Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca

Both cohorts will receive the identical doses and treatment schedules of decitabine and
pembrolizumab followed by a standard neoadjuvant chemotherapy regimen. Both cohorts will
receive 4 cycles of dose-dense AC followed by 12 doses of weekly paclitaxel. Paclitaxel will
be combined with carboplatin for Cohort A (TNBC). The primary safety objective will be to
evaluate the safety and toxicity of sequential decitabine plus pembrolizumab followed by
dose-dense AC, weekly paclitaxel (or paclitaxel plus carboplatin) administered as neoadjuvant
therapy. If the breast tumor is resectable following completion of all protocol therapy,
breast-conserving surgery or mastectomy and axillary surgical staging (either sentinel node
biopsy and/or axillary dissection) will be performed.

Inclusion Criteria:

- Invasive adenocarcinoma of the breast diagnosed by core needle biopsy

- Breast cancer determined to be HER2-negative per current American Society of Clinical
Oncologists/College of American Pathologists (ASCO/CAP) HER2 Guidelines (If IHC was
performed, IHC 0 or 1+; if fluorescence in situ hybridization [FISH] or other in situ
hybridization test, dual probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number
< 4.0 signals/cell)

- Breast cancer determined to be hormone receptor-positive or hormone receptor-negative.

- Locally advanced breast cancer defined as any of the following per American Joint
Committee on Cancer (AJCC) Staging Criteria:

- T2 based on tumor measurements by physical examination or imaging with clinically
positive regional lymph nodes (cN1 or cN2)

- Hormone receptor-negative breast cancer patients with tumor size of 3-5 cm
measured by physical examination or imaging with clinically negative regional
lymph nodes (cN0)

- Any T3 based on tumor measurements by physical examination or imaging

- Any T4 (including inflammatory breast cancer)

- Ipsilateral axillary lymph nodes must be evaluated by MRI or ultrasound within 12
weeks prior to study registration to determine clinical nodal status. If imaging is
suspicious or abnormal, an FNA or core biopsy of the questionable node(s) on imaging
is required. Nodal status should be classified according to the following criteria:

- Nodal status - negative

- Imaging of the axilla is negative; OR

- Imaging of the axilla is suspicious or abnormal AND FNA or core biopsy is
negative.

- Nodal status - positive

- FNA or core biopsy of node(s) is cytologically or histologically suspicious
or positive

- Breast imaging performed prior to study registration as follows:

- Ipsilateral breast - within 12 weeks

- Contralateral breast - within 24 weeks

- Age ≥ 18 years

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

- Adequate bone marrow function as defined below:

- Absolute neutrophil count (ANC) ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin ≥ 10.0 g/dL

- Adequate renal function as defined below:

- Serum creatinine ≤ upper limit of normal (ULN) for the lab or a calculated creatinine
clearance ≥ 60 mL/min

- Adequate hepatic function as defined below:

- Total bilirubin ≤ ULN for the laboratory

- Aspartate aminotransferase (AST) ≤ 1.5 x ULN for the laboratory

- Alanine aminotransferase (ALT) ≤ 1.5 x ULN for the laboratory

- Alkaline phosphatase (ALP) ≤ 2.5 x ULN for the laboratory

- LVEF assessment (ie, 2-D echocardiogram or MUGA scan) performed within 12 weeks prior
to study registration indicates an LVEF ≥ 50% regardless of the cardiac imaging
facility's lower limit of normal

- Women who are not postmenopausal or have not undergone hysterectomy must have a
documented negative serum pregnancy test within 72 hours prior to initiating study
treatment.

Note: Postmenopausal is defined as any of the following:

- Age ≥ 60 years

- Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone
(FSH) and plasma estradiol levels in the postmenopausal range

- Bilateral oophorectomy

- A female patient who is a woman of child-bearing potential (WCBP) and a male
patient with a partner who is a WCBP must agree to use a medically accepted
method for preventing pregnancy for the duration of immunotherapy and neoadjuvant
chemotherapy and until after completion of breast surgery or, for patients who do
not receive neoadjuvant chemotherapy, for a minimum of 4 months following the
last dose of pembrolizumab

- Ability to understand and willingness to sign the consent form

Exclusion Criteria:

- Breast cancer treatment for the currently diagnosed breast cancer including radiation
therapy, chemotherapy, targeted therapy, or endocrine therapy prior to study
registration

- Administration of a live vaccine within 30 days prior to initiating study treatment
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are permitted; however, intranasal influenza vaccines (eg, Flu-Mist) are live
attenuated vaccines, and are not allowed.

- Administration of a monoclonal antibody within 4 weeks prior to initiating study
treatment or has not recovered (ie, ≤ grade 1 or at baseline) from AEs due to a
monoclonal antibody administered more than 4 weeks earlier

- Administration of any investigational agent within 4 weeks prior to initiating study
treatment

- Evidence of metastatic disease that is extensive enough to preclude consideration of
subsequent definitive surgery for the primary tumor

- History of ipsilateral invasive breast cancer or ipsilateral ductal carcinoma in situ
(DCIS) Note: Patients with history of ipsilateral lobular carcinoma in situ (LCIS) are
eligible.

- Previous therapy for any malignancy with an anthracycline or taxane for Cohorts A and
B and carboplatin for Cohort A

- Cardiac disease that would preclude administration of the drugs included in the study
treatment regimen including, but not limited to:

- Angina pectoris that requires the current use of anti-anginal medication

- Ventricular arrhythmias except for benign premature ventricular contractions

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication

- Conduction abnormality requiring a pacemaker

- Valvular disease with documented compromise in cardiac function; and symptomatic
pericarditis

- Nervous system disorder (ie, paresthesia, peripheral motor neuropathy, or peripheral
sensory neuropathy) ≥ grade 2, per CTCAE v4.0

- Administration of or condition requiring administration of systemic steroid therapy or
any other form of immunosuppressive therapy within 7 days prior to initiating study
treatment Exception: Patients with conditions that can be managed with steroids
equivalent to or less than an oral prednisone dose of 10 mg daily would not be
excluded from the study.

- Previous therapy for this cancer with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or
any other immunomodulatory agent

- Known or presumed hypersensitivity to decitabine or pembrolizumab (or any of their
excipients)

- Diagnosed immunodeficiency, eg, human immunodeficiency virus (HIV)

- Active autoimmune disease requiring systemic treatment within the past 2 years (ie,
with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) or
a documented history of clinically severe autoimmune disease or a syndrome that
requires systemic steroids or immunosuppressive agents Note: Patients with the
conditions or medical history listed below are NOT excluded from this study.

- Vitiligo

- Resolved childhood asthma/atopy

- Requirement for intermittent use of bronchodilators or local steroid injections or
topical steroids

- Hypothyroidism stable on hormone replacement

- Sjogren's Syndrome

- Known history or evidence of interstitial lung disease or active, non-infectious
pneumonitis

- Known history of active bacillus tuberculosis (TB)

- Active infection requiring systemic therapy

- Known active Hepatitis B or C

- Pregnancy or breastfeeding

- Diagnosis or treatment for another malignancy within 5 years prior to study
registration, with the following exceptions: complete resection of basal cell
carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, and low-risk
prostate cancer after curative therapy

- Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk or limit the patient's adherence with study
requirements