Triple Therapy for Breast Cancer

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

57 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Entinostat in treating breast cancer?

Research shows that Entinostat, when combined with exemestane, improved survival in patients with advanced hormone receptor-positive breast cancer. It also helps overcome resistance to hormonal therapies and enhances immune responses, which may improve treatment outcomes. ^{1 2 3 4 5}

What safety data exists for the combination of ipilimumab and nivolumab in treating cancer?

The combination of ipilimumab and nivolumab has been associated with immune-related side effects, which can be more frequent and severe than when each drug is used alone. Common side effects include skin issues like rash and itching, gastrointestinal problems like diarrhea, and more serious conditions like inflammation of the liver and thyroid issues. It's important for doctors to monitor patients closely for these side effects. ^{6 7 8 9 10}

What makes the triple therapy for breast cancer unique?

This triple therapy combines entinostat, a drug that helps overcome resistance to hormonal therapies, with two immunotherapy drugs, ipilimumab and nivolumab, which boost the immune system to fight cancer. This combination is unique because it targets both hormone resistance and enhances the immune response, offering a novel approach for treating breast cancer. ^{2 3 4 11 12}

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of entinostat and nivolumab when given together with ipilimumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (metastatic) or that cannot be removed by surgery (unresectable) or human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread from where it started to nearby tissue or lymph nodes or other parts of the body. Entinostat is in a class of drugs called histone deacetylase (HDAC) inhibitors. It may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth (locally advanced/metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving entinostat and nivolumab together with ipilimumab may work better in treating in patients with solid tumors.

Research Team

Roisin Connolly, MD

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

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

The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat. [2021]

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

E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group. [2023]

3. England 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. [2022]

4. United States 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. [2022]

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

Entinostat Helps Thwart Immunotherapy Resistance. [2020]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

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

Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis. [2020]

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

Ipilimumab and nivolumab induced immune-related adverse events in metastatic mucosal melanoma. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Entinostat for the treatment of breast cancer. [2017]

12. England pubmed.ncbi.nlm.nih.gov

Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial. [2023]