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

Study Overview
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Brief Summary
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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)

Detailed Description
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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.

Official Title
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T-Cell Immune Checkpoint Inhibition Plus Hypomethylation for Locally Advanced HER2-Negative Breast Cancer - A Phase 2 Neoadjuvant Window Trial of Pembrolizumab and Decitabine Followed by Standard Neoadjuvant Chemotherapy

Conditions
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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

Intervention / Treatment
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* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Decitabine
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Triple Negative Breast Cancer (TNBC)<br>Triple Negative Breast Cancer (Cohort A): Decitabine IV over 60 minutes on 4 days and pembrolizumab IV over 30 minutes on days 8 and 22. Four cycles of dose-dense doxorubicin and cyclophosphamide (AC), followed by 12 doses of weekly paclitaxel and carboplatin. | Drug: Doxorubicin<br>* 60 mg/m2 once every 2 weeks for 4 cycles.<br>* Other names: Rubex;Drug: Cyclophosphamide<br>* cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.<br>* Other names: Neosar;Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.<br>* Other names: Abraxane;Drug: Carboplatin<br>* carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.<br>* Other names: Paraplatin;Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Drug: Pembrolizumab<br>* Given IV<br>* Other names: Lambrolizumab;|
| Experimental: Cohort B: HER2-negative hormone receptor-positive tumors<br>HER2-negative hormone receptor-positive tumors (Cohort B): Decitabine IV over 60 minutes on 4 days and pembrolizumab IV over 30 minutes on days 8 and 22. Four cycles of dose-dense doxorubicin and cyclophosphamide (AC), followed by 12 doses of weekly paclitaxel. | Drug: Doxorubicin<br>* 60 mg/m2 once every 2 weeks for 4 cycles.<br>* Other names: Rubex;Drug: Cyclophosphamide<br>* cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.<br>* Other names: Neosar;Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.<br>* Other names: Abraxane;Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Drug: Pembrolizumab<br>* Given IV<br>* Other names: Lambrolizumab;|
| Experimental: Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab<br>Triple Negative Breast Cancer (Cohort A2). Decitabine IV over 60 minutes on 4 days and pembrolizumab IV over 30 minutes on days 8 and 22. Four cycles of dose-dense doxorubicin and cyclophosphamide (AC), followed by 12 doses of weekly paclitaxel and carboplatin, and pembrolizumab every 3 weeks. | Drug: Doxorubicin<br>* 60 mg/m2 once every 2 weeks for 4 cycles.<br>* Other names: Rubex;Drug: Cyclophosphamide<br>* cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.<br>* Other names: Neosar;Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.<br>* Other names: Abraxane;Drug: Carboplatin<br>* carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.<br>* Other names: Paraplatin;Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Drug: Pembrolizumab<br>* Given IV<br>* Other names: Lambrolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Increase in Tumor and Stroma With Infiltrating Lymphocytes (TIL) From Baseline Pre-treatment Biopsy to Post-immunotherapy Biopsy Following Administration of Decitabine Followed by Pembrolizumab. | To determine and quantify if treatment with neoadjuvant decitabine followed by pembrolizumab increases lymphocyte infiltration into tumor and/or stroma in patients with locally advanced, HER2-negative breast cancer. | Baseline pre-treatment biopsy to post-immunotherapy biopsy following administration of decitabine followed by pembrolizumab, 3-7 day window after Day 22 medication administration, about one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab) | Using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), all adverse events (AEs) regardless of grade or attribution, will be captured from the beginning of study treatment (initiation of decitabine) until initiation of standard neoadjuvant chemotherapy. For patients who do not initiate pembrolizumab, all AEs will be captured until 30 days following the last dose of decitabine or until another cancer treatment is initiated, whichever occurs first.For patients who initiate pembrolizumab, immune related adverse events (irAEs) (clinically significant and non-clinically significant) will be captured from the initiation of pembrolizumab through the end of the 30- day post-surgery (or post-treatment, for those who don't have surgery) follow-up period and at a 12-month follow-up time point. | Time of study registration until 30 days following the last dose of decitabine, or until another cancer treatment was initiated, or 30 days following surgery, 12- months. | 
| Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab | To determine if the study treatment increases the proportion of tumors with ≥ 60% tumor or stromal area infiltrated with lymphocytes (ie, LPBC). The percentage of patients meeting criteria for LPBC following treatment with decitabine and pembrolizumab compared to the percentage before treatment (LPBC is defined as breast cancer with ≥ 60% intratumoral or stromal area with infiltrating lymphocytes.) | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 
| Number of Patients With Pathologic Complete Response (pCR) in the Breast and Post-therapy Lymph Nodes. | To determine the rate of pCR in the breast and lymph nodes (pCR breast and nodes). The number of patients with pCR in the breast and post-therapy lymph nodes defined as the absence of any invasive cancer in the resected breast specimen and absence of cancer on H&E evaluation of all resected lymph nodes following completion of neoadjuvant therapy (ypT0/is; ypN0). | 30 days following surgery or last dose of therapy | 
| Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | To determine the rate of Residual Cancer Burden (RCB) Index value of 0-1 following all neoadjuvant therapy. The number of patients with no (0) or (i) minimal residual disease in the resected breast and axillary specimen defined as RCB Index value 0 or i (Arabic numeral). | End of therapy surgery | 
| The Number of Patients With Clinical Complete Response (cCR) | To determine the rate of clinical complete response in the breast and lymph nodes (cCR breast and nodes) following all neoadjuvant therapy. The proportion of patients with cCR defined as the absence of tumor based on physical examination of the breast and nodes following completion of all neoadjuvant therapy. | End of therapy surgery | 
| Enumeration of T Cells and Immune Cell Subsets | To characterize the alteration of T lymphocyte and other host cell infiltration and immune response gene signatures in breast cancers resulting from treatment with decitabine and pembrolizumab. Enumeration of T cells and immune cell subsets, including cluster of differentiation 8 (CD8)+ cytotoxic T cells, cluster of differentiation 4 (CD4)+ helper T cells, FOXP3+ regulatory T Cells, cluster of differentiation 20 (CD20)+ B cells, and MDSC in the tumor sample procured by core needle biopsy following completion of sequential decitabine followed by pembrolizumab compared to the number of these cells in tumor samples procured at baseline. | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 
| Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | To evaluate the correlation of pre-existing and post-immunotherapy immune response signatures with response to neoadjuvant chemotherapy. The number of PD-L1 positive cells (including tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells (PD-L1 positive or negative) in an area. | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 
| Correlation of Intensity of PD-L1 Expression by Assay as it Relates to pCR Rates From Chemotherapy. | Discovery Life Sciences will use tumor samples for proprietary PD-L1 staining. | Day of surgery | 
| Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Evaluate the level of circulating MDSC per ml of blood at baseline, following treatment with decitabine alone. | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 
| Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Evaluate the level of circulating MDSC per ml of blood at baseline, following treatment with pembrolizumab administered after decitabine. | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 
| Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | Number of patients who are alive and have not had disease relapse at 12 months following last dose of pembrolizumab | 12 Months following surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer