021]

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

In a study of 93 Chinese patients with advanced melanoma treated with PD-1 inhibitors, those who developed immune-related adverse events (irAEs) had significantly higher overall response rates (ORR) and disease control rates (DCR) compared to those without irAEs.

Patients experiencing three or more irAEs showed even better clinical outcomes, including longer progression-free survival and overall survival, suggesting that the presence of irAEs may indicate a more effective immune response to PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. Zhao, JJ., Wen, XZ., Ding, Y., 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 real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

In a study of 448 patients treated with ipilimumab and nivolumab for metastatic melanoma, 30-40% discontinued treatment due to immune-related adverse events (irAEs), but this did not significantly affect their progression-free survival (PFS).

Interestingly, patients who discontinued treatment due to irAEs actually experienced a significantly longer overall survival (OS) compared to those who completed the full treatment, suggesting that early discontinuation may not negatively impact treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study. Fink, M., Vittrup, AS., Bastholt, L., et al.[2021]

In a study involving 194 patients with advanced melanoma, the combination of nivolumab and ipilimumab showed a high overall survival rate, with 80% of patients alive at 12 months and 76% at 18 months.

While the treatment was effective, it also had a significant safety profile, with 98% of patients experiencing treatment-related adverse events, leading to discontinuation in 40% of cases and resulting in two treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canadian cohort expanded-access program of nivolumab plus ipilimumab in advanced melanoma. Hogg, D., Monzon, JG., Ernst, S., 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]

References

1. 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]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations. [2023]

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

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. [2021]

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

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. [2023]

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

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. [2021]

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

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

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

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. [2023]

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

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Canadian cohort expanded-access program of nivolumab plus ipilimumab in advanced melanoma. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

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