Anti-PD-1 + Aldesleukin for Melanoma and Kidney Cancer

Overseen By Stephanie L Goff, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Nursing, Infections, Autoimmune, 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: 5

78 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Aldesleukin is used to treat metastatic or advanced melanoma and renal cell carcinoma. Pembrolizumab is used to treat many cancers including melanoma. Researchers want to see if these drugs can be used together to produce better results in people with these types of cancer. Objective: To learn if the combination of pembrolizumab and aldesleukin can be used to treat metastatic or advanced melanoma and renal cell cancer. Eligibility: Adults aged 18 years or older who have metastatic or advanced melanoma or renal cell carcinoma. Design: Participants will be screened with: * Medical history * Physical exam * Electrocardiogram * Blood and urine tests * Ability to perform tasks of daily living * Imaging scans (CT, MRI, PET, and/or X-rays). They may get a contrast agent to enhance the images. * Photographs, if needed Some of these tests will be repeated during the study. Participants will receive the study drugs by IV (a plastic tube that is put into a vein) for 4 days. A second cycle of treatment will be given 21 days later. They will stay in the hospital for each of the cycles in the first course of treatment. After 2 months, their cancer will be evaluated. They may receive a second course of pembrolizumab alone on Days 1 and 21. They will not have to stay in the hospital for this course. About 30 days after treatment ends, participants will have a safety follow-up visit. Then they will have visits every 3 months for up to 1 year, and then every 6 months for up to 4 years. Follow-up can also be done by phone, email, and mail. If their cancer gets worse, they will stop having visits. Participation will last for 5 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot be on systemic steroid therapy or other investigational agents. More than four weeks must have passed since your last systemic therapy before enrolling.

What data supports the effectiveness of the drug combination of Anti-PD-1 and Aldesleukin for treating melanoma and kidney cancer?

Aldesleukin (IL-2) has shown durable responses in some patients with kidney cancer and melanoma, and pembrolizumab (an anti-PD-1 drug) enhances the immune system's ability to fight tumors. Combining these drugs may improve treatment outcomes by leveraging their individual strengths. ^{1 2 3 4 5}

Is the combination of Anti-PD-1 and Aldesleukin safe for humans?

Aldesleukin can cause serious side effects like low blood pressure and heart, lung, and kidney problems, but these are usually manageable with treatment adjustments. Pembrolizumab has shown no significant toxic effects in animal studies and is generally considered safe in humans based on clinical trials. ^{1 5 6 7 8}

What makes the drug combination of Anti-PD-1 and Aldesleukin unique for treating melanoma and kidney cancer?

This drug combination is unique because it combines pembrolizumab, which blocks a protein called PD-1 to help the immune system attack cancer cells, with aldesleukin, which boosts the immune system's response. This approach aims to enhance the body's ability to fight cancer more effectively than using either drug alone. ^{1 2 5 9 10}

Research Team

Stephanie L Goff, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with advanced melanoma or renal cell carcinoma can join this trial. They must not have HIV, hepatitis B/C, be pregnant, or breastfeeding. Participants need to have finished any previous cancer treatments at least four weeks prior and agree to use birth control. They should be in good health otherwise, without severe infections or immune system problems.

Inclusion Criteria

I have melanoma or kidney cancer that can be measured for changes.

Subject must be co-enrolled on protocol 03-C-0277

You do not have hepatitis B or hepatitis C in your blood.

Exclusion Criteria

You have a condition that weakens your immune system from birth.

You had a serious allergic reaction to pembrolizumab or aldesleukin in the past.

I am currently on steroid medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment - Course 1

Participants receive pembrolizumab and aldesleukin for 2 cycles, each lasting 21 days. Pembrolizumab is administered on Day 1, followed by aldesleukin for up to 4 days.

6 weeks

Inpatient stay for each cycle

Treatment - Course 2

Participants receive pembrolizumab alone for 2 cycles, each lasting 21 days.

6 weeks

Outpatient visits on Day 1 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up visits occur every 3 months for the first year, then every 6 months for up to 5 years.

