Ipilimumab +/− Sargramostim for Skin Cancer

Not currently recruiting at 300 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic steroids, Interleukin 2

Disqualifiers: CNS metastases, Autoimmune disease, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two treatments, ipilimumab (an immunotherapy drug) and sargramostim, is more effective than using ipilimumab alone for treating advanced melanoma (a type of skin cancer) that cannot be removed by surgery. Ipilimumab activates the immune system to fight cancer, while sargramostim may increase the number of immune cells, aiding the body in recovering from treatment side effects. The trial seeks participants with stage III or stage IV melanoma that cannot be surgically removed and who have had no more than one prior systemic treatment for their cancer. 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 requires that you stop taking certain medications, such as systemic corticosteroids, at least 4 weeks before starting. If you're on medications like interleukin 2, interferon, or other immunotherapy regimens, you will also need to stop those. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining ipilimumab with sargramostim may make treatment for advanced melanoma safer. Studies indicate that adding sargramostim to ipilimumab reduces side effects compared to using ipilimumab alone. This combination results in fewer severe immune-related side effects, which are common with ipilimumab treatment.

Ipilimumab alone is effective but can cause serious side effects, such as inflammation in parts of the body like the skin or liver. Careful monitoring and medication can manage these side effects.

Overall, while both treatments can have side effects, adding sargramostim appears to make ipilimumab easier and safer for patients to tolerate. This is encouraging for those considering joining a trial with these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for skin cancer, like chemotherapy and radiation, focus on directly attacking cancer cells. But ipilimumab works differently by unleashing the immune system to fight the cancer, targeting CTLA-4, a protein on T-cells that normally helps keep the immune system in check. Researchers are excited about combining ipilimumab with sargramostim, which further stimulates the immune system, potentially leading to a more robust anti-cancer response. This combination aims to enhance the body's natural defenses against cancer more effectively than standard treatments.

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

In this trial, participants will receive either ipilimumab alone or a combination of ipilimumab and sargramostim. Research has shown that adding sargramostim to ipilimumab can extend survival in people with advanced melanoma. One study found that after one year, 68.9% of patients receiving both treatments were still alive, compared to 52.9% of those receiving only ipilimumab. This suggests that sargramostim may enhance ipilimumab's effects by boosting immune cell production, potentially leading to better cancer-fighting results. Ipilimumab alone has been shown to extend survival in some patients, with 10-20% experiencing significant benefits. However, combining it with sargramostim appears to improve these outcomes further. ^{1 2 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?

This trial is for adults with advanced melanoma that can't be surgically removed. They must have a certain level of white blood cells, no HIV or hepatitis infections, and be in good physical condition (ECOG 0-1). Women who could get pregnant must use effective birth control. Participants cannot have brain metastases, autoimmune diseases, or a history of certain treatments like ipilimumab.

Inclusion Criteria

I do not have an active hepatitis B infection.

Your AST and ALT levels are not more than 2.5 times the upper limit of normal.

I am not currently on treatments like IL2, interferon, chemotherapy, or steroids.

Exclusion Criteria

I do not have an autoimmune disease, or if I have thyroid issues, they are stable with treatment.

I have never been treated with ipilimumab or drugs targeting CD137 or CTLA-4.

I do not have any health or mental conditions that could make treatment risky.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Patients receive induction therapy with ipilimumab and sargramostim or ipilimumab alone. Treatment repeats every 21 days for 4 cycles.

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients receive maintenance therapy with ipilimumab and sargramostim or ipilimumab alone. Treatment with ipilimumab repeats every 12 weeks and sargramostim every 21 days.

12 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 2 years, then every 6 months for 3 years.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Sargramostim

Trial Overview The study is testing if combining the immune system booster Ipilimumab with Sargramostim (GM-CSF), which helps grow more immune cells, works better than Ipilimumab alone for treating unresectable stage III/IV melanoma. Patients are randomly assigned to one of the two treatment groups.

How Is the Trial Designed?

Group I: Arm A (ipilimumab and sargramostim) Experimental Treatment 2 Interventions

Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy comprising ipilimumab IV over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment with ipilimumab repeats every 12 weeks and treatment with sargramostim repeats every 21 days. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and patients with responsive or stable disease then continue maintenance therapy until disease progression or unacceptable toxicity.

