Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

Inclusion Criteria:

• Patient must have histologically or cytologically confirmed adenocarcinoma of thebreast triple-negative (ER-, progesterone receptor [PR]-, human epidermal growthfactor receptor 2 [HER2]-) or hormone positive/ HER2-, with evidence of locallyadvanced and inoperable or metastatic disease (American Joint Committee on Cancer [AJCC] Stage IV)

• NOTE: Triple-negative patients will be defined per American Society of ClinicalOncology-College of American Pathologists (ASCO-CAP) Guidelines; theseguidelines state that ER and PR assays be considered positive if there are atleast 1% positive tumor nuclei in the sample on testing in the presence ofexpected reactivity of internal (normal epithelial elements) and externalcontrols

• A patient who has a change in receptor status (e.g., PR negative to positive)may be stratified as triple negative or hormone positive, contrary to the mostrecent receptor testing, for the purposes of the study based upon the clinicalcourse at the discretion of the Study Chair; for HER2 assessment, a negativeresult is an immuno-histochemistry staining of 0 or 1+, a fluorescence in situhybridization (FISH) result of less than 4.0 HER2 gene copies per nucleus, or aFISH ratio of less than 1.8

• Patients with triple negative disease must have progressed through at least 1 priorchemotherapy regimen (administered in the adjuvant or metastatic setting); hormonereceptor-positive patients must have progressed through two lines of hormonaltherapy (administered in the adjuvant or metastatic setting), unless otherwiseeligible as per below, and at least 1 prior chemotherapy regimen (administered inthe adjuvant or metastatic setting) with no known curative options available

• NOTE: Patients with hormone receptor-positive disease may be consideredeligible if deemed clinically hormone-resistant taking into consideration therate of progression of disease or a short interval of time on first linehormonal therapy before progression, or if intolerant of hormonal therapy suchthat further hormonal therapy will not be considered as part of the treatmentstrategy

• In patients with metastatic disease in the liver, liver disease burden is limited tono more than 30% of total liver volume as assessed by local review

• Patients must have measurable disease

• Life expectancy of >= 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Hemoglobin (HgB) >= 9.0 g/dL

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelet count >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception tothis may be allowed for participants with Gilbert's syndrome with documentedapproval by the Protocol Chair

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN

• Creatinine =< institutional ULN or creatinine clearance >= 60 mL/min using theModified Cockcroft-Gault formula

• Negative (serum or urine) pregnancy test done =< 7 days prior to registration, forwomen of childbearing potential only

• Patient must have an accessible tumor lesion from which a biopsy specimen can beobtained; NOTE: if baseline biopsy is attempted and is unsuccessful (eg, patientintolerance, inadequate tissue), the patient will still be considered eligible forthe study

• Ability to understand and the willingness to sign a written informed consentdocument

• Willingness to provide tissue and blood samples for mandatory translational research

• Willingness to return to the enrolling institution for follow-up

Exclusion Criteria:

• Any of the following:

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequatecontraception

• NOTE: should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her treating physicianimmediately

• Any of the following:

• Chemotherapy < 3 weeks prior to registration

• Hormone therapy < 3 weeks prior to registration

• Radiotherapy < 3 weeks prior to registration

• Surgery < 3 weeks prior to registration

• Nitrosoureas/mitomycin C < 6 weeks prior to registration

• Trastuzumab < 6 weeks prior to registration

• Bevacizumab < 6 weeks prior to registration

• Those who have not recovered from acute adverse events to grade < 2 or baselinedue to agents administered, with exception of alopecia, unless approved by theProtocol Chair

• NOTE: concurrent bisphosphonate therapy is allowed; concurrent ovariansuppression therapy (i.e., Lupron or Zoladex) is also allowed at the discretionof the Protocol Chair/designee

• Any other ongoing investigational agents

• Known sensitivity to 5-AZA, entinostat or mannitol

• Uncontrolled intercurrent illness that in the judgment of the investigator, wouldmake the patient inappropriate for entry into this study or interfere significantlywith the proper assessment of safety and toxicity of the prescribed regimensincluding, but not limited to:

• Ongoing or active infection

• Symptomatic congestive heart failure (New York Heart Association [NYHA] classII or above)

• Unstable angina pectoris

• Cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• Other co-morbid systemic illness or other severe concurrent disease

• Active malignancy other than breast cancer =< 3 years prior to registration;EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: ifthere is a history of prior malignancy, they must not be receiving other specifictreatment for their cancer

• Immunocompromised patients (other than that related to the use of corticosteroids)including patients known to be human immunodeficiency virus (HIV) positive

• Received prior treatment with HDAC (histone deacetylase) inhibitors or demethylatingagents =< 2 weeks prior to registration

• Unstable brain metastases; NOTE: patients with brain metastases must have stableneurologic status and magnetic resonance imaging (MRI) imaging following localtherapy (surgery or radiation) for at least 4 weeks, with no dexamethasonerequirement (stable low dose dexamethasone allowed at discretion of Study Chair);patients with leptomeningeal disease are not eligible

• Patient taking valproic acid

• Patient who cannot swallow tablets