Interferon + Ipilimumab + Pembrolizumab for Melanoma

Recruiting at 657 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

1301 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This randomized phase III trial studies how well pembrolizumab works compared with the current standard of care, physician/patient choice of either high-dose recombinant interferon alfa-2B or ipilimumab, in treating patients with stage III-IV melanoma that has been removed by surgery but is likely to come back or spread. High-dose recombinant interferon alfa-2B may help shrink or slow the growth of melanoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether pembrolizumab is more effective than the current standard of care in treating patients with melanoma.

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.

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

The combination of Ipilimumab and Pembrolizumab, used for treating melanoma, can cause immune-related side effects affecting the skin, gastrointestinal system, liver, and endocrine system. Common side effects include skin rashes, diarrhea, and thyroid issues, and these effects can be more frequent when these drugs are used together. ^{1 2 3 4 5}

What makes the drug combination of Interferon, Ipilimumab, and Pembrolizumab unique for treating melanoma?

This drug combination is unique because it combines different mechanisms to enhance the immune response against melanoma. Interferon can boost the immune system, while Ipilimumab and Pembrolizumab are immune checkpoint inhibitors that help the body recognize and attack cancer cells more effectively. This combination may improve treatment outcomes compared to using these drugs individually. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination of Interferon, Ipilimumab, and Pembrolizumab for treating melanoma?

Research shows that combining pembrolizumab with interferon can improve treatment outcomes in melanoma, as prior interferon therapy enhances the effectiveness of pembrolizumab. Additionally, ipilimumab has been shown to prolong survival in melanoma patients, and combining it with other drugs like nivolumab has led to significant tumor regression. ^{7 9 10 11 12}

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

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 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 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]

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 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]

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]

Citations

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma. [2021]

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

Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma. [2021]

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

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. [2023]

5. England 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. [2022]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. [2021]

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

Novel melanoma therapies and their side effects. [2018]

10. United States 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. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related quality of life (QoL) in patients with advanced melanoma receiving immunotherapies in real-world clinical practice settings. [2020]

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

Pembrolizumab versus Ipilimumab in Advanced Melanoma. [2022]