Interferon + Ipilimumab + Pembrolizumab for Melanoma

Not currently recruiting at 671 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunotherapy, Biologic therapy

Disqualifiers: Brain metastases, Active infection, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 14

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the immunotherapy drug pembrolizumab is more effective than current standard treatments in preventing melanoma from returning or spreading after surgery. It compares pembrolizumab with two other treatments: high-dose interferon alfa-2B, which helps slow cancer growth, and ipilimumab, another immunotherapy that aids the immune system in attacking cancer. Eligible participants are those who have had melanoma surgically removed, are at risk of recurrence, and have no evidence of disease spread. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking advancements in melanoma treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have received certain treatments like immunotherapy or live vaccines recently, and you cannot plan to receive other therapies during the study.

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

Research has shown that pembrolizumab is generally well-tolerated. In a large study of 8,937 patients, most experienced some side effects, but serious issues were less common. Importantly, no new safety concerns emerged even after long-term use in melanoma patients.

The safety of recombinant interferon alfa-2b is well-documented from its use in other conditions like hepatitis and certain cancers. It is FDA-approved, indicating a well-understood safety profile, though side effects can still occur.

Ipilimumab, also FDA-approved for melanoma, has a known safety profile. Studies have demonstrated that it can extend survival, but like other treatments, it may cause side effects. These side effects align with previously reported data.

Overall, while each treatment may have side effects, their safety profiles are well-documented and generally understood. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative immunotherapies that could provide a more powerful attack against melanoma. Unlike traditional chemotherapy, which directly kills cancer cells, pembrolizumab and ipilimumab work by harnessing the body's immune system to recognize and fight cancer cells more effectively. In this treatment, pembrolizumab acts as a checkpoint inhibitor, blocking the proteins that prevent immune cells from attacking cancer, while ipilimumab strengthens the immune response by activating T-cells. Additionally, the use of recombinant interferon alfa-2b aims to boost the immune system's capacity to target melanoma cells. This combination could potentially offer a more robust and sustained response, with the hope of improving survival rates for melanoma patients.

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

Research shows that pembrolizumab, available to participants in Arm II of this trial, holds promise for treating advanced melanoma. Studies have demonstrated that it halted cancer progression in 43% of patients, compared to 32% for ipilimumab. Additionally, 34% of patients who received pembrolizumab survived for 10 years, highlighting its long-term benefits.

Interferon alfa-2b, included in Arm I of this trial, has helped prevent melanoma recurrence, improving both cancer-free duration and overall survival.

Ipilimumab, also part of Arm I, delayed cancer recurrence by an average of 9 months and reduced the risk of death by 28% in some studies. These treatments enhance the immune system's ability to fight cancer cells, potentially slowing or stopping the disease. ^{4 6 7 8 9}

Who Is on the Research Team?

Sapna Patel

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for patients with high-risk stage III-IV melanoma that's been surgically removed but may return or spread. Participants must have proper organ function, no active infections, and not be pregnant. They should agree to contraception use and complete quality of life assessments in English, Spanish or French. Those with autoimmune diseases treated within the last 2 years, live vaccines recently received, HIV positive without meeting specific criteria, hepatitis B/C infection, prior neoadjuvant treatment for melanoma or a history of certain conditions are excluded.

Inclusion Criteria

As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Your ANC (a type of white blood cell) count must be at least 1,500 microliters within 42 days before enrolling in the trial.

Your total bilirubin level must be within a certain range, unless you have Gilbert's syndrome, in which case it can be slightly higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive high-dose recombinant interferon alfa-2B or ipilimumab. Treatment repeats weekly for 4 weeks or every 3 weeks for 4 cycles.

4-12 weeks

Weekly or every 3 weeks

Maintenance Therapy

Patients receive maintenance therapy with high-dose recombinant interferon alfa-2B or ipilimumab. Treatment repeats every 6 weeks for up to 48 weeks or every 12 weeks for 3 years.

