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 IIA Breast Cancer, Stage IIB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Triple-negative Breast Carcinoma
Conditions
Keywords
Breast Cancer
Brief 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)
Detailed description
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.
Interventions
DRUGDoxorubicin
60 mg/m2 once every 2 weeks for 4 cycles.
DRUGCyclophosphamide
cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
DRUGPaclitaxel
Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
DRUGCarboplatin
carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.
DRUGDecitabine
Given IV
DRUGPembrolizumab
Given IV
Sponsors
Virginia Commonwealth University
Merck Sharp & Dohme LLC
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | 12 Months following surgery | Number of patients who are alive and have not had disease relapse at 12 months following last dose of pembrolizumab |
| Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab) | Time of study registration until 30 days following the end of administration of decitabine and pembrolizumab, or until another cancer treatment was initiated, or 30 days following surgery, 12- months. | 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. |
| Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 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.) |
| Number of Patients With Pathologic Complete Response (pCR) in the Breast and Post-therapy Lymph Nodes. | End of administration of decitabine and pembrolizumab Day- Window of time Days 25-29, or 30 days following surgery | 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). |
| Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | End of therapy surgery | 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). |
| The Number of Patients With Clinical Complete Response (cCR) | End of therapy surgery | 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. |
| Enumeration of T Cells and Immune Cell Subsets | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 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. |
| Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29 | 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. |
| Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | Baseline biopsy (BX1) before treatment, end of therapy (EOT) surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab (i.e after the second dose of pembrolizumab) | Combined positive score (CPS) is calculated by the number of PD-L1 positive cells, including tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells multiplied by 100 (n\>100 is possible). The point biserial correlation coefficient (RPB) was calculated to quantify the association between the binary factor (BFA) pCR,and continuous factor PD-L1-CPS. The two PD-L1-cps variables (BX2\_PD-L1\_cps, Change\_PD-L1\_cps) were considered separately. |
| Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | Baseline biopsy (BX1) prior to therapy, EOT surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab | A semi-quantitative method used to assess the expression level of proteins or other markers in tissue samples, particularly in immunohistochemistry (IHC) studies. It helps to determine the intensity and proportion of staining, providing a numerical representation of biomarker abundance. The H-score is calculated by multiplying the percentage of positive cells by their staining intensity and summing these values, as described in Dolled-Filhart et al, which calculates a score based on intensity of tumor staining and the percentage of cells implemented. Point Biserial correlation coefficient (RPB) was calculated to quantify the association between the binary factor pCR, and continuous factor PDL-1-Hscore.The PD-L1-Hscore variables (BX2\_PD-L1\_Hscore, Change\_PD-L1\_Hscore) were considered separately. |
| Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Assessed at end of administration of decitabine compared to assessment at baseline prior to protocol treatments. | Evaluate the level of circulating MDSC per ml of blood at baseline, following treatment with decitabine alone. |
| Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Assessed at baseline, after administration of decitabine, after decitabine and 2 doses of pembrolizumab. | Evaluate the level of circulating MDSC per ml of blood at baseline, following treatment with decitabine, and following treatment with decitabine and 2 doses of pembrolizumab. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORHarry D. Bear, M.D., Ph.D.
Massey Cancer Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) 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.
Doxorubicin: 60 mg/m2 once every 2 weeks for 4 cycles.
Cyclophosphamide: cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
Paclitaxel: Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
Carboplatin: carboplatin AUC 1.5 once weekly for 12 weeks.
Decitabine: Given IV
Pembrolizumab: Given IV | 21 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors 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.
Doxorubicin: 60 mg/m2 once every 2 weeks for 4 cycles.
Cyclophosphamide: cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
Paclitaxel: Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
Decitabine: Given IV
Pembrolizumab: Given IV | 18 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab 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.
Doxorubicin: 60 mg/m2 once every 2 weeks for 4 cycles.
Cyclophosphamide: cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
Paclitaxel: Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
Carboplatin: carboplatin AUC 1.5 once weekly for 12 weeks.
