IL2 + Ipilimumab and Nivolumab for Melanoma

Overseen By Arnay Marshall

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Systemic corticosteroids

Disqualifiers: Active brain metastasis, Cardiovascular disease, Autoimmune disorders, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks per course (up to 3 courses)

29 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to determine if they can more effectively combat advanced melanoma, a type of skin cancer that has spread or cannot be treated surgically. The study combines Interleukin-2 (also known as IL-2, Aldesleukin, or PROLEUKIN), ipilimumab, and nivolumab to evaluate their combined effectiveness against the cancer. Individuals with advanced melanoma that has spread, who have previously tried certain immunotherapies, and have no active brain tumors might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants, providing an opportunity to contribute to significant advancements in melanoma treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must not have had systemic therapy or radiotherapy within 3 weeks before joining. If you are on steroids, you need to stop them at least 2 weeks before starting the trial.

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

Research shows that using Interleukin-2, Ipilimumab, and Nivolumab together can be safe for treating melanoma. Studies have found that Nivolumab and Ipilimumab, when used together, generally have a similar safety profile for different types of melanoma, causing expected and manageable side effects.

Previous patients demonstrated that high doses of Interleukin-2 with low doses of Ipilimumab, followed by Nivolumab, can be tolerated. However, some patients might experience common side effects of these treatments, such as tiredness, skin rashes, or nausea.

Overall, these drugs have been used in other treatments, providing insight into their safety. For those considering joining a trial, this information can clarify what to expect regarding safety. Discuss potential risks with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Interleukin-2, Ipilimumab, and Nivolumab for melanoma because this approach could enhance the immune system's ability to attack cancer cells. While standard treatments often involve either checkpoint inhibitors like Ipilimumab or Nivolumab alone, this combination aims to boost the immune response more effectively by using Interleukin-2 to activate immune cells. This innovative regimen might offer a more robust defense against melanoma, especially for patients who haven't responded well to current therapies. By integrating these treatments, researchers hope to achieve a more powerful and sustained attack on cancer cells, potentially improving outcomes for patients.

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

This trial will evaluate the combination of three treatments—Interleukin-2, ipilimumab, and nivolumab—for advanced melanoma, a type of skin cancer. Research has shown that using nivolumab and ipilimumab together is more effective than using each one alone for treating advanced melanoma, helping patients live longer. Interleukin-2 boosts the immune system's ability to fight cancer cells, potentially improving results when added to the ipilimumab and nivolumab mix. These treatments enhance the immune system's ability to find and destroy cancer cells more effectively. ^{1 2 3 6 7}

Who Is on the Research Team?

Ahmad Tarhini, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma who have had prior anti-PD1 immunotherapy but their disease got worse. They must be in good health otherwise, not have serious heart issues or brain metastasis, and agree to use contraception. It's not for those with autoimmune diseases on steroids, other cancers (unless free of disease for over 2 years), or recent treatments that they haven't recovered from.

Inclusion Criteria

I haven't had a stroke or mini-stroke in the last 6 months.

I am over 50 or have a history of lung issues or smoking, and need lung function tests.

I had major surgery over 4 weeks ago and have fully recovered.

Exclusion Criteria

I do not have serious heart or brain blood vessel problems.

Receiving any other investigational agents

I have active cancer spread to my brain.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive high dose bolus IL2 in combination with low dose ipilimumab followed by nivolumab for up to 3 courses

12 weeks per course (up to 3 courses)

Multiple visits per cycle

Response Assessment

Response assessment occurs at the end of the 4th cycle of each course

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Interleukin-2
• Ipilimumab
• Nivolumab

Trial Overview

The study tests if giving Interleukin-2 at the same time as ipilimumab followed by nivolumab can better fight advanced melanoma. Participants will receive these drugs sequentially to see if this combination improves cancer control compared to previous treatments they've received.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 3 Interventions

HD IL2 (600,000 units/kg/dose IV) will be given during week 1 of the 2 initial cycles or each course. Ipilimumab will be given concurrently at the low dose of 1 mg/kg during week one of the 2 initial cycles of each course for up to 2 doses, total. Nivolumab will be given on during week one of the 3rd cycle of each course. No systemic treatment will be administered during the 4th cycle. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities will be offered additional courses of treatment for up to a maximum of 3 courses, total.

Interleukin-2 is already approved in United States, European Union for the following indications:

Approved in United States as Aldesleukin for:

• Metastatic melanoma
• Metastatic renal cell carcinoma

Approved in European Union as PROLEUKIN for:

• Metastatic renal cell carcinoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Clinigen, Inc.

Industry Sponsor

Trials

10

Recruited

360+

Published Research Related to This Trial

A patient with metastatic renal cell carcinoma showed no tumor regression with PD-1 blockade but achieved a near-complete response after receiving high-dose IL-2 therapy, highlighting IL-2's potential as an effective second-line treatment.

This case underscores the importance of developing better predictors for response to immunotherapies, which could help optimize treatment sequences and determine when to switch to alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti-PD-1) treatment. Brayer, J., Fishman, M.[2020]

Immune checkpoint inhibitors, particularly anti-PD1 antibodies like nivolumab and pembrolizumab, have shown superior efficacy and better tolerance compared to earlier treatments like ipilimumab in advanced stage melanoma.

