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Advanced Breast CancerPhase 3NCT03538171

Ph3 Study of Exemestane With or Without Entinostat in Chinese Patients With Hormone Receptor-Positive, Locally Advanced or Metastatic Breast Cancer

A Phase 3 study testing Entinostat and Exemestane in people with Advanced Breast Cancer, run by Taizhou EOC Pharma Co., Ltd. at 1 site in China.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

The purpose of this randomized phase III trial is to evaluate the clinical benefit of combining entinostat with exemestane in Chinese patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer, who have disease progression on endocrine therapy. Read more about this study

Who is it for?
Ages 18 to 75 years, women only
Conditions the study is for
Advanced Breast Cancer
What is being tested?
Entinostat and Exemestane
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
375 participants
Where
1 siteChina
Study dates
15 May 2018to Mar 2023
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed informed consent.
  • Female, age≥18 years and ≤75 years (For the Open-label study， only the patients with natural menopause or surgical ovariectomy are enrolled).
  • Note: surgical ovariectomy is defined as bilateral oophorectomy.
  • The ECOG score is 0-1.
  • Life expectancy duration ≥12 weeks.
  • Estrogen receptor (ER) and/or progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER-2) negative.
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  • ER and PR status should be histologically confirmed with staining of ≥ 1% cells.
  • Positive human epidermal growth factor receptor 2 (HER-2) should be defined as positive ISH test or immunohistochemical test +++ or ++ with positive ISH amplification test.
  • Receptor status may be based on any time during treatment prior to study randomization, and from any site (i.e. primary, recurrent, or metastatic).
  • The patient must have measurable or non-measurable but can only be bone metastasis Stage III /locally advanced or metastatic breast cancer (in accordance with the general evaluation criteria, RECIST Version 1.1). Bone metastasis includes osteolytic or mixed type (osteolytic and osteogenic).
  • For Part 2 the Randomized, double-blind study: the ratio of patients with non-measurable lesion (only bone metastasis) should be ≤ 20%; not required for Part 1-the Open-label study.
  • Notes:
  • Evaluation of lesions must be performed within 4 weeks prior to the randomization. The radiological examination includes cranial MRI (magnetic resonance imaging), thoracic and abdominal contrast-enhanced CT (computed tomography, the lower limit of abdominal scan must reach anterior superior iliac spine). MRI is optional in patients who are allergic to the contrast substance. It needs to ensure that the lesions should be scanned and evaluated in accordance with the requirement in the general evaluation criteria RECIST version 1.1.
  • Non-measurable lesion is defined as all the other lesions, including small foci (the maximum diameter<10 mm or minor axis of pathological lymph node ≥10 mm but <15 mm) and unmeasurable foci (meningeal foci, ascites, hydrothorax, pericardial effusion, pelvic effusion, inflammatory breast cancer, carcinomatous lymphangitis of skin or lung, abdominal mass that can't be diagnosed or followed up by radiology, and cystic lesion).
  • At least one previous treatment of endocrine therapy other than Exemestane.
  • As previous adjuvant therapy,Exemestane is allowed to be used, if the disease-free interval is >12 months after discontinuation of Exemestane.
  • For the patients with metastatic breast cancer who have already received at most one chemotherapeutic regimen，the end of chemotherapy should be at least 4 weeks before the randomization.
  • The end of previous radiotherapy should be at least 2 weeks before the randomization, and the patient must have recovered from the toxicity of radiotherapy (grade 1 or below).
  • The patient is allowed to receive the medications to regulatebone metabolism, for example, bisphosphonates and RANK-L (nuclear factor κB ligand receptor activator, e.g., denosumab); the bone metabolism-regulating therapy needs to be initiated 1 week prior to the first administration of treatment in the clinical trial, the same drug must be used throughout the clinical trial, except that actual clinical situation that requires amendment to the therapeutic regimen;
  • Patients must have adequate hematological, hepatic and renal function one week (7 days) prior to the Run-in period in open-label study and prior to randomization in randomized, double-blind study, which are defined as below:
  • Haemoglobin (Hgb) ≥ 90 g/L;
  • platelet count ≥ 100×109/L
  • Absolute neutrophil count ≥ 1.5×109/L
  • Serum creatinine ≤ 2.0 mg/dL
  • Total bilirubin < 1.5 ×ULN (upper limit of normal) (≤3 mg/dL in case of Gilbert syndrome);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; ALT and AST ≤5×ULN for liver metastasis.
  • Open-label study only enroll the patients with natural menopause or surgical ovariectomy. Postmenopausal, premenopausal/perimenopausal and menopausal female patients can be enrolled in the randomized, double-blind study; patients with childbearing potential must agree to use recognized effective methods for contraception (including condom containing sperm inactivation, vaginal septum, oral or injectable contraceptives, etc.) or abstain from sex life during participation in the study and within three months after discontinuation of the treatment.
  • Postmenopause is defined as:
  • Underwent irreversible surgical sterilization such as amputation of uterus, bilateral oophorectomy, but not tubal ligation;
  • Age≥60 years;
  • Age<60 years, natural menopause≥12 months, blood follicle stimulating hormone (FSH) and estradiol (E2) levels within the postmenopausal range (FSH>40 IU/L and E2<30 pg/mL) in case of no use of chemotherapy, Tamoxifen, Toremifene or ovariectomy in recent one year;
  • Age <60 years, currently using Tamoxifen or Toremifene, blood follicle stimulating hormone (FSH) and estradiol (E2) levels within the postmenopausal range (FSH>40 IU/L and E2<30 pg/mL).
  • Notes:
  • It will be considered as the premenopausal or perimenopausal state if the above criteria on menopause are not met;
  • The premenopausal/perimenopausal female patients can be enrolled only when they agree to use the concomitant drug LHRH agonist Goserelin, and need to start the dose of LHRH agonist at least 4 weeks prior to randomization;
  • If the patient has received other LHRH agonist prior to entry in the study, he/she must switch to Goserelin during the study.