Decitabine: Given IV
Pembrolizumab: Given IV | 7 |
| Total | 46 |
Baseline characteristics
| Characteristic | Cohort A: Triple Negative Breast Cancer (TNBC) | Total | Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Cohort B: HER2-negative Hormone Receptor-positive Tumors |
|---|---|---|---|---|
| Age, Continuous | 56 Years | 54.5 Years | 55 Years | 54 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 45 Participants | 7 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 33 Participants | 6 Participants | 12 Participants |
| Region of Enrollment United States | 21 participants | 46 participants | 7 participants | 18 participants |
| Sex: Female, Male Female | 21 Participants | 46 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 21 | 0 / 18 | 0 / 7 |
| other Total, other adverse events | 21 / 21 | 18 / 18 | 7 / 7 |
| serious Total, serious adverse events | 7 / 21 | 6 / 18 | 4 / 7 |
Outcome results
Primary
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | 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. | Post Treatment | 35.00 % of stromal area occupied by TIL | Standard Deviation 21.43 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | 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. | Absolute Change Value | 7.65 % of stromal area occupied by TIL | Standard Deviation 15.12 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | 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. | Baseline | 27.35 % of stromal area occupied by TIL | Standard Deviation 17.69 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | 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. | Absolute Change Value | 6.07 % of stromal area occupied by TIL | Standard Deviation 8.13 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | 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. | Baseline | 17.50 % of stromal area occupied by TIL | Standard Deviation 9.95 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | 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. | Post Treatment | 23.57 % of stromal area occupied by TIL | Standard Deviation 12 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | 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. | Post Treatment | 32.50 % of stromal area occupied by TIL | Standard Deviation 11.73 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | 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. | Baseline | 25.83 % of stromal area occupied by TIL | Standard Deviation 12.01 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | 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. | Absolute Change Value | 6.67 % of stromal area occupied by TIL | Standard Deviation 12.11 |
Secondary
Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining.
A semi-quantitative method used to assess the expression level of proteins or other markers in tissue samples, particularly in immunohistochemistry (IHC) studies. It helps to determine the intensity and proportion of staining, providing a numerical representation of biomarker abundance. The H-score is calculated by multiplying the percentage of positive cells by their staining intensity and summing these values, as described in Dolled-Filhart et al, which calculates a score based on intensity of tumor staining and the percentage of cells implemented. Point Biserial correlation coefficient (RPB) was calculated to quantify the association between the binary factor pCR, and continuous factor PDL-1-Hscore.The PD-L1-Hscore variables (BX2\_PD-L1\_Hscore, Change\_PD-L1\_Hscore) were considered separately.
Time frame: Baseline biopsy (BX1) prior to therapy, EOT surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab
Population: Positive RPB indicates a positive relationship between the binary factor pCR and continuous factor PDL-1-Hscore. As the binary factor pCR value increases, the value of the continuous factor PDL-1-Hscore also tends to increase. The positive RPB means that pCR patient group tends to have higher PDL-1-Hscore. A negative RPB indicates an inverse relationship between the binary factor pCR and continuous factor PDL-1-Hscore, a negative RPB indicates pCR patient group tends to have lower PDL-1-Hscore.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | BX2 (only) Hscore (After therapy) | 0.25211 Corr. Coefficient pCR & PD-L1 H-Score |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | Change_Hscore of Bx-2-Bx-1 | 0.3699 Corr. Coefficient pCR & PD-L1 H-Score |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | BX2 (only) Hscore (After therapy) | 0.7121 Corr. Coefficient pCR & PD-L1 H-Score |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | Change_Hscore of Bx-2-Bx-1 | -0.1407 Corr. Coefficient pCR & PD-L1 H-Score |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | BX2 (only) Hscore (After therapy) | -0.3647 Corr. Coefficient pCR & PD-L1 H-Score |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Change of Intensity of PD-L1 Expression by Assay as it Relates to Pathologic Complete Response pCR Rates From Chemotherapy Tumor Samples for Proprietary PD-L1 Staining. | Change_Hscore of Bx-2-Bx-1 | -0.8592 Corr. Coefficient pCR & PD-L1 H-Score |
Secondary
Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy
Combined positive score (CPS) is calculated by the number of PD-L1 positive cells, including tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells multiplied by 100 (n\>100 is possible). The point biserial correlation coefficient (RPB) was calculated to quantify the association between the binary factor (BFA) pCR,and continuous factor PD-L1-CPS. The two PD-L1-cps variables (BX2\_PD-L1\_cps, Change\_PD-L1\_cps) were considered separately.
