Breast AdenocarcinomaPhase 2NCT02957968
Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
A Phase 2 study testing Doxorubicin, Cyclophosphamide and Paclitaxel in people with Breast Adenocarcinoma and Estrogen Receptor- Negative Breast Cancer, run by Virginia Commonwealth University at 4 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Adenocarcinoma, Estrogen Receptor- Negative Breast Cancer, Estrogen Receptor-positive Breast Cancer
- What is being tested?
- Doxorubicin, Cyclophosphamide and Paclitaxel
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 46 participants
- Where
- 4 sitesUnited States
- Study dates
- 24 Jan 2017to 31 Mar 2027
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
4 sites in 1 country.
United States4 sites
University of Virginia
Charlottesville, Virginia, 22903
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
St. Elizabeth Healthcare
Edgewood, Kentucky, 41017
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, 23298
About this study
Official title: 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
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)
Read the 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.
- Conditions
- Breast Adenocarcinoma, Estrogen Receptor- Negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2/Neu Negative, Invasive Breast Carcinoma, Progesterone Receptor Negative
- Being tested
- Doxorubicin, Cyclophosphamide, Paclitaxel, Carboplatin, Decitabine
- Keywords
- Breast Cancer
- Medical subject headings
- Breast Neoplasms, Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DoxorubicinDrug
Also called Adriamycin, Rubex
60 mg/m2 once every 2 weeks for 4 cycles.
CyclophosphamideDrug
Also called Cytoxan, Neosar
cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
PaclitaxelDrug
Also called Taxol, Onxol, Abraxane
Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
CarboplatinDrug
Also called Paraplatin
carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.
DecitabineDrug
Also called Dacogen, Deoxyazacytidine, Dezocitidine
Given IV
PembrolizumabDrug
Also called Keytruda, Lambrolizumab
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Experimental | 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. Receives: Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Carboplatin; Drug: Decitabine; Drug: Pembrolizumab |
| Cohort B: HER2-negative hormone receptor-positive tumors | Experimental | 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. Receives: Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Decitabine; Drug: Pembrolizumab |
| Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab | Experimental | 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. Receives: Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Carboplatin; Drug: Decitabine; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (12)
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.
Measured: 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.
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.)
Measured: 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).
Measured: End of administration of decitabine and pembrolizumab Day- Window of time Days 25-29, or 30 days following surgery
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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29
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.
Measured: 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)
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.
Measured: Baseline biopsy (BX1) prior to therapy, EOT surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab
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.
Measured: Assessed at end of administration of decitabine compared to assessment at baseline prior to protocol treatments.
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.
Measured: Assessed at baseline, after administration of decitabine, after decitabine and 2 doses of pembrolizumab.
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
Measured: 12 Months following surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2016 (estimated)
- Study start24 Jan 2017
- Primary completion4 Aug 2022
- Study completion31 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast AdenocarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Virginia Commonwealth University
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Harry D. Bear, M.D., Ph.D., Principal investigator, Massey Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02957968
- Sponsor's protocol ID
- MCC-15-11083
- Other IDs
- NCI-2016-01980, P30CA016059
- Status last verified
- Jun 2026
- First submitted
- 3 Nov 2016
- Last updated
- 1 Jul 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Bear HD, Deng X, Bandyopadhyay D, Idowu M, Jenkins TM, Kmieciak M, Williams M, Archer G, Gwaltney L, Dillon P, Flora D, Stover D, Poklepovic AS, Hackney M, Ross M, Vachhani H, Louie R, McGuire KP, Grover A, Rahman T, Hendrix A. T-cell immune checkpoint inhibition plus hypomethylation for locally advanced HER2-negative breast cancer: a phase 2 neoadjuvant window trial of decitabine and pembrolizumab followed by standard neoadjuvant chemotherapy. J Immunother Cancer. 2025 Feb 27;13(2):e010294. doi: 10.1136/jitc-2024-010294.