Who cannot join

  • Previous or current metastatic foci in central nervous system, or leptomeningeal disease;
  • Patients with stable symptoms of CNS metastasis can be accepted only during the open label phase, but the following conditions need to be met at the same time:
  • The patient has lesions outside the CNS system. The CNS metastases did not involve the midbrain, pons, medulla oblongata or spinal cord.
  • The patients did not receive whole brain radiotherapy within 6 weeks.
  • Confirmed that CNS disease remained stable for at least four weeks (including radiotherapy and/or surgical resection).
  • Patients do not need hormone therapy for CNS diseases, such as dexamethasone combined with mannitol; Patients are unlikely to have any medical symptoms associated with CNS metastasis, such as headache, dizziness, nausea, vomiting, and intracranial hypertension.
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  • Current or previous history of other malignant tumor (except for cured basal cell carcinoma or squamous cell carcinoma of skin, carcinoma in situ of cervix), unless taking radical therapy and no evidence of recurrence or metastasis in recent 5 years;
  • Uncontrolled or serious cardiovascular disease, for example, refractory angina pectoris, congestive heart failure within half a year prior to the screening; myocardial infarction within 12 months prior to screening; any history of clinically significant ventricular arrhythmia, prolonged QT interval; history of cerebrovascular accident, symptomatic coronary heart disease requiring drug therapy;
  • The 3rd space effusion (e.g., hydrothorax and ascites) which can not be controlled with drainage or other therapeutic method;
  • Patients with a history of immune deficiency, including HIV-positive;
  • Clinically significant abnormality in gastrointestinal function that may affect intake, transportation or absorption of oral administration of drugs (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.);
  • Unrecovered toxicity resulted from previous medication or toxicity, evaluation score is still > grade 1 (except alopecia);
  • Use of HDAC inhibitor (e.g., valproic acid, Entinostat, Vorinostat, chidamide, etc.) prior to enrollment or intended use of HDAC inhibitor during the study;
  • Known allergic to Exemestane, Entinostat or other drugs containing benzamide structure (e.g., Tiapride, Remoxipride, clebopride, etc.); allergic to Goserelin in premenopausal/perimenopausal female patients;
  • Any cognitive disorder resulted from mental or neurological disease, including epilepsy and dementia;
  • Clinically uncontrolled active infection, for example, acute pneumonia, active phase of hepatitis B (positive Hepatitis B surface antigen, and copy of DNA > upper limit of normal) two weeks (14 days) prior to the dose in the Open-label study and prior to randomization in the double-blind study;
  • Major surgery (judged by investigators in accordance with the previous history), major trauma or fracture 4 weeks (28 days) prior to the first dose in the Open-label study and prior to randomization in the double-blind study;
  • Organ transplant recipient;
  • Women who are pregnant or breastfeeding;
  • Patients who plan to receive other anticancer therapy or other investigational product during the study;
  • Participation in any other drug clinical trial 4 weeks (28 days) prior to the screening or currently receiving treatment in other clinical trials (except those who are participating in the follow-up of overall survival in one study);
  • Patients who are considered by investigators as inappropriate to participate in this clinical trial.