Time frame: Baseline biopsy (BX1) before treatment, end of therapy (EOT) surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab (i.e after the second dose of pembrolizumab)
Population: Positive RPB indicates a positive relationship between the BFA pCR and continuous factor PDL-1-CPS as values of BFA pCR increase, the value of the continuous factor PDL-1-CPS tends to increase. The positive RPB means that pCR patient group tends to have larger PDL-1-CPS score. The negative RPB indicates an inverse relationship between the binary factor pCR and continuous factor PDL-1-cps. The negative RPB indicates pCR patient group tends to have lower PDL-1-cps score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | BX2 (only) CPS After Therapy | 0.1211 Corr. Coefficient pCR & PD-L1 CPS |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | Change CPS of BX2-BX1 | 0.44541 Corr. Coefficient pCR & PD-L1 CPS |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | BX2 (only) CPS After Therapy | 0.0031 Corr. Coefficient pCR & PD-L1 CPS |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | Change CPS of BX2-BX1 | -0.4719 Corr. Coefficient pCR & PD-L1 CPS |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | BX2 (only) CPS After Therapy | -0.0094 Corr. Coefficient pCR & PD-L1 CPS |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy | Change CPS of BX2-BX1 | -0.8011 Corr. Coefficient pCR & PD-L1 CPS |
Secondary
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.
Time frame: Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29
Secondary
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.
Time frame: Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29
Population: Not all participants had surgery performed, therefore response could not be assessed for all patients (3/36). Specimen issues limited number who could have PD-L1 assessments to 37/46
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Post Immunotherapy | 50.00 Number of PD-L1 positive cells | Standard Deviation 34.73 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Baseline (Bx 1) | 31.00 Number of PD-L1 positive cells | Standard Deviation 29.63 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Change (Bx2-Bx1) | 19.00 Number of PD-L1 positive cells | Standard Deviation 24.27 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Post Immunotherapy | 29.07 Number of PD-L1 positive cells | Standard Deviation 28.15 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Baseline (Bx 1) | 13.07 Number of PD-L1 positive cells | Standard Deviation 17.22 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Change (Bx2-Bx1) | 16.00 Number of PD-L1 positive cells | Standard Deviation 28.15 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Baseline (Bx 1) | 22.50 Number of PD-L1 positive cells | Standard Deviation 23.36 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Change (Bx2-Bx1) | 13.00 Number of PD-L1 positive cells | Standard Deviation 17.12 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy. | Post Immunotherapy | 35.50 Number of PD-L1 positive cells | Standard Deviation 26.04 |
Secondary
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.
