Entinostat + Aldesleukin for Kidney Cancer

Not currently recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Valproic acid, Investigational agents

Disqualifiers: CNS metastases, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with kidney cancer that has spread. It examines the effects of combining entinostat, which may halt tumor growth, with aldesleukin (also known as Interleukin-2 or IL-2), which could enhance the immune system's ability to attack cancer cells. The main goal is to determine the optimal dose and assess the effectiveness of this combination. Ideal participants are those with metastatic kidney cancer who have clear cell carcinoma and have undergone up to two previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not allow the use of valproic acid and other investigational agents. If you are taking these, you will need to stop. The protocol does not specify about other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that entinostat and aldesleukin have been studied separately for their safety in treating cancer. Entinostat, a drug that can stop cancer cells from growing, has been tested in various cancer trials. It shows promise, but researchers continue to study its safety in different combinations and situations.

Aldesleukin, also known as Proleukin, has FDA approval for treating advanced kidney cancer. It aids the immune system in fighting cancer but can cause serious side effects in some patients, such as low blood pressure or breathing problems. These side effects are well-documented, and doctors closely monitor patients using it.

In summary, researchers are still exploring the safety of entinostat, while aldesleukin is known for its serious side effects but is FDA-approved for kidney cancer. Both treatments are under study together to determine if they are more effective when combined, with safety as a key focus of the research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for kidney cancer, such as surgery, targeted therapies, and immunotherapies, entinostat combined with aldesleukin introduces a novel approach. Entinostat is an HDAC inhibitor, which can enhance the immune response by altering gene expression and making cancer cells more vulnerable to attack. Researchers are excited about this combination because it pairs entinostat's ability to modify the tumor environment with aldesleukin's capacity to boost immune cells, potentially leading to more effective tumor shrinkage. This dual-action strategy could offer a powerful alternative for patients who don't respond well to existing therapies.

What evidence suggests that entinostat and aldesleukin might be an effective treatment for kidney cancer?

This trial will evaluate the combination of Entinostat and high-dose Aldesleukin for kidney cancer. Studies have shown that high-dose Aldesleukin can help about 14% of patients with metastatic renal cell carcinoma (mRCC) by shrinking tumors or slowing their growth, sometimes leading to long-lasting remissions. Entinostat is a drug that stops cancer cells from growing by affecting certain necessary enzymes. Research indicates that when combined with other treatments, Entinostat might enhance the immune system's ability to fight cancer. Early findings suggest that combining Entinostat with Aldesleukin could provide a stronger response against metastatic kidney cancer. ^{4 5 6 7 8}

Who Is on the Research Team?

Saby George

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with metastatic kidney cancer who have good physical function and a life expectancy over 6 months. They can have had up to two prior treatments, but not more, and must be able to perform daily activities without significant difficulty (ECOG status 0). Participants need normal organ function tests, no recent heart issues or strokes, and non-pregnant women/men must agree to use contraception. People with certain medical conditions or those on conflicting medications cannot join.

Inclusion Criteria

I've had up to two treatments for my cancer and may have had radiation, but still have measurable cancer.

You are expected to live for at least 6 more months.

Your lactate dehydrogenase (LDH) levels are normal.

Exclusion Criteria

I am not allergic to entinostat or similar medications.

I am not HIV-positive or taking antiretroviral therapy.

Your heart's pumping ability is less than 45%.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive entinostat orally every 2 weeks and high-dose aldesleukin intravenously every 8 hours on days 1-5 and 15-19. Cycles repeat every 84 days in the absence of disease progression or unacceptable toxicity.

12 weeks per cycle

Multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 months.

Up to 12 months

Follow-up visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Aldesleukin
• Entinostat

Trial Overview The trial is testing the combination of entinostat (which blocks enzymes needed for tumor growth) with aldesleukin (which may activate white blood cells against cancer) in patients with advanced kidney cancer. It aims to find the best dose of entinostat that works well with aldesleukin by observing side effects and effectiveness.

How Is the Trial Designed?

Group I: Treatment (entinostat, aldesleukin) Experimental Treatment 7 Interventions

Patients receive entinostat PO every 2 weeks beginning on day -14 and high-dose aldesleukin IV every 8 hours on days 1-5 and 15-19. Cycles repeat every 84 days\* in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients with evidence of tumor shrinkage may receive up to 3 cycles of high-dose aldesleukin therapy. Patients with stable disease by RECIST version 1.0 criteria, but without evidence of tumor shrinkage after two cycles will receive only entinostat until disease progression is documented.

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+

Published Research Related to This Trial

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]

In a phase I/II clinical study involving 47 patients with metastatic clear cell renal cell carcinoma, the combination of the HDAC inhibitor entinostat and high-dose IL2 showed a promising objective response rate of 37% and a median overall survival of 65.3 months.

Treatment with entinostat led to a decrease in regulatory T cells (Tregs), which was associated with better treatment responses, indicating a potential mechanism of action for enhancing the efficacy of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870). Pili, R., Quinn, DI., Hammers, HJ., et al.[2022]

BAY 50-4798, a novel IL-2 analog, shows similar potency to aldesleukin in stimulating T cell proliferation but with significantly reduced inflammatory responses, indicating a potentially safer profile for patients.

In studies comparing cytokine responses, BAY 50-4798 induced about 5-fold lower levels of endogenous IL-2 and at least 50% lower levels of proinflammatory cytokines compared to aldesleukin, suggesting it may have fewer side effects in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. Steppan, S., Eckart, MR., Bajsarowicz, K., et al.[2013]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4315731/

The High-Dose Aldesleukin “Select” Trial - PubMed Central High-dose aldesleukin (HD IL-2) received FDA approval for the treatment of mRCC in 1992, producing a 14% objective response rate (ORR) and durable remissions.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00554515

The High-Dose Aldesleukin (IL-2) "Select" Trial for Patients ... To determine, in a prospective fashion, the response rate to high-dose IL-2 for patients with metastatic renal cell carcinoma and "poor" pathologic predictive ...

3. cancernetwork.com cancernetwork.com/view/current-status-interleukin-2-therapy-metastatic-renal-cell-carcinoma-and-metastatic-melanoma

Current Status of Interleukin-2 Therapy for Metastatic Renal ... The overall 5-year survival rate was 6%, although 60% of patients with a complete response were alive at 5 years. The results of a randomized, phase III study ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.1995.13.3.688

Results of treatment of 255 patients with metastatic renal ... Conclusion. High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1558767311700210

The High-Dose Aldesleukin (IL-2) “Select” Trial: A ... For patients with metastatic renal cell carcinoma (RCC), the prognosis is poor. Despite the recent approval of drugs such as sorafenib, sunitinib, ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf

Proleukin (aldesleukin) injection label - accessdata.fda.gov The following data on life-threatening adverse events (reported in greater than 1% of patients, grade 4), presented by body system, and by preferred term ( ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2409650/

Safety and efficacy of subcutaneous and continuous ... Data from these i.v.b. studies showed that this regimen has efficacy in terms of regression in several types of cancer, particularly renal cell carcinoma and ...

8. iovance.com iovance.com/PROLEUKIN_USPI/

HIGHLIGHTS OF PRESCRIBING INFORMATION ... The safety of Proleukin was evaluated in a series of single and multicenter, controlled studies enrolling a total of 525 patients with metastatic renal cell ...