Group II: Arm B (ipilimumab) Active Control 1 Intervention

Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles. After 12 weeks of induction treatment, anti-tumor response is assessed and patients then receive maintenance therapy of ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 12 weeks. After 12 weeks of maintenance therapy, anti-tumor response is reassessed and cycles repeat every 12 weeks in the absence of disease progression or unacceptable toxicity

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

Ipilimumab (Yervoy®) is an approved monoclonal antibody for treating malignant melanoma by blocking the CTLA-4 protein, which enhances T-cell responses against tumor cells, showing its efficacy in cancer immunotherapy.

Currently, ipilimumab is also being tested in phase III trials for prostate cancer and phase II trials for non-small cell lung cancer, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. Cameron, F., Whiteside, G., Perry, C.[2021]

Ipilimumab (Yervoy) is the first new therapy approved for melanoma in over a decade, functioning as an antibody that blocks CTLA-4, which enhances the immune response against tumors, leading to durable tumor regression and improved overall survival in patients with advanced melanoma.

The clinical development of ipilimumab revealed its unique side effects profile and the long-lasting nature of its therapeutic responses, paving the way for future combination therapies with other checkpoint inhibitors currently being tested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory therapy for melanoma: ipilimumab and beyond. Callahan, MK., Postow, MA., Wolchok, JD.[2021]

Ipilimumab, a first-in-class T-cell potentiator, has shown significant improvements in overall survival for advanced melanoma patients in a phase 3 trial, with median survival extending to 10.1 months compared to 6.4 months for the control group.

The treatment demonstrated long-term survival benefits, with 24-month survival rates increasing from 13.7% with the gp100 vaccine alone to 21.6% and 23.5% for patients receiving ipilimumab alone or in combination, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Tarhini, A., Lo, E., Minor, DR.[2021]

Ipilimumab, a monoclonal antibody targeting CTLA-4, has shown potential activity in prostate cancer, particularly in patients with lower disease burden, despite not improving overall survival in a Phase III study.

While immune-related adverse events are common with ipilimumab treatment, they can generally be managed effectively using standard immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab in the treatment of prostate cancer. Reese, Z., Straubhar, A., Pal, SK., et al.[2018]

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]

Ipilimumab, a monoclonal antibody used to enhance anti-tumor T-cell responses, can cause significant side effects, including ipilimumab-induced hypophysitis (IH), which affects hormone levels and requires hormone replacement therapy in most cases.

In a review of 10 patients with IH, early detection and management guidelines were developed, highlighting the importance of monitoring hormone levels and recognizing imaging abnormalities, which often resolve without high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Lam, T., Chan, MM., Sweeting, AN., et al.[2022]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

Ipilimumab significantly improves overall survival in patients with advanced melanoma compared to the gp100 peptide vaccine, reducing the risk of death by 34% with monotherapy and 32% when combined with the vaccine.

The treatment can cause unique immune-related side effects, particularly affecting the skin and gastrointestinal system, which require careful monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: a guide to its use in advanced melanoma. Lyseng-Williamson, KA., Sanford, M.[2017]

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]

Citations

1. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/yervoy-ipilimumab

Ipilimumab, Yervoy - MRA Results from studies and clinical trials found that ipilimumab prolongs overall survival compared to a vaccine, leading to approximately 20 percent of patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6094709/

Ipilimumab for the treatment of melanoma - PMC Response rates ranged from 10 to 20% with approximately 4–6% of patients obtaining a durable complete remission (CR) [3–5]. These results were the foundation ...

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23942774/

Efficacy and safety of ipilimumab in metastatic melanoma ... Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2772611825000060

Selecting first-line immunotherapy in advanced melanoma In BRAF WT disease, ipilimumab-nivolumab and nivolumab had similar outcomes (5-year PFS: 35 % vs 32 %, 5-year OS: 48 % vs 43 %, 10-year OS: 39 % vs 37 %). BRAF- ...

6. 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4818672/

Phase I/II study of metastatic melanoma patients treated ... One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 ...

8. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...