Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

PRIMARY OBJECTIVES:

I. To evaluate objective response rate by Response Evaluation Criteria In Solid Tumors
(RECIST) criteria of the combination of azacitidine (5-AZA) and entinostat in women with
advanced breast cancer; triple-negative and hormone-refractory.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of 5-AZA and entinostat in
women with advanced breast cancer.

II. To determine progression-free survival, overall survival, and clinical benefit rate of
the combination of 5-AZA and entinostat.

TERTIARY OBJECTIVES:

I. To collect safety and toxicity data as well as the feasibility and response rate where
hormonal therapy is added to the combination under investigation at the time of progressive
disease. (Exploratory) II. To determine the pharmacokinetic profile of 5-AZA (full profile)
and entinostat (trough concentrations) in patients with advanced breast cancer. (Exploratory)
III. To assess serum cytidine deaminase pharmacogenetics and phenotypic activity as a
potential biomarker of response to 5-AZA. (Exploratory) IV. To evaluate baseline and change
in candidate gene re-expression (e.g., estrogen receptor [ER] alpha, retinoic acid receptor
[RAR] beta) in malignant tissue obtained from selected patients through fine-needle
aspiration (FNA) and core biopsy, prior to and following combination therapy. (Exploratory)
V. To evaluate baseline and change in gene methylation silencing in circulating
deoxyribonucleic acid (DNA) obtained prior to and following combination therapy.
(Exploratory) VI. To evaluate baseline and change in gene methylation in malignant tissue
obtained through FNA and core biopsy. (Exploratory)

OUTLINE: This is a multicenter study.

Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10, and entinostat orally
(PO) on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients with progressive disease may continue azacitidine and
entinostat in combination with hormonal therapy, at treating physician discretion, or undergo
event monitoring.

After completion of study therapy, patients are followed up every 3-6 months for up to 3
years.

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