Anti-PD-1 + Aldesleukin for Melanoma and Kidney Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Steroids, Investigational agents
Disqualifiers: Nursing, Infections, Autoimmune, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
12345Is 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.
15678What 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.
125910Eligibility 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.
+10 more
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.
+9 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: 1 - Pembro and IL-2Experimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
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]High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2.
Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti-PD-1) treatment. [2020]Aldesleukin [interleukin-2 (IL-2)] induces durable complete responses in some kidney cancer and melanoma patients. Nivolumab is an investigational antibody drug targeting programmed death-1 (PD-1) as a treatment, demonstrating activity in multiple cancer types. An expanding complement of immunotherapeutics raises important issues regarding the best way to use them. There are issues beyond identifying an agent that provides the superior front-line response: when does one therapy potentiate another immune therapy? When is the capacity of immune response exhausted and an approach without immune mechanism the better therapy? In this case report, we present a patient with metastatic renal cell carcinoma with no tumor regression evident on a PD-1 blockade (given on an investigational trial), who then achieved near-complete response to bolus high-dose IL-2 therapy, maintaining a persistent response off therapy. This case emphasizes on the need to develop improved predictors of response to immune therapies, especially as they can be applied to optimize sequential immunotherapeutic modalities versus predict when to turn to alternative targeted agents in renal cell carcinoma, and is an example of efficacious IL-2 application as a second-line treatment.
High-dose interleukin-2: is it still indicated for melanoma and RCC in an era of targeted therapies? [2017]Immunotherapy with interleukin-2 (IL-2) has been the mainstay of systemic therapy for advanced kidney cancer and melanoma. Although IL-2 treatment is limited to healthy patients, a select group of these patients have derived substantial, durable benefit from it-in some translating into cures with no ongoing therapy or chronic toxicity. Over the past 10 years, insights into the biology of renal cell carcinoma and into key signaling mechanisms in melanoma, and growth in our understanding of immune checkpoints, have led to the development and approval of targeted and immune-modulatory therapeutic options with clinically relevant benefit. Our improved understanding of the relationship between the host environment, immune system, and malignancy has helped identify compounds and therapies that are changing the way we think about cancer and our approach to cancer therapeutics. While the newer options may be applicable to most patients, durable responses measured in years are rare. In this review, we examine the currently approved options available for these disease processes, including the newer agents and selected combinatorial approaches under investigation, and we attempt to identify the role of high-dose IL-2 in the context of current clinical practice.
Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. [2020]Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment.
Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.
Aldesleukin (recombinant interleukin-2): a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. [2018]Aldesleukin (recombinant interleukin-2), like endogenous interleukin-2 (IL-2), has a variety of immunomodulatory properties. It is currently approved for intravenous use in patients with renal cell carcinoma, in whom it appears to have an indirect antitumour effect mediated by increased activity of the host's immune system. A large number of clinical trials (typically noncomparative) have established the efficacy of aldesleukin monotherapy in patients with renal cell carcinoma. Response rates of 13 to 20% achieved after intravenous administration and 18 to 31% after subcutaneous administration are greater than those previously reported ( approximately 10%) for other chemo- and immunotherapeutic agents. Furthermore, many patients who were previously refractory to treatment have achieved stable disease status or better after aldesleukin therapy. Median survival times of at least 37 months have been achieved, and perhaps more encouraging is an isolated report of a 5-year actuarial survival rate of 23%. Bolus intravenous administration of aldesleukin was associated with frequent, and occasionally life-threatening, adverse events. Hypotension and renal, pulmonary and cardiac complications were primarily manifestations of increased vascular permeability. Symptoms were generally manageable with treatment interruption and standard pharmaceutical and/or clinical intervention, although some treatment-related deaths were reported. The severity of adverse events was reduced with continuous infusion of the agent and more substantially so when aldesleukin was administered subcutaneously. In conclusion, despite a lack of comparative and phase III trials, aldesleukin therapy appears to result in a slightly better response rate than those previously reported with other antineoplastic therapies in this difficult-to-treat patient population. Retrospective data indicate that survival duration may be moderately increased by aldesleukin, but further prospective comparative data are required before this may be proven. In view of the poor prognosis associated with renal cell carcinoma, efficacy data from clinical trials evaluating aldesleukin, together with the potential for reducing adverse events by changing its route of administration, suggest the drug may be a worthwhile therapy for patients with this disease.
Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. [2021]To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma.
A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma. [2023]High-dose interleukin-2 (HD IL-2) and pembrolizumab are each approved as single agents by the U.S. F.D.A. for the treatment of metastatic melanoma. There is limited data using the agents concurrently. The objectives of this study were to characterize the safety profile of IL-2 in combination with pembrolizumab in patients with unresectable or metastatic melanoma.
Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.
Aldesleukin (recombinant interleukin-2). [2022]Aldesleukin [recombinant interleukin-2 (IL-2)] is a biological response modifier which, like endogenous IL-2, has a range of immunomodulatory properties. Although aldesleukin is currently approved only for treatment of renal cell carcinoma, it has been widely used in patients with metastatic melanoma and has been assessed in numerous noncomparative trials in this indication. Durable complete responses have been reported in a small proportion of patients with good performance status who received immunotherapy or chemoimmunotherapy involving aldesleukin in several clinical trials. Overall median survival times of about 10 or 11 months are typical. Combination chemoimmunotherapy involving aldesleukin has produced relatively high response rates (up to 56%), but these are not predictive of increased survival time. Aldesleukin has not been directly compared with standard chemotherapy in randomised studies. The use of continuous intravenous infusion and subcutaneous administration of aldesleukin, together with improved patient selection, has successfully reduced the severity of adverse events produced by the drug (the original intravenous bolus regimen is particularly toxic and often necessitates admission to an intensive care unit). However, the risk/benefit profile of aldesleukin in the treatment of melanoma requires further study, particularly after subcutaneous administration. Thus, aldesleukin has shown modest efficacy in the treatment of metastatic melanoma. Although aldesleukin-containing regimens have produced promising results in many noncomparative trials, their clinical value in comparison with standard chemotherapy remains to be determined in phase III studies. Until results from such trials are available, clinicians will need to carefully balance the potential benefits of the drug against the risks and likely quality-of-life implications associated with its toxicity in each patient. Current investigations centre on the use of aldesleukin as part of complex biochemotherapy regimens, and results from these trials are awaited with interest.