IL-2 + Nivolumab for Melanoma

Overseen By Gregory Daniels, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gregory Daniels

Must be taking: Anti-PD-1 therapy

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Active infection, CNS metastases, 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: Up to 3 courses

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, IL-2 (Proleukin or Aldesleukin) and Nivolumab (Opdivo), to evaluate their effectiveness in treating advanced melanoma and kidney cancer. The main goal is to measure the number of patients whose tumors shrink or disappear after treatment. This trial suits those with advanced melanoma or kidney cancer who have previously tried anti-PD-1 therapy without success. Participants should have a tumor measurable by imaging and have melanoma or kidney cancer that cannot be surgically removed. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to potentially benefit from a promising new therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot be on high-dose systemic steroids or immunosuppressive medications, and you must not have taken any investigational agents within 21 days before starting the trial. Please 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 high-dose IL-2 (Interleukin-2) has treated advanced melanoma since 1998. While it can lead to long-lasting improvements in some patients, it often causes significant side effects, such as low blood pressure, fever, and tiredness.

Studies have found that nivolumab, another treatment for melanoma, is generally safe and well-tolerated. It can cause side effects like tiredness, skin rash, and diarrhea, but these are usually manageable.

Researchers are exploring the combination of IL-2 with nivolumab to determine if it can better help the body fight cancer. The safety of this combination is still under study, but previous research suggests that each drug alone shows promise against melanoma.

Patients considering joining this clinical trial should discuss the possible risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of IL-2 and Nivolumab for treating melanoma because it offers a unique approach compared to current standard treatments. Most treatments for melanoma, such as targeted therapies and standard immunotherapies, focus on attacking cancer cells directly or boosting the immune system in general. However, IL-2 actively stimulates the growth of immune cells, while Nivolumab blocks a specific pathway that tumors use to hide from the immune system. This dual approach not only enhances the body's ability to fight cancer but also potentially increases the effectiveness of the immune response against melanoma.

What evidence suggests that IL-2 and Nivolumab might be an effective treatment for metastatic melanoma and renal cell carcinoma?

Research shows that high-dose interleukin-2 (IL-2) effectively treats advanced melanoma, a type of skin cancer that has spread. Some patients have experienced long-lasting complete responses, where their cancer completely disappears. Studies have found that this treatment can lead to complete responses in up to 10% of patients. Nivolumab, an immunotherapy drug, helps the immune system better recognize and attack cancer cells. In this trial, participants will receive a combination of IL-2 and Nivolumab, which may boost the immune response against melanoma. Early research suggests that using these two treatments together might improve response rates compared to using them separately. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

Adults with metastatic melanoma or renal cell carcinoma who've previously tried anti-PD-1 therapy without success. They must be in good physical condition, not pregnant, willing to use birth control, and have recovered from previous treatments' side effects. Exclusions include active infections, other recent cancers (except certain localized ones), uncontrolled hypertension, mental conditions preventing consent, and certain medical histories like autoimmune diseases.

Inclusion Criteria

I've had anti-PD-1 therapy for over 6 weeks and my cancer progressed after.

I am fully active or restricted in physically strenuous activity but can do light work.

I am not pregnant and agree to use two forms of birth control.

Exclusion Criteria

I am mentally and physically capable of participating in a clinical trial.

I am taking more than 10 mg of prednisone daily.

I haven't had a heart attack or stroke in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combined therapy with nivolumab and high dose IL-2 for up to 3 courses, with response assessments after each course

Up to 3 courses

Visits prior to each treatment and after each course

Follow-up

Participants are monitored for safety, effectiveness, and progression-free survival after treatment

1 year +/- 3 months

What Are the Treatments Tested in This Trial?

Interventions

• IL-2
• Nivolumab

Trial Overview The trial is testing the combination of nivolumab (an anti-PD-1 drug) and high-dose IL-2 to see if they can work together to treat patients whose cancer didn't respond to just anti-PD-1 treatment alone. Patients will receive these drugs for up to three courses and their response will be measured using standard criteria.

How Is the Trial Designed?

Group I: High Dose IL-2 and Nivolumab Experimental Treatment 1 Intervention

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

Approved in United States as Proleukin for:

• Renal cell carcinoma
• Melanoma

Approved in European Union as Proleukin for:

• Renal cell carcinoma
• Melanoma

Who Is Running the Clinical Trial?

Gregory Daniels

Lead Sponsor

Trials

2

Recruited

30+

Published Research Related to This Trial

In a study of 24 melanoma patients treated with the anti-PD-1 antibody nivolumab, a clinical response rate of 29% was observed, indicating that while some patients benefit from this treatment, many do not.

The presence of multifunctional CD8+ PD-1+ T cells and higher PD-L1 expression in tumors were associated with better responses to nivolumab, suggesting these could serve as potential biomarkers for predicting treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multifunctionality of CD8+ T cells and PD-L1 expression as a biomarker of anti-PD-1 antibody efficacy in advanced melanoma. Manabe, K., Yamasaki, O., Nakagawa, Y., et al.[2022]

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]

EMD 273063, an immunocytokine treatment for metastatic melanoma, was found to induce immune activation and was administered safely at a maximum-tolerated dose (MTD) of 7.5 mg/m2/d, with 19 out of 33 patients showing stable disease after the first treatment course.