Trial locations and contacts

1 site in 1 country.

China1 site

  • Cancer Hospital Chinese Academy Medical Sciences

    Beijing, Beijing Municipality, 10021

Other trials in China

About this study

Official title: A Randomized Phase III Clinical Study of Entinostat/Placebo in Combination With Exemestane in Chinese Patients With Hormone Receptor-positive Advanced Breast Cancer

The purpose of this randomized phase III trial is to evaluate the clinical benefit of combining entinostat with exemestane in Chinese patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer, who have disease progression on endocrine therapy. Additionally，the safety, tolerability, and PK profile of the treatment combination are evaluated.

Read the detailed description

This randomized phase III trial studies entinostat combination with exemestane to see how well they work compared to exemestane alone in treating Chinese patients with hormone receptor-positive, locally advanced or metastatic breast cancers.

Estrogen can drive the growth of breast cancer cells. Exemestane may fight breast cancer by lowering the amount of estrogen the body makes from tissue aromatase. Entinostat may enhance the anti-tumor effect of exemestane in breast cancer by helping to overcome tumor resistance via epigenetic modifications. Previous Phase II trial in US breast cancer patients have demonstrated significant effects of combined therapy in slowing disease progression and on patient survival when compared to exemestane alone. It is not yet known whether exemestane is more effective when combined with entinostat in Chinese patients with advanced breast cancer. In this parallel, randomized, double blind, active controlled study, we will study the effect of entinostat/placebo in combination with exemestane in Chinese patients with hormone receptor-positive, HER2 receptor-negative, locally advance or metastatic breast cancer, who have experienced disease progression with prior endocrine therapies.

Being tested
Entinostat, Placebo, Exemestane

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EntinostatDrug

    Entinostat will be repeatedly administered PO on days 1, 8, 15 and 22 of each treatment cycle. Exemestane PO once daily on day 1-28.

  • PlaceboDrug

    Patients receive Exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

  • ExemestaneDrug

    Exemestane PO once daily on day 1-28.

Study groups in NCT03538171
Study groupRoleWhat they receive
ARM Entinostat+ExemestaneActive comparatorPatients receive Exemestane orally (PO) once daily (QD) on days 1-28 and Entinostat PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Entinostat; Drug: Exemestane
ARM Placebo+ExemestanePlacebo comparatorPatients receive Exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Placebo; Drug: Exemestane

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. PFS (The Randomized Double-blinded Part)

    Progression Free Survival, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). The distribution of PFS will be estimated using the Kaplan- Meier method, with 95% confidence intervals calculated using Greenwood's formula. In the primary analysis of PFS, differences in treatment effect will be tested using stratified log rank tests, stratifying on the randomization stratification factors. Stratified univariate and multivariable Cox proportional-hazard models will be built to estimate the hazard ratios (HRs) for treatment effect for PFS as a supportive analysis. In all analyses, P-values will be two-sided.