Time frame: Assessed at end of administration of decitabine compared to assessment at baseline prior to protocol treatments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Granulocytic | 6279.00 absolute cell count per ml of blood | Standard Deviation 8391.41 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Granulocytic | -6992.20 absolute cell count per ml of blood | Standard Deviation 27388.05 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Total MDSC | 35606.00 absolute cell count per ml of blood | Standard Deviation 26267.93 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Total MDSC | -48321.60 absolute cell count per ml of blood | Standard Deviation 89365.64 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline Granulocytic | 13271.20 absolute cell count per ml of blood | Standard Deviation 24742.36 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 59222.05 absolute cell count per ml of blood | Standard Deviation 85757.8 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Monocytic | 20524.50 absolute cell count per ml of blood | Standard Deviation 16081.57 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change | -38697.55 absolute cell count per ml of blood | Standard Deviation 77519.71 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total-MDSC | 83927.60 absolute cell count per ml of blood | Standard Deviation 96291.84 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Granulocytic | 38759.50 absolute cell count per ml of blood | Standard Deviation 67973.42 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total-MDSC | 213321.11 absolute cell count per ml of blood | Standard Deviation 579434.8 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 45450.33 absolute cell count per ml of blood | Standard Deviation 46641.67 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline Granulocytic | 22575.50 absolute cell count per ml of blood | Standard Deviation 34814.99 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Total MDSC | 146345.39 absolute cell count per ml of blood | Standard Deviation 310850.15 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Granulocytic | 16184.00 absolute cell count per ml of blood | Standard Deviation 46253.09 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change | -26564.33 absolute cell count per ml of blood | Standard Deviation 35958.06 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Total MDSC | -66975.72 absolute cell count per ml of blood | Standard Deviation 283701.53 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Monocytic | 18886.00 absolute cell count per ml of blood | Standard Deviation 18101.69 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Total MDSC | -46294.71 absolute cell count per ml of blood | Standard Deviation 146651.36 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Granulocytic | 43120.00 absolute cell count per ml of blood | Standard Deviation 60999.23 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change- Granulocytic | -33918.71 absolute cell count per ml of blood | Standard Deviation 107087.59 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 15843.29 absolute cell count per ml of blood | Standard Deviation 10160.61 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Monocytic | 16081.57 absolute cell count per ml of blood | Standard Deviation 13631.21 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Change | 238.29 absolute cell count per ml of blood | Standard Deviation 10580.07 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total-MDSC | 138957.43 absolute cell count per ml of blood | Standard Deviation 222790.89 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Decitabine- Total MDSC | 92662.71 absolute cell count per ml of blood | Standard Deviation 100386.82 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline Granulocytic | 77038.71 absolute cell count per ml of blood | Standard Deviation 127561.51 |
Secondary
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 decitabine, and following treatment with decitabine and 2 doses of pembrolizumab.
Time frame: Assessed at baseline, after administration of decitabine, after decitabine and 2 doses of pembrolizumab.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 59222.05 Absolute cell count per ml of blood | Standard Deviation 85757.8 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro-Baseline)- Total MDSC | -9357.85 Absolute cell count per ml of blood | Standard Deviation 82232.7 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro- Baseline)- Monocytic | -36722.10 Absolute cell count per ml of blood | Standard Deviation 72130.68 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Monocytic | 22499.95 Absolute cell count per ml of blood | Standard Deviation 23347.79 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Granulocytic | 13271.20 Absolute cell count per ml of blood | Standard Deviation 24742.36 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Total MDSC | 74569.75 Absolute cell count per ml of blood | Standard Deviation 119875.91 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change(Post Pembro-Baseline) Granulocytic | 19828.20 Absolute cell count per ml of blood | Standard Deviation 81974.04 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Granulocytic | 33099.40 Absolute cell count per ml of blood | Standard Deviation 83017.97 |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total MDSC | 83927.60 Absolute cell count per ml of blood | Standard Deviation 96291.84 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Monocytic | 21651.56 Absolute cell count per ml of blood | Standard Deviation 38761.1 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Granulocytic | 22575.50 Absolute cell count per ml of blood | Standard Deviation 34814.99 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Granulocytic | 25780.33 Absolute cell count per ml of blood | Standard Deviation 34038.45 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change(Post Pembro-Baseline) Granulocytic | 3204.83 Absolute cell count per ml of blood | Standard Deviation 38451.35 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 45450.33 Absolute cell count per ml of blood | Standard Deviation 46641.67 