Triple Therapy for Breast Cancer

Not currently recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Valproic acid, others

Disqualifiers: Autoimmune disease, Brain metastases, HIV, others

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

Compensation: Varies

Number of Visits: 10

Duration: Up to 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—entinostat, nivolumab, and ipilimumab—to evaluate their effectiveness in treating advanced breast cancer that has spread or cannot be surgically removed. Researchers aim to determine the best doses and monitor for side effects. The trial seeks to enhance the immune system's ability to fight cancer. Suitable participants have HER2-negative breast cancer that has spread and progressed despite standard treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before joining. Specifically, you must stop chemotherapy, hormone therapy, targeted therapy, and some other treatments for a specified period before registration. It's best to discuss your current medications with the trial team to see if they need to be paused.

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

Research shows that entinostat, a drug under investigation, is being evaluated for its safety and effectiveness in treating various cancers, including breast cancer. However, specific safety details for entinostat remain incomplete.

Studies have tested the combination of two immunotherapy drugs, nivolumab and ipilimumab, and found promising results in breast cancer patients. This combination was generally well-tolerated, though some patients experienced side effects like tiredness and skin rash, common with these treatments.

As this trial is in an early stage, the primary goal is to determine the treatment's safety and optimal dosage. Detailed safety information may not yet be fully available. However, both nivolumab and ipilimumab are already approved for other uses, indicating an established safety record. Participants in this trial can contribute to improving the combined use of these drugs, potentially leading to better cancer treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple therapy of entinostat, ipilimumab, and nivolumab for breast cancer because it combines targeted and immune-based approaches. Unlike traditional treatments like chemotherapy, which mainly attack cancer cells directly, this combination includes immune checkpoint inhibitors (ipilimumab and nivolumab) that help the immune system recognize and attack cancer cells more effectively. Entinostat, an HDAC inhibitor, can also modify the tumor environment to make it more susceptible to immune attack. This innovative strategy aims to enhance the body's natural defenses against cancer, offering a potentially powerful alternative to existing treatments.

What evidence suggests that this trial's treatments could be effective for metastatic HER2-negative breast cancer?

This trial will evaluate the combination of entinostat, nivolumab, and ipilimumab for treating certain cancers. Research suggests that entinostat blocks enzymes that aid cancer cell growth, potentially stopping or slowing cancer spread. Nivolumab and ipilimumab, as types of immunotherapy, help the immune system find and attack cancer cells. Previous studies have shown that using these drugs together might improve outcomes for patients with difficult-to-treat cancers. While this combination remains under study in this trial, these methods offer hope for managing advanced or hard-to-remove solid tumors. ^{1 4 6 7 8}

Who Is on the Research Team?

Roisin Connolly, MD

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with solid tumors that are metastatic/unresectable or HER2-negative breast cancer that's advanced despite treatment. Must have had prior chemotherapy for metastatic breast cancer and hormone therapy if applicable. No active autoimmune diseases, untreated brain metastases, another recent malignancy, or need for immune suppressive drugs.

Inclusion Criteria

Your platelet count is at least 100,000 per microliter.

If you are a woman who could become pregnant, you need to have a negative pregnancy test.

My oxygen levels stay above 90% when I move around without needing extra oxygen.

Exclusion Criteria

I do not have HIV, hepatitis B, or hepatitis C.

You are allergic to entinostat, nivolumab, or ipilimumab, or have had a severe allergic reaction to any monoclonal antibody.

Patients with certain autoimmune diseases or a history of these diseases that may affect vital organ function or require immune suppressive treatment should be excluded. This includes diseases such as multiple sclerosis, lupus, and inflammatory bowel disease. However, patients with certain autoimmune conditions that are well-controlled with medication may be eligible.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive entinostat orally on days -14 and -7 and then weekly, nivolumab intravenously on day 1 and then every 2 weeks, and ipilimumab intravenously on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 5 years

Bi-weekly visits for nivolumab, every 6 weeks for ipilimumab

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months until disease progression and then every 6 months for up to 5 years.

Up to 5 years

Every 3 months, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Entinostat
• Ipilimumab
• Nivolumab

Trial Overview

The trial is testing the combination of entinostat (an HDAC inhibitor) with nivolumab and ipilimumab (monoclonal antibodies) to see if they can better treat patients with advanced cancers by inhibiting enzymes needed for cell growth and boosting the immune system's ability to fight cancer.

How Is the Trial Designed?

Group I: Treatment (entinostat, nivolumab, ipilimumab) Experimental Treatment 10 Interventions

Patients receive entinostat PO on days -14 and -7 and then weekly, nivolumab IV over 60 minutes on day 1 and then every 2 weeks, and ipilimumab IV over 90 minutes on day 1 and then every 6 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT as clinically indicated throughout the trial. Patients may undergo PET/CT or bone scan throughout the trial. Patients also undergo tissue biopsy and blood sample collection during screening and on the trial.

Entinostat is already approved in China, European Union for the following indications:

Approved in China as Entinostat for:

• Cancer

Approved in European Union as Entinostat for:

• Orphan Drug designation for cancer treatment

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

Entinostat, a class I histone deacetylase (HDAC) inhibitor, shows promise in treating various subtypes of breast cancer, particularly in overcoming resistance to anti-tumor treatments and enhancing immune response.

Clinical trials indicate that combining entinostat with antiestrogen therapy may effectively target resistance pathways in hormone-positive breast cancer, suggesting a potential new strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat for the treatment of breast cancer. Trapani, D., Esposito, A., Criscitiello, C., et al.[2017]

Entinostat, both as a monotherapy and in combination with exemestane, was well tolerated in a phase 1 study involving 12 Japanese postmenopausal women with advanced hormone receptor-positive breast cancer, showing no dose-limiting toxicities or severe adverse events.

Half of the patients achieved stable disease for at least 6 months, with a median progression-free survival of 13.9 months, indicating that entinostat may be an effective treatment option for patients resistant to standard endocrine therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. Masuda, N., Tamura, K., Yasojima, H., et al.[2022]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a phase II study involving 130 postmenopausal women with ER+ advanced breast cancer, the combination of entinostat and exemestane improved median progression-free survival (PFS) to 4.3 months compared to 2.3 months with exemestane alone, suggesting enhanced efficacy of the combination treatment.

Entinostat was generally well tolerated, although there was a higher rate of treatment discontinuation due to adverse events in the entinostat group (11% vs. 2%). Additionally, changes in protein lysine acetylation were linked to prolonged PFS, indicating a potential biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Yardley, DA., Ismail-Khan, RR., Melichar, B., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In the phase III CheckMate 238 trial, 67.7% of patients receiving nivolumab experienced treatment-related adverse events (TRAEs), with the most common being pruritus and diarrhea, primarily occurring within the first 3 months of treatment.

Despite the high incidence of TRAEs, there was no significant association found between these adverse events and recurrence-free survival (RFS), indicating that the safety profile of nivolumab remains consistent and does not negatively impact long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. Mandala, M., Larkin, J., Ascierto, PA., et al.[2022]

Citations

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Names and Synonyms ; ENTINOSTAT · CARBAMIC ACID, N-((4-(((2-AMINOPHENYL)AMINO)CARBONYL)PHENYL)METHYL)-, 3- PYRIDINYLMETHYL ESTER · entinostat [INN] ; Official Name ...

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Entinostat has been investigated for the treatment of Non-Small Lung Cancer, Epigenetic Therapy. Investigational. Matched Synonyms: … N-(2-aminophenyl)-4-(N-( ...