IL2 + Ipilimumab and Nivolumab for Melanoma

Overseen By Leticia Tetth

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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out if the administration of Interleukin-2 concurrently with ipilimumab followed by Nivolumab will result in improved anti-cancer activity and if it is effective for advanced melanoma.

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.

What data supports the effectiveness of the drug combination IL2, Ipilimumab, and Nivolumab for treating melanoma?

Research shows that IL-2 can induce durable responses in some melanoma patients, and the combination of Ipilimumab and Nivolumab has been effective in improving survival in advanced melanoma. Additionally, adding IL-2 to Ipilimumab and Nivolumab has shown promise in overcoming resistance in some cancer treatments, suggesting potential benefits for melanoma. ^{1 2 3 4 5}

What safety data exists for the combination of IL2, Ipilimumab, and Nivolumab in humans?

Nivolumab and Ipilimumab, used to treat various cancers, can cause immune-related side effects, including colitis (inflammation of the colon). These side effects are known as immune-related adverse events (irAEs) and can sometimes be managed with other medications like infliximab. ^{6 7 8 9 10}

What makes the IL2 + Ipilimumab and Nivolumab treatment unique for melanoma?

This treatment combines three drugs that work together to boost the immune system's ability to fight melanoma. Interleukin-2 (IL-2) helps grow immune cells, while Ipilimumab and Nivolumab block proteins that stop the immune system from attacking cancer cells, making this combination a novel approach compared to using each drug alone. ^{1 11 12 13 14}

Research Team

Ahmad Tarhini, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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 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]

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]

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]

References

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

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

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

Focus on FOCIS: interleukin 2 treatment associated autoimmunity. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors. [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Immune checkpoint inhibitors for treatment of advanced stage melanoma]. [2020]

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

Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors. [2022]

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

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

7. United States 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. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. [2022]

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

Impact of Selective Immunosuppressive Therapy on Subsequent Immune-Related Adverse Events After Immune Checkpoint Inhibitor-Induced Colitis Treatment. [2023]

10. United States 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. [2019]

11. United States 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. [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. [2023]

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

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma. [2023]