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

Inclusion Criteria:

• Invasive adenocarcinoma of the breast diagnosed by core needle biopsy

• Breast cancer determined to be HER2-negative per current American Society ofClinical Oncologists/College of American Pathologists (ASCO/CAP) human epidermalgrowth factor receptor 2 (HER2) Guidelines (If IHC was performed, IHC 0 or 1+; iffluorescence in situ hybridization (FISH) or other in situ hybridization test, dualprobe HER2/Chromosome 17 Centromere (CEP17) ratio < 2.0 with an average HER2 copynumber < 4.0 signals/cell)

• Breast cancer determined to be hormone receptor-positive or hormonereceptor-negative defined as follows:

• Hormone receptor-positive: ≥ 10% staining by IHC for either estrogen receptor (ER) or progesterone receptor (PgR)

• Hormone receptor-negative: < 10% staining by IHC for both ER and PgR

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

• T2 based on tumor measurements by physical examination or imaging and withclinically positive regional lymph nodes (cN1 or cN2), irrespective of hormonereceptor status

• Hormone receptor-negative breast cancer patients with tumor size of 3-5 cmmeasured by physical examination or imaging with clinically negative regionallymph nodes (cN0)

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

• Any T4 (including inflammatory breast cancer), irrespective of hormone receptorstatus

• Ipsilateral axillary lymph nodes must be evaluated by MRI or ultrasound within 12weeks prior to study registration to determine clinical nodal status. If imaging issuspicious or abnormal, a fine needle aspiration (FNA) or core biopsy of thequestionable node(s) on imaging is required. Nodal status should be classifiedaccording 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 isnegative.

• Nodal status - positive

• FNA or core biopsy of node(s) is cytologically or histologicallysuspicious 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 calculatedcreatinine 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 Note: If ALP is > 1.5x ULN, imaging to rule out bone and liver metastasis is required.

• Left ventricular ejection fraction (LVEF) assessment (ie, 2-D echocardiogram ormultigated acquisition (MUGA) scan) performed within 12 weeks prior to studyregistration indicates an LVEF ≥ 50% regardless of the cardiac imaging facility'slower limit of normal

• Women who are not postmenopausal or have not undergone hysterectomy must have adocumented negative serum pregnancy test within 72 hours prior to initiating studytreatment.

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 malepatient with a partner who is a WCBP must agree to use a medically acceptedmethod for preventing pregnancy for the duration of immunotherapy andneoadjuvant chemotherapy and until after completion of breast surgery or, forpatients who do not receive neoadjuvant chemotherapy, for a minimum of 6 monthsfollowing the last dose of pembrolizumab or decitabine

• Ability to understand and willingness to sign the consent form

Exclusion Criteria:

• Breast cancer treatment for the currently diagnosed breast cancer includingradiation therapy, chemotherapy, targeted therapy, or endocrine therapy prior tostudy registration

• Administration of a live vaccine within 30 days prior to initiating study treatmentNote: Seasonal influenza vaccines for injection are generally inactivated fluvaccines 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 studytreatment or has not recovered (ie, ≤ grade 1 or at baseline) from adverse events (AEs) due to a monoclonal antibody administered more than 4 weeks earlier

• Administration of any investigational agent within 4 weeks prior to initiating studytreatment

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

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

• History of solid organ or allogeneic stem cell transplant

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

• Cardiac disease that would preclude administration of the drugs included in thestudy 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 controlledwith medication

• Conduction abnormality requiring a pacemaker

• Valvular disease with documented compromise in cardiac function; andsymptomatic pericarditis

• Nervous system disorder (ie, paresthesia, peripheral motor neuropathy, or peripheralsensory neuropathy) ≥ grade 2, per CTCAE v5.0

• Administration of or condition requiring administration of systemic steroid therapyor any other form of immunosuppressive therapy within 7 days prior to initiatingstudy treatment Exception: Patients with conditions that can be managed withsteroids equivalent to or less than an oral prednisone dose of 10 mg daily would notbe excluded from the study.

• Previous therapy for this cancer with an anti-anti-programmed death-1 (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 theirexcipients)

• 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 thatrequires systemic steroids or immunosuppressive agents Note: Patients with theconditions 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 injectionsor topical steroids

• Hypothyroidism stable on hormone replacement

• Sjogren's Syndrome

• Known history or evidence of interstitial lung disease or active, non-infectiouspneumonitis

• 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 studyregistration, with the following exceptions: complete resection of basal cellcarcinoma or squamous cell carcinoma of the skin, any in situ malignancy, andlow-risk prostate cancer after curative therapy

• Medical, psychological, or social condition that, in the opinion of theinvestigator, may increase the patient's risk or limit the patient's adherence withstudy requirements