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro- Baseline)- Monocytic | -23798.78 Absolute cell count per ml of blood | Standard Deviation 53965 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total MDSC | 213321.11 Absolute cell count per ml of blood | Standard Deviation 579434.8 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Total MDSC | 78836.72 Absolute cell count per ml of blood | Standard Deviation 89861.88 |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro-Baseline)- Total MDSC | -134484.39 Absolute cell count per ml of blood | Standard Deviation 595746.3 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change(Post Pembro-Baseline) Granulocytic | -13993.43 Absolute cell count per ml of blood | Standard Deviation 136887.63 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Granulocytic | 77038.71 Absolute cell count per ml of blood | Standard Deviation 127561.51 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Total MDSC | 138957.43 Absolute cell count per ml of blood | Standard Deviation 222790.89 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Granulocytic | 63045.29 Absolute cell count per ml of blood | Standard Deviation 87400.02 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro-Baseline)- Total MDSC | -5875.43 Absolute cell count per ml of blood | Standard Deviation 203496.45 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Monocytic | 18028.43 Absolute cell count per ml of blood | Standard Deviation 20787.9 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Baseline- Monocytic | 15843.29 Absolute cell count per ml of blood | Standard Deviation 10160.61 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Post Pembrolizumab- Total MDSC | 133082.00 Absolute cell count per ml of blood | Standard Deviation 91911.07 |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline. | Change (Post Pembro- Baseline)- Monocytic | 2185.14 Absolute cell count per ml of blood | Standard Deviation 21374.82 |
Secondary
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
Time frame: 12 Months following surgery
Population: Patients who did not have surgery due to disease progression or experienced disease progression before undergoing surgery were excluded.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | Had Progression at 12-month after Surgery | 2 Participants |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | No Progression at 12-month after Surgery | 16 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | Had Progression at 12-month after Surgery | 0 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | No Progression at 12-month after Surgery | 16 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | Had Progression at 12-month after Surgery | 0 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab. | No Progression at 12-month after Surgery | 6 Participants |
Secondary
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 frame: Time of study registration until 30 days following the end of administration of decitabine and pembrolizumab, or until another cancer treatment was initiated, or 30 days following surgery, 12- months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab) | 215 Adverse Events Reported |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab) | 151 Adverse Events Reported |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab) | 98 Adverse Events Reported |
Secondary
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.)
Time frame: Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab | 3 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab | 0 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab | 0 Participants |
Secondary
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).
Time frame: End of therapy surgery
Population: All participants in trial either did not have surgery performed, or did not have a suitable biopsy, therefore pathological response could not be assessed for all participants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | 0 (no MRD) | 10 Participants |
| Cohort A: Triple Negative Breast Cancer (TNBC) | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | i (MRD present) | 3 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | 0 (no MRD) | 3 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | i (MRD present) | 2 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | 0 (no MRD) | 1 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen. | i (MRD present) | 1 Participants |
Secondary
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).
Time frame: End of administration of decitabine and pembrolizumab Day- Window of time Days 25-29, or 30 days following surgery
Population: All participants in trial either did not have surgery performed, or did not have a suitable biopsy, therefore pathological response could not be assessed for all participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Number of Patients With Pathologic Complete Response (pCR) in the Breast and Post-therapy Lymph Nodes. | 10 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | Number of Patients With Pathologic Complete Response (pCR) in the Breast and Post-therapy Lymph Nodes. | 3 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | Number of Patients With Pathologic Complete Response (pCR) in the Breast and Post-therapy Lymph Nodes. | 1 Participants |
Secondary
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.
Time frame: End of therapy surgery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | The Number of Patients With Clinical Complete Response (cCR) | cCR=No | 6 Participants |
| Cohort A: Triple Negative Breast Cancer (TNBC) | The Number of Patients With Clinical Complete Response (cCR) | cCR=Yes | 14 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | The Number of Patients With Clinical Complete Response (cCR) | cCR=No | 8 Participants |
| Cohort B: HER2-negative Hormone Receptor-positive Tumors | The Number of Patients With Clinical Complete Response (cCR) | cCR=Yes | 8 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | The Number of Patients With Clinical Complete Response (cCR) | cCR=No | 5 Participants |
| Cohort A2: Triple Negative Breast Cancer (TNBC) With Extended Pembrolizumab | The Number of Patients With Clinical Complete Response (cCR) | cCR=Yes | 2 Participants |