While there were some grade 3 adverse events, such as hypophosphatemia and hyperglycemia, these were manageable and resolved, indicating that the treatment has a tolerable safety profile despite the associated toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. King, DM., Albertini, MR., Schalch, H., et al.[2021]

In a phase I/II trial involving 38 patients with newly diagnosed metastatic melanoma, the combination of bempegaldesleukin and nivolumab resulted in responses in 20 patients, indicating potential efficacy.

The treatment combination was associated with relatively few side effects, suggesting a favorable safety profile for this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin Ups Melanoma Responses. [2020]

The combination of bempegaldesleukin (BEMPEG) and nivolumab has shown promising clinical activity and good tolerability as a first-line treatment for metastatic melanoma in the Phase I/II PIVOT-02 trial.

The ongoing Phase III PIVOT IO 001 trial aims to compare the effectiveness of this combination therapy against nivolumab alone, focusing on key outcomes like objective response rate and overall survival in patients with untreated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Khushalani, NI., Diab, A., Ascierto, PA., et al.[2021]

The combination of bempegaldesleukin (BEMPEG) and nivolumab (NIVO) has shown promising results as a well-tolerated first-line treatment for metastatic melanoma, indicating its potential effectiveness in this patient population.

The ongoing PIVOT-12 study aims to determine if BEMPEG plus NIVO can improve recurrence-free survival compared to NIVO alone in patients with completely resected stage III/IV melanoma, which could provide important insights into its efficacy as an adjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIVOT-12: a phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence. Eggermont, AM., Ascierto, PA., Khushalani, NI., et al.[2022]

In a phase II study involving 41 patients with untreated stage III/IV metastatic melanoma, the combination of bempegaldesleukin (BEMPEG) and nivolumab (NIVO) showed a promising objective response rate of 52.6%, with 34.2% achieving complete responses.

The treatment was well-tolerated, with only 17.1% of patients experiencing grade 3 or 4 adverse events, and it resulted in a median progression-free survival of 30.9 months, indicating its potential as an effective first-line therapy for metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. Diab, A., Tykodi, SS., Daniels, GA., et al.[2022]

Aldesleukin (recombinant IL-2) has shown modest efficacy in treating metastatic melanoma, with response rates up to 56% in combination therapies, but median survival times remain around 10 to 11 months, indicating limited long-term benefits.

The administration methods of aldesleukin have evolved to reduce toxicity, with continuous intravenous infusion and subcutaneous options leading to fewer severe adverse events, but further studies are needed to fully understand its risk/benefit profile compared to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldesleukin (recombinant interleukin-2). Noble, S., Goa, KL.[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]

Nivolumab, an antibody treatment for metastatic non-small cell lung cancer, can lead to rare but serious immune-related adverse events, including grade 3 febrile neutropenia and liver dysfunction, as seen in a case study of a 57-year-old man.

Management of these adverse effects is crucial, as neutropenia can recur after treatment, necessitating careful monitoring and potential re-treatment with supportive therapies like G-CSF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Febrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab. Hisamatsu, Y., Morinaga, R., Watanabe, E., et al.[2020]

Citations

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Update on use of aldesleukin for treatment of high-risk ... High-dose interleukin-2 has been used for the treatment of metastatic melanoma since 1998 based on data proving durable complete responses in up to 10% of ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00172

The Open-Label, Phase III PIVOT IO 001 Trial Results High-dose interleukin-2 (IL-2) monotherapy has shown efficacy, including durable complete responses (CRs), in patients with metastatic melanoma ...

3. curemelanoma.org curemelanoma.org/blog/clinical-trials-to-watch-july-2025

Melanoma Clinical Trials to Watch: July 2025 Promising data was presented at the 2025 American Society of Clinical Oncology annual conference on results from the Agni-01 phase 1/2 trial ( ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03889782

High Dose IL-2 in Combination With Anti-PD-1 to ... The primary endpoint will be the response rate [complete response (CR) and partial response (PR)] of combined therapy with nivolumab and HD IL-2 in metastatic ...

5. cancerresearch.org cancerresearch.org/immunotherapy-by-cancer-type/melanoma-cancer

Melanoma Cancer - Cancer Research ... Immunotherapy has dramatically shifted the treatment landscape for melanoma, significantly enhancing survival rates and offering new hope.

6. jitc.bmj.com jitc.bmj.com/content/7/1/49

Therapy with high-dose Interleukin-2 (HD IL-2) in ... 38% of the mM patients and 47% of the mRCC patients had stable disease. Response data is summarized in Table 1. None of the melanoma patients ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4811023/

Survival, Durable Tumor Remission, and Long-Term Safety in ... We now report overall survival outcomes in patients with melanoma who received nivolumab. Response characteristics, including durability and persistence ...