Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
This study is a 2-cohort, open-label, multicenter, phase 2 study of a short course of
 immunotherapy consisting of sequential decitabine followed by pembrolizumab administered
 prior to a standard neoadjuvant chemotherapy regimen for patients with locally advanced
 HER2-negative breast cancer. The primary efficacy objective is to determine if the
 immunotherapy increases the presence and percentage of tumor and/or stromal area of
 infiltrating lymphocytes prior to initiation of standard neoadjuvant chemotherapy. Efficacy
 will be evaluated in 2 cohorts based on hormone receptor status.
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
 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 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), irrespective of hormone receptor
 status

 -  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), irrespective of hormone receptor
 status

 -  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, a 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 Note: If ALP is > 1.5 x
 ULN, imaging to rule out bone and liver metastasis is required.

 -  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 6 months following 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 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.

 -  History of solid organ or allogeneic stem cell transplant

 -  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 v5.0

 -  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