Nivolumab + Ipilimumab + Sargramostim for Advanced Melanoma

Recruiting at 757 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two immunotherapy drugs, nivolumab and ipilimumab, to evaluate their effectiveness with or without sargramostim in treating advanced melanoma, a serious skin cancer that cannot be surgically removed. The goal is to determine if adding sargramostim enhances the immune system's ability to attack the cancer. Participants include individuals with advanced melanoma that has spread and who have not received certain treatments for the cancer in its current stage. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering hope for more effective treatment options.

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.

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

Research shows that the combination of nivolumab and ipilimumab is generally well-tolerated by people with melanoma. In long-term studies, patients treated with this combination have demonstrated promising survival rates, with some living for many years after treatment. However, side effects can occur. Common side effects include tiredness, skin rash, and diarrhea. More serious side effects can happen too, but they are less common.

Studies are ongoing to assess the addition of sargramostim to this combination. Sargramostim is known to help increase white blood cell counts, which can be beneficial. However, its impact on side effects when used with nivolumab and ipilimumab remains unclear.

Overall, while most patients handle these treatments well, discussing any potential risks with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nivolumab, ipilimumab, and sargramostim for advanced melanoma because this treatment targets the immune system in a unique way. Nivolumab and ipilimumab are immune checkpoint inhibitors that work by releasing the brakes on the immune system, allowing it to attack cancer cells more effectively. Sargramostim, on the other hand, is a growth factor that stimulates the production of white blood cells, potentially enhancing the effectiveness of the immune response. Unlike standard treatments that might focus on one mechanism, this combination aims to boost the immune system's ability to fight melanoma from multiple angles, offering hope for improved outcomes.

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

Research shows that using nivolumab and ipilimumab together effectively treats advanced melanoma, a type of skin cancer. Studies found that 52% of patients treated with this combination were alive after 5 years, compared to 44% for those using only nivolumab and 26% for those using only ipilimumab. In this trial, participants in Arm A will receive nivolumab, ipilimumab, and sargramostim, while those in Arm B will receive nivolumab and ipilimumab without sargramostim. Adding sargramostim may boost the immune system's response, possibly leading to better results. This treatment approach helps the body's immune system attack cancer cells, potentially improving disease control. ^{3 4 6 7 8}

Who Is on the Research Team?

Frank S Hodi

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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 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 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]

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]

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]

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 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]

Citations

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

Advanced Melanoma Skin Cancer | Clinical Trial Results OPDIVO + YERVOY is FDA approved to treat advanced melanoma regardless of your test results. More people given OPDIVO + YERVOY were alive compared to YERVOY ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39282897/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

3. 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.

4. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-Landmark-10-Year-Follow-Up-Data-from-CheckMate--067-Which-Showed-Continued-Durable-Long-Term-Survival-Benefit-with-Opdivo-plus-Yervoy-in-Advanced-Melanoma/default.aspx

067 Which Showed Continued Durable Long-Term ... With a minimum follow up of 10 years, median overall survival (OS) was 71.9 months with Opdivo plus Yervoy (95% CI: 38.2-114.4) - the longest ...

5. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy

Advanced Melanoma Skin Cancer | Clinical Trial Results In the clinical trial, people given OPDIVO had a 37% lower risk of dying than those given YERVOY alone. People given OPDIVO lived longer without their cancer ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In patients who were progression-free at 3-years, 10-year melanoma-specific survival rates were 96% with nivolumab-plus-ipilimumab, 97% with ...

7. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2407417

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00400

Pooled Long-Term Outcomes With Nivolumab Plus ... Patients in these equivalent subgroups who had been treated with NIVO + IPI had 5-year OS rates of 66%, 64%, and 36%, respectively. Open in ...