Breast Cancer Clinical Trial
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. 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)
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 AC and 12 doses of weekly paclitaxel or Nab-paclitaxel. Paclitaxel or Nab-paclitaxel will be combined with carboplatin for Cohorts A and A2 (TNBC). The sequence of the 2 regimens will be at the discretion of the treating medical oncologist following the safety lead-in phase. For the primary endpoint, Cohorts A and A2 will be evaluated together, separate from Cohort B.
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 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 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
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
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.
Resolved childhood asthma/atopy
Requirement for intermittent use of bronchodilators or local steroid injections or topical steroids
Hypothyroidism stable on hormone replacement
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
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There are 5 Locations for this study
Edgewood Kentucky, 41017, United States
Columbus Ohio, 43210, United States
Charlottesville Virginia, 22903, United States
Richmond Virginia, 23298, United States
Richmond Virginia, 23950, United States
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