I. To evaluate whether the addition of entinostat to endocrine therapy (exemestane) improves
progression-free survival (PFS) and/or overall survival (OS) in postmenopausal patients with
hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative
locally advanced or metastatic breast cancer who have previously progressed on a
non-steroidal aromatase inhibitor (Al).
I. To evaluate the safety and tolerability of entinostat in combination with exemestane, and
to compare the safety profile to that of endocrine therapy with placebo.
II. To evaluate the objective response rate of exemestane in combination with entinostat or
III. To evaluate whether the efficacy of exemestane with entinostat varies with changes in
acetylation status in peripheral blood mononuclear cells (PBMCs).
IV. To evaluate the time to treatment deterioration (as defined by decrease in
health-related quality of life [HRQL], progression, death) of exemestane + entinostat versus
exemestane + placebo arms.
V. To evaluate the differences in overall health-related quality of life (HRQL) between the
exemestane + entinostat versus exemestane + placebo arms.
VI. To evaluate the difference with respect to specific symptoms that are associated with
entinostat, i.e., fatigue, nausea, anorexia and diarrhea, between the exemestane +
entinostat versus exemestane + placebo arms.
VII. To measure adherence to protocol therapy.
I. To collect archival tumor samples and germline deoxyribonucleic acid (DNA) to explore
other potential biomarkers of therapeutic efficacy.
II. To collect patient ratings of adverse events (AEs) using select patient-reported
outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) items to evaluate the
psychometric properties of PRO-CTCAE items and explore the incorporation of PRO-CTCAE items
into a phase III double-blind placebo-controlled trial.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: 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.
ARM B: 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.
In both arms, male patients also receive goserelin acetate subcutaneously (SC) on day 1.
After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for 5 years.
- Estrogen receptor (ER) and/or progesterone receptor (PR) positive histologically
confirmed adenocarcinoma of the breast with staining of >= 1% cells will be
considered positive; receptor status may be based on any time during treatment prior
to study randomization, and from any site (i.e. primary, recurrent, or metastatic)
- Patients whose tumors have HER2 immunohistochemistry (IHC) 3+, in situ hybridization
(ISH) >= 2.0, or average HER2 copy number >= 6.0 signals per cell are not eligible;
receptor status may be based on any time during treatment prior to study
randomization, and from any site (i.e. primary, recurrent, or metastatic)
- Patients must have measurable or non-measurable stage III/locally advanced or
metastatic carcinoma of the breast where local therapy with curative intent is not
possible; lesions must be evaluated =< 4 weeks prior to study randomization;
diagnostic-quality computed tomography (CT) scans with both oral and intravenous (IV)
contrast are the expected radiologic method, unless an alternative is approved
- NOTE: Where baseline imaging has already been performed =< 6 weeks prior to
study randomization, repeat imaging may not be required
- Postmenopausal women and all men are eligible for this trial; postmenopausal is
- Age >= 55 years and one year or more of amenorrhea
- Age < 55 years and one year or more of amenorrhea, with estradiol < 20 pg/ml
- Age < 55 with prior hysterectomy but intact ovaries, with estradiol < 20 pg/ml
- Prior bilateral oophorectomy NOTE: Men can enroll provided they agree to receive
concomitant luteinizing hormone-releasing hormone (LHRH) agonist; LHRH agonist
use is not permitted for female patients
- Sexually active males must be strongly advised to use an accepted and effective
method of contraception or to abstain from sexual intercourse for the duration of
their participation in the study and for 3 months after discontinuation of therapy
- Patients must not have known central nervous system metastasis or a history of
central nervous system (CNS) metastases; patients with leptomeningeal disease are not
- Patients must be disease-free of prior invasive malignancies for > 5 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix; NOTE: if there is a history of prior malignancy,
patients must not be receiving other specific treatment for that cancer
- Patients must meet at least one of the following criteria:
- Disease progression any time after non-steroidal aromatase inhibitor (AI) use in
the advanced disease setting
- Relapse while on or within =< 12 months of end of adjuvant non-steroidal AI
therapy with no prior endocrine therapy for advanced disease
- NOTE: Treatment with any prior endocrine therapy must be completed >= 2 weeks
prior to randomization, with the exception of exemestane which is allowed in the
advanced disease setting for =< 4 weeks immediately prior to study entry
(defined as date of randomization); prior exemestane (other than =< 4 weeks as
above) or fulvestrant in any setting is not allowed; prior everolimus therapy is
allowed and must have been completed 2 weeks prior to randomization
- Patients may have received one prior chemotherapy regimen for metastatic disease
provided treatment was completed >= 3 weeks prior to randomization
- Patients may be treated with bone modifying agents such as bisphosphonates or
receptor activator of nuclear factor kappa-B (RANK)-ligand agents (e.g. denosumab)
per American Society of Clinical Oncology (ASCO) guidelines; whenever possible,
patients requiring bone modifying agents should start treatment >= 7 days prior to
study therapy and should continue the same agent throughout study unless clinically
compelled to change
- Prior radiotherapy must in general have been completed >= 2 weeks prior to
randomization and patients must have recovered from the toxicity of the radiation;
NOTE: patients may receive concurrent radiation therapy to painful sites of bony
disease or areas of impending fracture as long as sites of measurable or
non-measurable disease outside the radiation therapy port are available to follow
- Patients must NOT receive concurrent anti-cancer therapy or investigational agent
unless specified in protocol
- Patients must NOT be receiving valproic acid, an histone deacetylase (HDAC)
inhibitor, and may not have previously received any HDAC inhibitor prior to
enrollment (e.g. valproic acid, entinostat, vorinostat)
- Patients must have no known allergies to imidazole drugs (e.g. clotrimazole,
ketoconazole, miconazole, econazole, sulconazole, ticonazole, or terconazole),
exemestane or entinostat
- Patients must NOT suffer from medical or psychiatric conditions that would interfere
with protocol compliance, the ability to provide informed consent, or assessment of
response or anticipated toxicities; this includes uncontrolled intercurrent illness
including, but not limited to ongoing or active infection
- Patients must have recovered from all clinically relevant adverse events to grade 1
or baseline due to previous agents administered (except alopecia)
- Patients must have adequate hematologic, liver and renal function =< 28 days prior to
randomization; NOTE: it is preferred that laboratory values for eligibility be
assessed after the last dose of prior treatment, especially in cases where
most-recent treatment prior to study entry is chemotherapy
- Hemoglobin (HgB) >= 9.0 g/dL
- Platelet count >= 100,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Creatinine =< 2.0 mg/dL
- Total bilirubin < 1.5 x institutional upper limit of normal (=< 3 mg/dL in case of
- Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =<
2.5 x institutional upper limit normal
- Known human immunodeficiency virus (HIV)-positive patients should have a cluster of
differentiation (CD)4 count > 250/mm^3
- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Patients must have a life expectancy >= 12 weeks
- Patients must be able to swallow tablets
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both