48 weeks to 3 years

Every 6-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

5 years

Multiple visits over 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Pembrolizumab
• Recombinant Interferon Alfa-2b

Trial Overview The study compares three treatments: high-dose recombinant interferon alfa-2B (which might shrink/slow tumor growth), ipilimumab and pembrolizumab (both monoclonal antibodies that could help the immune system fight cancer). It aims to determine which is more effective post-surgery in preventing melanoma recurrence.

How Is the Trial Designed?

Group I: Arm II (pembrolizumab) Experimental Treatment 5 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Group II: Arm I (high-dose recombinant interferon alfa-2B, ipilimumab) Active Control 7 Interventions

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

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

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 56 patients with metastatic melanoma who had severe immune-related adverse events (AEs) from ipilimumab, 36% experienced at least one immune-related AE after receiving anti-PD-1 therapy, indicating a notable risk of recurrence but also a manageable safety profile.

Despite the risk of AEs, anti-PD-1 therapy showed a 43% overall response rate and a median overall survival of 21 months, suggesting it may offer improved outcomes for patients previously affected by severe toxic effects from ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. Brunot, A., Grob, JJ., Jeudy, G., et al.[2021]

In a study of 56 melanoma patients, those who received prior treatment with pegylated interferon alpha (PEG-IFN-α) showed significantly improved efficacy from subsequent adjuvant pembrolizumab therapy, with a hazard ratio of 0.37 indicating a lower risk of recurrence.

Patients treated with prior PEG-IFN-α had a longer recurrence-free survival (RFS) of 8.5 months compared to 4.5 months for those without prior treatment, suggesting that PEG-IFN-α enhances the effectiveness of PD-1 blockade in melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma. Jia, DD., Niu, Y., Zhu, H., et al.[2021]

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

In a randomized phase III trial involving 1301 patients with high-risk resected melanoma, adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) compared to standard treatments like high-dose IFNα-2b and ipilimumab, with a hazard ratio of 0.77.

Pembrolizumab had a much lower rate of severe treatment-related adverse events (19.5%) compared to IFNα-2b (71.2%) and ipilimumab (49.2%), indicating a better safety profile while improving RFS but not overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Grossmann, KF., Othus, M., Patel, SP., et al.[2023]

In a study involving 43 patients with advanced melanoma, the combination of pembrolizumab and pegylated interferon (PEG-IFN) showed a promising objective response rate of 60.5%, indicating significant efficacy in treating PD-1-naïve patients.

The treatment was associated with an acceptable safety profile, with 48.8% of patients experiencing grade 3/4 treatment-related adverse events, and a median progression-free survival of 11 months, suggesting that this combination therapy warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma. Davar, D., Wang, H., Chauvin, JM., et al.[2021]

Citations

1. 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 ...

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

Ipilimumab, Yervoy - MRA The results showed that ipilimumab extended the amount of time before cancer returned by an average of 9 months.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2210233

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in ... The estimates of 6-month progression-free survival were 34% (90% CI, 25 to 44) in the combination-treatment group and 13% (90% CI, 4 to 27) in ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)37101-7/fulltext

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. news.bms.com news.bms.com/news/details/2016/Yervoy-ipilimumab-Improves-Overall-Survival-in-Fully-Resected-Stage-III-Melanoma-Patients-From-Phase-3-Study/default.aspx

Yervoy (ipilimumab) Improves Overall Survival in Fully ... Yervoy demonstrated a 28% reduction in the risk of death versus placebo in first disclosure of overall survival data from pivotal study ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf

YERVOY (ipilimumab) - accessdata.fda.gov The safety of YERVOY was evaluated in CA184-029, a randomized (1:1), double-blind, placebo- controlled trial in which 945 patients with resected Stage IIIA (>1 ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28398170/

Ipilimumab in real-world clinical practice: efficacy and ... In patients with metastatic melanoma, ipilimumab has been shown to improve long-term survival. This observational multicenter study reports ...

8. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/yervoy

Yervoy | European Medicines Agency (EMA) The European Medicines Agency noted that Yervoy improves survival in melanoma, a condition where overall survival rates are low. Yervoy has also been shown ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0923753420336875

Efficacy and Safety Data from Patients with Advanced ... Ipilimumab shows activity in patients with advanced melanoma metastatic to brain, with safety results consistent to what has been previously reported for ...