Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
Condition: Breast Adenocarcinoma; Estrogen Receptor- Negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive Tumor; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Triple-negative Breast Carcinoma
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Doxorubicin; Cyclophosphamide; Paclitaxel; Carboplatin; Decitabine; Pembrolizumab
Intervention description: 60 mg/m2 once every 2 weeks for 4 cycles.; cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.; Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.; carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.; Given IV; Given IV
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Carboplatin; Doxorubicin; Pembrolizumab; Decitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer

Summary:

      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. At
      enrollment, patients will be assigned to one of 2 cohorts based on hormone receptor status.

        -  Cohort A - patients with HER2-negative, hormone receptor-negative breast cancer (defined
           as both ER and PgR with < 10% positive staining on IHC) Note: before beginning standard
           neoadjuvant chemotherapy, patients in Cohort A may be reassigned to Cohort A2 to receive
           extended pembrolizumab as part of new standard neoadjuvant and postoperative adjuvant
           therapy.

        -  Cohort B - patients with HER2-negative, hormone receptor-positive breast cancer (defined
           as either ER or PgR with ≥ 10% positive staining on IHC)
    

Eligibility criteria:

        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) human epidermal growth factor
             receptor 2 (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/Chromosome 17 Centromere (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 and 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 fine needle aspiration (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.

          -  Left ventricular ejection fraction (LVEF) assessment (ie, 2-D echocardiogram or
             multigated acquisition (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 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 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-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 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