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

6 Participants Needed

Trial Summary

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.

What data supports the idea that IL-2 + Nivolumab for Melanoma is an effective treatment?

The available research shows that combining IL-2 with Nivolumab can be effective for treating melanoma. In particular, a study found that adding bempegaldesleukin (a form of IL-2) to Nivolumab improved responses in patients with metastatic melanoma, with 20 out of 38 patients showing positive results. This combination was also well-tolerated, meaning it didn't cause many side effects. Additionally, another study compared this combination to Nivolumab alone and found it to be more effective in preventing the return of melanoma after surgery. These findings suggest that IL-2 combined with Nivolumab can be a promising treatment option for melanoma. ^{1 2 3 4 5}

What safety data exists for IL-2 and Nivolumab treatment in melanoma?

Safety data for IL-2 (Aldesleukin) and Nivolumab (Opdivo) in melanoma includes reports of immune-related adverse events (irAEs) such as pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy associated with Nivolumab. IL-2 has been associated with severe adverse events, particularly with the original intravenous bolus regimen, which often requires intensive care. However, continuous intravenous infusion and subcutaneous administration have reduced the severity of these adverse events. The combination of Bempegaldesleukin (a modified IL-2) and Nivolumab was well-tolerated in early trials, with further safety assessments ongoing in a Phase III trial. Overall, while both treatments have shown efficacy, their risk/benefit profiles require careful consideration due to potential toxicities. ^{1 2 6 7 8}

Is the drug IL-2 and Nivolumab a promising treatment for melanoma?

Yes, IL-2 and Nivolumab show promise as a treatment for melanoma. IL-2 can lead to long-lasting responses in melanoma patients by boosting the immune system. Nivolumab, which helps the immune system attack cancer cells, has been shown to improve survival in advanced melanoma. Together, they have demonstrated clinical activity and potential for effective treatment. ^{1 3 5 9 10}

What is the purpose of this trial?

The primary objective of this single arm phase 2 trial is to assess the response rate \[complete response (CR) + partial response (PR)\] of combined nivolumab and HD IL-2 in subjects with metastatic melanoma and renal cell carcinoma. Response will be performed after each course of nivolumab and IL-2 using RECIST 1.1. Patients will be treated for one course past best response for a maximum of 3 courses.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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 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 (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]

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]

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]

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]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. [2021]

3. 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]

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

Bempegaldesleukin Ups Melanoma Responses. [2020]

5. England 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. [2022]

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

Aldesleukin (recombinant interleukin-2). [2022]

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

Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. [2021]

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

Febrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab. [2020]

9. England 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. [2022]

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

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. [2022]