Entinostat + Aldesleukin for Kidney Cancer

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

47 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of entinostat when given together with aldesleukin and to see how well this works in treating patients with kidney cancer that has spread to other places in the body. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Aldesleukin may stimulate the white blood cells to kill kidney cancer cells. Giving entinostat together with aldesleukin may be a better treatment for metastatic kidney cancer.

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 the combination of Entinostat and Aldesleukin safe for humans?

Aldesleukin, also known as IL-2, has been used in cancer treatment but is associated with severe side effects, including life-threatening complications like low blood pressure and organ issues. These side effects can be managed by adjusting the administration method, such as using continuous infusion or subcutaneous injection, which reduces their severity. ^{1 2 3 4 5}

What makes the drug combination of Entinostat and Aldesleukin unique for kidney cancer?

The combination of Entinostat and Aldesleukin is unique because Entinostat, an epigenetic agent, works with Aldesleukin to enhance the immune response against kidney cancer by reducing regulatory T cells, which can suppress the immune system. This combination has shown a higher response rate and longer survival in patients compared to Aldesleukin alone. ^{2 4 6 7 8}

What data supports the effectiveness of the drug Entinostat + Aldesleukin for kidney cancer?

Aldesleukin, a component of the treatment, has shown effectiveness in treating metastatic renal cell carcinoma, with response rates of 13 to 31% and median survival times of at least 37 months. It works by boosting the immune system to fight cancer, although it can have serious side effects. ^{2 4 5 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 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]

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]

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 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]

Citations

1. 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]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

Aldesleukin in advanced renal cell carcinoma. [2013]

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

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. [2021]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

INBRX-120, a CD8α-targeted detuned IL-2 that selectively expands and activates tumoricidal effector cells for safe and durable in vivo responses. [2023]

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

Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. [2013]

8. United States 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). [2022]