Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

Inclusion Criteria:

• Patient must have histologically or cytologically confirmed adenocarcinoma of the breast meeting 1 of the following criteria:

  • Triple-negative (estrogen-receptor negative [(ER-], progesterone-receptor negative [PR-], and HER2-)

  • Hormone-resistant/ HER2-

    • HER2- by any of the following: an immuno-histochemistry staining of 0 or 1+; a fluorescent in situ hybridization (FISH) result of less than 4.0 HER2 gene copies per nucleus; or a FISH ratio of less than 1.8
• Locally advanced and inoperable or metastatic disease
• Patients with ER-positive disease must have progressed through two lines of hormonal therapy (administered in the adjuvant or metastatic setting), and at least 1 prior chemotherapy regimen for locally advanced or metastatic breast cancer with no known curative options available
• Triple-negative patients must have progressed through at least 1 prior chemotherapy regimen (administered in the adjuvant or metastatic setting)
• Patients must have measurable disease
• Patient must have an accessible tumor lesion from which a fine needle aspirate or preferably a core biopsy specimen can be obtained

• No clinically unstable brain metastases

  • Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • Patients with leptomeningeal disease are not eligible
• Pre- or post-menopausal
• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Hemoglobin ≥ 9.0 g/dL
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 3 times ULN
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Negative (serum or urine) pregnancy test
• Not pregnant or nursing
• Men or women of childbearing potential who are willing to employ adequate contraception
• Willing to provide tissue and blood samples for mandatory translational research
• Willing to return to the enrolling institution for follow-up
• No known sensitivity to azacitidine (5-AZA), entinostat, or mannitol

• No uncontrolled intercurrent illness that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure (NYHA class II or above)
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Other co-morbid systemic illness or other severe concurrent disease

• No active malignancy ≤ 3 years prior to registration except non-melanotic skin cancer or carcinoma-in-situ of the cervix

  • If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
• No immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be HIV positive
• Patients who cannot swallow tablets not allowed

• No other concurrent anticancer chemotherapy, antiestrogen therapy, biologic therapy, radiotherapy, or investigational systemic therapy

  • Concurrent bisphosphonate allowed
  • Addition of hormone therapy at disease progression allowed
• Recovered from prior therapy
• More than 3 weeks since prior chemotherapy or radiotherapy
• More than 3 weeks since prior surgery
• More than 3 weeks since prior hormone therapy
• More than 6 weeks since prior nitrosoureas, mitomycin C, trastuzumab, or bevacizumab
• No other concurrent investigational agents
• No prior treatment with HDAC (histone deacetylase) inhibitors or demethylating agents ≤ 2 weeks prior to registration
• No patients taking valproic acid