    Measured: From the day of randomization, assessment will be made every 8 weeks (±3 days) to the earliest of documented disease progression (PD) or death caused by any reason (whichever happens first), assessed up to 40 months.

Secondary outcomes (5)

  1. OS (both the Open-label and Randomized Double-blinded parts)

    Overall Survival

    Measured: From the day of first administration to the date of death from any cause, assessed up to 48 months.

  2. Safety and tolerability (both the Open-label and Randomized Double-blinded parts)

    Incidence of toxicity graded according to National Cancer Institute CTCAE version 4.0. All treatment-emergent, baseline adverse events and hematological/biochemical toxicities based on laboratory measurements, as well as drug related AEs, will be summarized by both groups. The incidence of deaths and treatment-emergent serious AEs (defined as number of patients experiencing the AE divided by all treated patients) will be summarized and compared between Arm Entinostat+Exemestane and Arm Placebo+Exemestane. Also, the incidence of adverse events leading to discontinuation of investigational product and/or patient's withdrawal from the study will be summarized and listed.

    Measured: From the first administration of the investigational product to 30 days after the last administration. The Randomized Double-blinded: assessed up to 48 months

  3. ORR (both the Open-label and Randomized Double-blinded parts)

    Objective Response Rate, defined as the proportion of patients with complete response (CR) or partial response (PR) among all patients assessed per RESIST v1.1. Objective response in the two arms will be evaluated by comparing objective response rate (ORR, PR+CR) on the intention-to-treat patients with one-sided type I error of 2.5%. ORR will be summarized along with the exact binomial 95% confidence interval. In all analyses, P-values will be two-sided.

    Measured: From the first administration on Day 1 Run-in Period or randomization day, evaluation will be made every 8 weeks (±3 days), until the earliest of documented PD or death caused by any reason (whichever happens first), assessed up to 48 months.

  4. Pharmacokinetics (The Randomized Double-blinded Part)

    Time at which maximum plasma concentration was observed.

    Measured: Cycle 1 Day 1, within 3h and 5h after the administration; Cycle 1 Day 15,1h after the administration; Cycle 2 Day 1, within 72h prior to administration.

  5. CBR (both the Open-label and Randomized Double-blinded parts)

    Clinical Benefit Rate, defined as CR+PR+SD≥ 24 weeks

    Measured: Estimated per 8 weeks (±3 days) from the first administration of the investigational product on Day 1 Run-in Period or randomization day, to the earliest of documented PD or death caused by any reason (whichever happens first),assessed up to 48 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 May 2018
  2. Study start15 May 2018
  3. Primary completionJul 2021 (estimated)
  4. Study completionMar 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
375 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03538171
Sponsor's protocol ID
EOC103A3101
Status last verified
Jul 2021
First submitted
27 Apr 2018
Last updated
9 Jul 2021
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Xu B, Zhang Q, Hu X, Li Q, Sun T, Li W, Ouyang Q, Wang J, Tong Z, Yan M, Li H, Zeng X, Shan C, Wang X, Yan X, Zhang J, Zhang Y, Wang J, Zhang L, Lin Y, Feng J, Chen Q, Huang J, Zhang L, Yang L, Tian Y, Shang H. 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. Acta Pharm Sin B. 2023 May;13(5):2250-2258. doi: 10.1016/j.apsb.2023.02.001. Epub 2023 Feb 9.

    PubMed 37250148

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Entinostat and Exemestane in people with Advanced Breast Cancer, run by Taizhou EOC Pharma Co., Ltd. at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 36 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 9 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PFS (The Randomized Double-blinded Part) (time frame: From the day of randomization, assessment will be made every 8 weeks (±3 days) to the earliest of documented disease progression (PD) or death caused by any reason (whichever happens first), assessed up to 40 months.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03538171, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2021.

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