Exemestane + Entinostat for Advanced Breast Cancer

Not currently recruiting at 792 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment for hormone receptor-positive breast cancer that has spread locally or to other parts of the body. Researchers aim to determine if combining exemestane, which lowers estrogen levels, with entinostat, a potential cancer growth blocker, is more effective than exemestane alone. Individuals with this breast cancer profile who have experienced disease progression after certain therapies might be eligible. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that the combination of exemestane and entinostat is generally safe and well-tolerated. Studies have not identified any unexpected safety issues when these two drugs are used together. Patients have managed the treatment without major problems beyond what is typically expected from cancer treatments.

Exemestane lowers estrogen levels, which can slow the growth of some breast cancers. Entinostat blocks certain enzymes that cancer cells need to grow. While these treatments can cause side effects like tiredness or nausea, these are usually manageable and similar to those seen with exemestane alone.

For those considering joining a clinical trial, this information may provide confidence in the treatment's safety. Always consult a doctor to determine what might be best. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of exemestane and entinostat for advanced breast cancer because it offers a unique approach compared to standard hormone therapies like tamoxifen or aromatase inhibitors alone. Entinostat is a histone deacetylase inhibitor, which means it can potentially make cancer cells more sensitive to exemestane by altering gene expression. This dual action could enhance the effectiveness of treatment and delay resistance. Additionally, the combination may provide an option for patients who have not responded well to other hormonal treatments, offering renewed hope for managing advanced stages of the disease.

What evidence suggests that exemestane and entinostat could be effective for advanced breast cancer?

This trial will compare two treatment arms for advanced breast cancer. In one arm, participants will receive a combination of exemestane and entinostat. Research has shown that adding entinostat to exemestane may help treat advanced hormone receptor-positive breast cancer. Some studies found this combination extended the time before cancer grew or spread. However, other studies found it did not increase overall survival. Entinostat blocks certain enzymes that aid cancer cell growth. Despite mixed results, this combination has shown promise in slowing cancer progression for some patients. ^{3 4 6 7 8}

Who Is on the Research Team?

Roisin M Connolly

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23650416/

Randomized phase II, double-blind, placebo-controlled ... Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34357781/

E2112: Randomized Phase III Trial of Endocrine Therapy Plus ... The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.1050

Entinostat, a class I selective histone deacetylase inhibitor ... In a randomized, double-blind, phase 3 trial, entinostat with exemestane demonstrated a statistically significant progression-free survival (PFS) ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S221138352300028X

Entinostat, a class I selective histone deacetylase inhibitor, ... In this multicenter phase III trial in Chinese patients with hormone receptor-positive advanced breast cancer, entinostat plus exemestane significantly ...

5. ascopost.com ascopost.com/issues/january-25-2021/adding-entinostat-to-exemestane-fails-to-overcome-aromatase-inhibitor-resistance-in-advanced-breast-cancer/

Adding Entinostat to Exemestane Fails to Overcome ... “The combination of exemestane and entinostat did not improve survival in aromatase inhibitor–resistant advanced hormone receptor–positive, HER2 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8611843/

Phase 1 trial of entinostat as monotherapy and combined with ... Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02115282

Study Details | NCT02115282 | Exemestane With or ... 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 ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02820961

Drug-Drug Interaction Study of Entinostat and Exemestane ... The purpose of this study is to determine the effect of exemestane on the pharmacokinetics (PK) of entinostat and to determine the effect of entinostat on the ...