5 years

Every 3 months x 3, then every 6 months x 8

Treatment Details

Interventions

• Aldesleukin
• Pembrolizumab

Trial Overview The trial is testing the combination of two drugs: Aldesleukin and Pembrolizumab given through IV for metastatic melanoma and renal cell carcinoma. The treatment involves hospital stays during cycles and follow-ups for up to five years including physical exams, scans, blood tests.

Participant Groups

Group I: 1 - Pembro and IL-2 Experimental Treatment 2 Interventions

Course 1: pembrolizumab (200 mg IV) on Day 1 of each cycle with aldesleukin (600,000 IU/kg intravenous bolus every eight hours) continuing for up to 4 days (maximum 10 doses) for 2 cycles (each 21 days). Course 2: pembrolizumab (200 mg IV) on Day 1 of each cycle for 2 cycles (each 21 days).

Aldesleukin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Proleukin for:

• Metastatic renal cell carcinoma
• Metastatic melanoma

Approved in European Union as Proleukin for:

• Metastatic renal cell carcinoma

Approved in Canada as Proleukin for:

• Metastatic renal cell carcinoma
• Metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a prospective trial involving 120 patients with metastatic renal cell carcinoma (mRCC), high-dose aldesleukin (HD IL2) achieved a 25% objective response rate (ORR), which is significantly higher than historical rates, indicating its efficacy in treating this condition.

The study found that tumor PD-L1 expression was positively associated with response to HD IL2, suggesting it could be a useful biomarker for predicting treatment outcomes, although the integrated selection model (ISM) did not enhance patient selection for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. McDermott, DF., Cheng, SC., Signoretti, S., et al.[2018]

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]

Interleukin-2 (IL-2) immunotherapy remains a key treatment for advanced kidney cancer and melanoma, providing substantial and durable benefits for a select group of healthy patients, sometimes leading to cures without ongoing therapy.

Recent advancements in understanding cancer biology and immune mechanisms have led to new targeted and immune-modulatory therapies, which, while beneficial for many patients, typically do not achieve the same long-lasting responses as high-dose IL-2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose interleukin-2: is it still indicated for melanoma and RCC in an era of targeted therapies? Amin, A., White, RL.[2017]

In a study of 425 patients with metastatic renal-cell carcinoma, the combination of interleukin-2 and interferon alfa-2a resulted in the highest response rate of 18.6%, compared to 6.5% for interleukin-2 alone and 7.5% for interferon alfa-2a alone.

While the combination treatment showed better event-free survival rates (20% at one year), it also had higher toxicity, particularly with interleukin-2, highlighting the need to weigh treatment benefits against potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. Negrier, S., Escudier, B., Lasset, C., et al.[2020]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Aldesleukin (recombinant interleukin-2) has shown efficacy in treating renal cell carcinoma, with response rates of 13-20% for intravenous and 18-31% for subcutaneous administration, which are higher than the approximately 10% response rates of other treatments.

While aldesleukin can lead to serious side effects, particularly with bolus intravenous administration, the severity of these adverse events is reduced with continuous infusion or subcutaneous administration, making it a potentially safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldesleukin (recombinant interleukin-2): a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. Jeal, W., Goa, KL.[2018]

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 Ib study involving 10 patients with unresectable or metastatic melanoma, the combination of high-dose interleukin-2 (HD IL-2) and pembrolizumab was found to be feasible and tolerable, with no dose-limiting toxicities observed.

Among the 9 evaluable patients, there was one partial response, indicating some efficacy of the combination treatment, particularly in a patient who had previously received anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma. Silk, AW., Curti, B., Bryan, J., et al.[2023]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

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]

References

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

The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. [2018]

2. 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]

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

High-dose interleukin-2: is it still indicated for melanoma and RCC in an era of targeted therapies? [2017]

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

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. [2020]

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

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

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

Aldesleukin (recombinant interleukin-2): a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. [2018]

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

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Aldesleukin (recombinant interleukin-2). [2022]