The combination of ipilimumab and nivolumab is currently the most effective treatment, although it comes with higher toxicity, while anti-PD1 antibodies are also being tested for their benefits in earlier stages of melanoma, showing promise in improving relapse-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immune checkpoint inhibitors for treatment of advanced stage melanoma]. Lupu, J., Herrscher, H., Robert, C.[2020]

Neoadjuvant immunotherapy combining anti-CTLA4 and anti-PD1 monoclonal antibodies has shown an impressive 80% response rate in patients with stage III melanoma, but about 20% of patients do not respond due to low CD4/IL-2 gene signatures.

Adding IL-2 to the anti-CTLA4 and anti-PD1 treatment significantly enhanced T cell activation and improved outcomes in both human tumor specimens and a mouse model, suggesting that this combination could effectively overcome resistance and should be further tested in early-stage cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors. Kaptein, P., Jacoberger-Foissac, C., Dimitriadis, P., et al.[2022]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

In a phase Ib clinical trial involving 14 patients with advanced melanoma, both infliximab and certolizumab were found to be safe when combined with nivolumab and ipilimumab, with only one dose-limiting toxicity reported.

The certolizumab cohort showed a high response rate, with 100% of evaluable patients achieving objective responses, including four complete responses, suggesting that this combination warrants further investigation for its potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial. Montfort, A., Filleron, T., Virazels, M., et al.[2022]

High-dose Interleukin-2 (HDIL2) is FDA-approved for treating metastatic melanoma and renal cell carcinoma, showing durable responses in 5-10% of patients by enhancing T cell activity and altering the tumor microenvironment.

The use of HDIL2 can lead to autoimmunity in some patients, indicating that while it can effectively promote antitumor responses, it may also disrupt immune tolerance, necessitating further investigation into its mechanisms of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focus on FOCIS: interleukin 2 treatment associated autoimmunity. Moschos, SJ., Mandic, M., Kirkwood, JM., et al.[2021]

In a study of 15 melanoma patients treated with nivolumab, those who experienced immune-related adverse events (irAEs) had a significantly higher disease control rate (75% vs. 14%) and better overall survival compared to those without irAEs.

The occurrence of irAEs was associated with an increase in baseline peripheral lymphocyte counts, suggesting that this increase could serve as a potential biomarker for predicting irAEs in patients undergoing nivolumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study. Okada, N., Kawazoe, H., Takechi, K., et al.[2019]

In metastatic melanoma patients, treatment with the immune checkpoint inhibitor Nivolumab altered the proportions and functions of innate lymphoid cells (ILCs), leading to increased secretion of important cytokines like IL-13 and TNFα.

Higher levels of CCL2 before treatment were linked to better survival outcomes, while after two months of Nivolumab therapy, certain ILC subpopulations and serum cytokine levels negatively correlated with overall survival and progression-free survival, indicating their potential role in therapy response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors. Cristiani, CM., Capone, M., Garofalo, C., et al.[2022]

In a phase 2 trial involving 89 patients with advanced melanoma, the combination of ziv-aflibercept and IL-2 significantly improved progression-free survival (PFS) to a median of 6.9 months compared to 2.3 months for IL-2 alone (P<.001).

The combination therapy showed similar overall survival rates between the two groups, indicating that while PFS improved, the overall survival benefit may need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma. Tarhini, AA., Frankel, P., Ruel, C., et al.[2023]

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

In a study of 31 patients with resectable advanced melanoma, the combination of neoadjuvant pembrolizumab and high-dose interferon alpha-2b (HDI) showed a high overall response rate of 73.3% and a pathologic complete response (pCR) rate of 43%, indicating significant clinical activity.

Despite the promising results, treatment discontinuation rates were high, with 73% of patients stopping HDI and 43% stopping pembrolizumab, suggesting that while the therapy is effective, it may also present challenges in terms of tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma. Najjar, YG., McCurry, D., Lin, H., et al.[2023]

In a meta-analysis of 2,946 cancer patients, the combination therapy of nivolumab and ipilimumab was found to significantly increase the risk of immune-related adverse events (irAEs) compared to nivolumab alone.

Patients receiving the combination therapy experienced higher rates of various irAEs, including skin reactions, gastrointestinal issues, and liver enzyme elevation, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. Zhou, S., Khanal, S., Zhang, H.[2022]

In a study of 156 patients with immune checkpoint inhibitor-mediated colitis treated with selective immunosuppressive therapy, 16% developed new immune-related adverse events (irAEs) after treatment, with skin reactions being the most common.

Higher grades of diarrhea and receiving two or more doses of immunosuppressive therapy were associated with a lower incidence of new irAEs, suggesting that more severe initial symptoms may provide some protective effect against subsequent adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Selective Immunosuppressive Therapy on Subsequent Immune-Related Adverse Events After Immune Checkpoint Inhibitor-Induced Colitis Treatment. Pizuorno Machado, A., Shatila, M., Glitza Oliva, IC., et al.[2023]

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