Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer
Condition: Male Breast Carcinoma; Recurrent Breast Carcinoma; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma
MeSH terms: Carcinoma; Breast Neoplasms; Breast Neoplasms, Male
Intervention: Azacitidine; Entinostat; Laboratory Biomarker Analysis; Pharmacological Study
Intervention description: Given SC; Given PO; Correlative studies; Correlative studies
Intervention MeSH terms: Azacitidine; Entinostat; Histone Deacetylase Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well giving azacitidine and entinostat work in treating
      patients with advanced breast cancer. Drugs used in chemotherapy, such as azacitidine, work
      in different ways to stop the growth of tumor cells, either by killing the cells or by
      stopping them from dividing. Entinostat may stop the growth of tumor cells by blocking some
      of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill
      more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patient must have histologically or cytologically confirmed adenocarcinoma of the
             breast triple-negative (ER-, progesterone receptor [PR]-, human epidermal growth
             factor receptor 2 [HER2]-) or hormone positive/ HER2-, with evidence of locally
             advanced and inoperable or metastatic disease (American Joint Committee on Cancer
             [AJCC] Stage IV)

               -  NOTE: Triple-negative patients will be defined per American Society of Clinical
                  Oncology-College of American Pathologists (ASCO-CAP) Guidelines; these guidelines
                  state that ER and PR assays be considered positive if there are at least 1%
                  positive tumor nuclei in the sample on testing in the presence of expected
                  reactivity of internal (normal epithelial elements) and external controls

               -  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 most recent
                  receptor testing, for the purposes of the study based upon the clinical course at
                  the discretion of the Study Chair; for HER2 assessment, a negative result is an
                  immuno-histochemistry staining of 0 or 1+, a fluorescence in situ hybridization
                  (FISH) result of less than 4.0 HER2 gene copies per nucleus, or a FISH ratio of
                  less than 1.8

          -  Patients with triple negative disease must have progressed through at least 1 prior
             chemotherapy regimen (administered in the adjuvant or metastatic setting); hormone
             receptor-positive patients must have progressed through two lines of hormonal therapy
             (administered in the adjuvant or metastatic setting), unless otherwise eligible as per
             below, and at least 1 prior chemotherapy regimen (administered in the adjuvant or
             metastatic setting) with no known curative options available

               -  NOTE: Patients with hormone receptor-positive disease may be considered eligible
                  if deemed clinically hormone-resistant taking into consideration the rate of
                  progression of disease or a short interval of time on first line hormonal therapy
                  before progression, or if intolerant of hormonal therapy such that further
                  hormonal therapy will not be considered as part of the treatment strategy

          -  In patients with metastatic disease in the liver, liver disease burden is limited to
             no 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 to
             this may be allowed for participants with Gilbert's syndrome with documented approval
             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 the
             Modified Cockcroft-Gault formula

          -  Negative (serum or urine) pregnancy test done =< 7 days prior to registration, for
             women of childbearing potential only

          -  Patient must have an accessible tumor lesion from which a biopsy specimen can be
             obtained; NOTE: if baseline biopsy is attempted and is unsuccessful (eg, patient
             intolerance, inadequate tissue), the patient will still be considered eligible for the
             study

          -  Ability to understand and the willingness to sign a written informed consent document

          -  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 adequate
                  contraception

               -  NOTE: should a woman become pregnant or suspect she is pregnant while
                  participating in this study, she should inform her treating physician immediately

          -  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 baseline
                  due to agents administered, with exception of alopecia, unless approved by the
                  Protocol Chair

               -  NOTE: concurrent bisphosphonate therapy is allowed; concurrent ovarian
                  suppression therapy (i.e., Lupron or Zoladex) is also allowed at the discretion
                  of 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, 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:

               -  Ongoing or active infection

               -  Symptomatic congestive heart failure (New York Heart Association [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

          -  Active malignancy other than breast cancer =< 3 years prior to registration;
             EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if
             there is a history of prior malignancy, they must not be receiving other specific
             treatment 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 demethylating
             agents =< 2 weeks prior to registration

          -  Unstable brain metastases; NOTE: patients with brain metastases must have stable
             neurologic status and magnetic resonance imaging (MRI) imaging following local therapy
             (surgery or radiation) for at least 4 weeks, with no dexamethasone requirement (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