Exemestane + Entinostat for Advanced Breast Cancer

Recruiting at 762 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must be taking: LHRH agonist

Must not be taking: Valproic acid

Disqualifiers: CNS metastasis, Prior malignancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: Until disease progression or unacceptable toxicity

608 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on certain medications like valproic acid or other HDAC inhibitors, and any prior endocrine therapy should be completed at least 2 weeks before starting the trial, except for exemestane, which can be continued if it was started within 4 weeks before the trial.

What data supports the effectiveness of the drug combination of Exemestane and Entinostat for advanced breast cancer?

Research shows that adding entinostat to exemestane improves survival in women with ER+ (estrogen receptor-positive) advanced breast cancer. Additionally, exemestane alone has been shown to effectively control disease in hormone receptor-positive breast cancer, with moderate improvements in progression-free survival and response rates. ^{1 2 3 4 5}

Is the combination of Exemestane and Entinostat safe for humans?

Exemestane is generally safe for humans, with mild side effects like menopausal symptoms, and has been used in treating advanced breast cancer in postmenopausal women. However, specific safety data for the combination with Entinostat is not provided in the available research. ^{6 7 8 9 10}

What makes the drug combination of Exemestane and Entinostat unique for advanced breast cancer?

The combination of Exemestane and Entinostat is unique because it targets hormone receptor-positive advanced breast cancer by adding Entinostat, a histone deacetylase inhibitor, to Exemestane, an aromatase inhibitor, which helps overcome resistance to hormonal therapies and improves survival rates. ^{1 4 11 12 13}

What is the purpose of this trial?

This randomized phase III trial studies exemestane and entinostat to see how well they work compared to exemestane alone in treating patients with hormone receptor-positive breast cancer that has spread to nearby tissue or lymph nodes (locally advanced) or another place in the body (metastatic). Estrogen can cause the growth of breast cancer cells. Endocrine therapy using exemestane may fight breast cancer by lowering the amount of estrogen the body makes. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether exemestane is more effective with or without entinostat in treating breast cancer.

Research Team

Roisin M Connolly

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with hormone receptor-positive breast cancer that's advanced or spread, who can swallow pills and have no known allergies to the drugs being tested. They should not be pregnant, breastfeeding, or have certain medical conditions that could affect participation. Only one prior chemo regimen for metastatic disease is allowed.

Inclusion Criteria

My breast cancer is advanced and cannot be cured with surgery or radiation.

I do not have, nor have I ever had, cancer spread to my brain.

My blood, liver, and kidney functions are all within normal ranges.

Exclusion Criteria

Patients must NOT be pregnant or breast-feeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive exemestane and either entinostat or placebo in 28-day cycles, with imaging and blood sample collection

Until disease progression or unacceptable toxicity

CT/MRI at baseline, end of cycle 3, every 3 cycles, and at treatment discontinuation

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 3 months for 2 years, every 6 months for 3 years, then annually for 5 years

Treatment Details

Interventions

• Entinostat
• Exemestane

Trial Overview The study compares exemestane alone versus exemestane with entinostat in treating advanced breast cancer. Exemestane lowers estrogen to fight cancer; entinostat blocks enzymes needed by tumor cells to grow. The effectiveness of combining these treatments is being evaluated.

Participant Groups

Group I: Arm A (exemestane, entinostat) Experimental Treatment 8 Interventions

Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1.

Group II: Arm B (exemestane, placebo) Placebo Group 8 Interventions

Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1.

Exemestane is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Aromasin for:

• Early breast cancer
• Advanced breast cancer

Approved in United States as Aromasin for:

• Early breast cancer
• Advanced breast cancer

Approved in Canada as Aromasin for:

• Early breast cancer
• Advanced breast cancer

Approved in Japan as Aromasin for:

• Early breast cancer
• Advanced breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of entinostat and exemestane has been shown to improve survival rates in women with estrogen receptor-positive (ER+) advanced breast cancer.

This finding suggests that entinostat may enhance the effectiveness of exemestane, a common treatment for this type of cancer, potentially offering a new therapeutic strategy for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat plus exemestane has activity in ER+ advanced breast cancer. [2016]

Exemestane effectively suppresses aromatase and plasma estrogen levels in postmenopausal women with recurrent breast cancer, showing significant efficacy even in patients who have failed other treatments like tamoxifen and other aromatase inhibitors.

The drug has a favorable safety profile with mild toxicity primarily consisting of menopausal symptoms, and it has demonstrated an early survival advantage over megestrol acetate in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exemestane: a novel aromatase inactivator for breast cancer. Jones, SA., Jones, SE.[2016]

In a phase 3 trial involving 354 Chinese patients with hormone receptor-positive advanced breast cancer, the combination of entinostat and exemestane significantly improved progression-free survival (PFS) to a median of 6.32 months compared to 3.72 months with placebo (P = 0.046).

While the combination treatment showed efficacy, it was associated with a higher incidence of grade ≥3 adverse events (65.5% in the entinostat group vs. 19.3% in the placebo group), with neutropenia being the most common severe side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Xu, B., Zhang, Q., Hu, X., et al.[2023]

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]

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]

References

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

Entinostat plus exemestane has activity in ER+ advanced breast cancer. [2016]

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

Exemestane as first-line therapy in postmenopausal women with recurrent or metastatic breast cancer. [2018]

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

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. [2020]

4. 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]

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

Aromatase inhibition and antiestrogen therapy in early breast cancer treatment and chemoprevention. [2013]

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

Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group. [2017]

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

Exemestane: a novel aromatase inactivator for breast cancer. [2016]

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

Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. [2017]

9. China pubmed.ncbi.nlm.nih.gov

[Clinical trial on exemestane in the treatment of postmenopausal women with advanced breast cancer]. [2016]

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

Exemestane: treatment of breast cancer with selective inactivation of aromatase. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. [2023]

12. 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]

13. 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]