PubMed 40021215
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02957968
- Acronym / sponsor ID
- MCC-15-11083
- Conditions
- Breast Adenocarcinoma, Estrogen Receptor- Negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2/Neu Negative, Invasive Breast Carcinoma, Progesterone Receptor Negative
- Keywords
- Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Virginia Commonwealth UniversityUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, National Cancer Institute (NCI)
- Study start
- 24 Jan 2017 (actual)
- Primary completion
- 4 Aug 2022 (actual)
- Study completion
- 31 Mar 2027 (estimated)
- First posted
- 8 Nov 2016 (estimated)
- Results
- Posted 9 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort A: Triple Negative Breast Cancer (TNBC) | Experimental | Drug: Doxorubicin, Drug: Cyclophosphamide, Drug: Paclitaxel, Drug: Carboplatin, Drug: Decitabine, Drug: PembrolizumabTriple 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. |
| Cohort B: HER2-negative hormone receptor-positive tumors | Experimental | Drug: Doxorubicin, Drug: Cyclophosphamide, Drug: Paclitaxel, Drug: Decitabine, Drug: PembrolizumabHER2-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. |
| Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab | Experimental | Drug: Doxorubicin, Drug: Cyclophosphamide, Drug: Paclitaxel, Drug: Carboplatin, Drug: Decitabine, Drug: PembrolizumabTriple 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (40 listed)
- 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:
- Locally advanced breast cancer defined as any of the following per American Joint Committee on Cancer (AJCC) Staging Criteria:
- 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:
Key exclusion criteria (32 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DoxorubicinAlso: Adriamycin, Rubex60 mg/m2 once every 2 weeks for 4 cycles. | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC), Cohort B: HER2-negative hormone receptor-positive tumors |
| CyclophosphamideAlso: Cytoxan, Neosarcyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles. | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC), Cohort B: HER2-negative hormone receptor-positive tumors |
| PaclitaxelAlso: Taxol, Onxol, AbraxanePaclitaxel 80 mg/m2 IV once weekly for 12 weeks. | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC), Cohort B: HER2-negative hormone receptor-positive tumors |
| CarboplatinAlso: Paraplatincarboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks. | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC) |
| DecitabineAlso: Dacogen, Deoxyazacytidine, DezocitidineGiven IV | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC), Cohort B: HER2-negative hormone receptor-positive tumors |
| PembrolizumabAlso: Keytruda, LambrolizumabGiven IV | Drug | Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab, Cohort A: Triple Negative Breast Cancer (TNBC), Cohort B: HER2-negative hormone receptor-positive tumors |
Primary outcome
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.
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
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.
12 secondary outcomes
Number of Adverse Events (AEs) Reported During and After Immune Treatment (ie, Decitabine and Pembrolizumab)
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.
Number of Patients Meeting Criteria for Lymphocyte-predominant Breast Cancer (LPBC) Following Treatment With Decitabine and Pembrolizumab
Time frame: 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.
Time frame: End of administration of decitabine and pembrolizumab Day- Window of time Days 25-29, or 30 days following surgery
Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen.
Time frame: End of therapy surgery
The Number of Patients With Clinical Complete Response (cCR)
Time frame: End of therapy surgery
Enumeration of T Cells and Immune Cell Subsets
Time frame: 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.
Time frame: Assessed at end of administration of decitabine and pembrolizumab Day- Window of time Days 25-29
Change of Intensity of Programmed Death-Ligand 1 (PD-L1) Expression by Assay as it Relates to Pathologic Complete Response (pCR) Rates From Chemotherapy
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)
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.
Time frame: Baseline biopsy (BX1) prior to therapy, EOT surgery 2nd core biopsy (BX2) 3-7 days following last dose of pre-chemotherapy pembrolizumab
Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-decitabine Compared to MDSC Found in Blood Samples Collected at Baseline.
Time frame: Assessed at end of administration of decitabine compared to assessment at baseline prior to protocol treatments.
Evaluation of Myeloid-derived Suppressor Cells (MDSC) Identified in Blood Samples Post-pembrolizumab Compared to MDSC Found in Blood Samples Collected at Baseline.
Time frame: Assessed at baseline, after administration of decitabine, after decitabine and 2 doses of pembrolizumab.
Event Free Survival (EFS) Rate at 12 Months Following the Last Dose of Pembrolizumab.
Time frame: 12 Months following surgery
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 40021215Bear HD, Deng X, Bandyopadhyay D, Idowu M, Jenkins TM, Kmieciak M, Williams M, Archer G, Gwaltney L, Dillon P, Flora D, Stover D, Poklepovic AS, Hackney M, Ross M, Vachhani H, Louie R, McGuire KP, Grover A, Rahman T, Hendrix A. T-cell immune checkpoint inhibition plus hypomethylation for locally advanced HER2-negative breast cancer: a phase 2 neoadjuvant window trial of decitabine and pembrolizumab followed by standard neoadjuvant chemotherapy. J Immunother Cancer. 2025 Feb 27;13(2):e010294. doi: 10.1136/jitc-2024-010294.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Harry D. Bear, M.D., Ph.D. principal investigator
Massey Cancer Center
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Doxorubicin, Cyclophosphamide and Paclitaxel in people with Breast Adenocarcinoma and Estrogen Receptor- Negative Breast Cancer, run by Virginia Commonwealth University at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 40 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 1 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Nov 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02957968, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2026.