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

NCT03538171 | Unknown Phase 3

• 1 other identifier: EOC103A3101
• Study Type: interventional
• Target: 375
• Locations: 1 country
• Sites: 1

Brief 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. Additionally，the safety, tolerability, and PK profile of the treatment combination are evaluated.

Conditions

Advanced Breast Cancer

Outcome Measures

Primary Outcomes (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.

  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)

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

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

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

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

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

  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.

• Pharmacokinetics (The Randomized Double-blinded Part)

  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.

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

  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.

Other Outcomes (1)

• PBMC acetylation

  Cycle 1 Day 1, prior to administration; ; Cycle 2 Day 1, prior to administration.

Study Arms (2)

ARM Entinostat+Exemestane

ACTIVE COMPARATOR

Patients 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.

Drug: Entinostat; Drug: Exemestane

ARM Placebo+Exemestane

PLACEBO COMPARATOR

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.

Drug: Placebo; Drug: Exemestane

Interventions

Entinostat DRUG

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.

ARM Entinostat+Exemestane

Placebo DRUG

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.

ARM Placebo+Exemestane

Exemestane DRUG

Exemestane PO once daily on day 1-28.

ARM Entinostat+Exemestane; ARM Placebo+Exemestane

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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;

Sponsors & Collaborators

• Taizhou EOC Pharma Co., Ltd.: lead

Study Sites (1)

Cancer Hospital Chinese Academy Medical Sciences

Beijing, Beijing Municipality, 10021, China

Location

Related Publications (1)

• 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.

  PMID: 37250148 DERIVED

MeSH Terms

Interventions

entinostat; exemestane

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2018
• First Posted: May 29, 2018
• Study Start: May 15, 2018
• Primary Completion: July 1, 2021
• Study Completion: March 1, 2023
• Last Updated: July 9, 2021

Record last verified: 2021-07

Locations

CN (1)