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

NCT ID: NCT02957968

Last Updated: 2025-08-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-24
• Study Completion Date: 2026-03-31

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.

Conditions

Breast Adenocarcinoma; Estrogen Receptor- Negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive Tumor; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Triple-negative Breast Carcinoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Doxorubicin

Intervention Type: DRUG

60 mg/m2 once every 2 weeks for 4 cycles.

Cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.

Paclitaxel

Intervention Type: DRUG

Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.

Carboplatin

Intervention Type: DRUG

carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.

Decitabine

Intervention Type: DRUG

Given IV

Pembrolizumab

Intervention Type: DRUG

Given IV

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.

Group Type: EXPERIMENTAL

Doxorubicin

Intervention Type: DRUG

60 mg/m2 once every 2 weeks for 4 cycles.

Cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.

Paclitaxel

Intervention Type: DRUG

Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.

Decitabine

Intervention Type: DRUG

Given IV

Pembrolizumab

Intervention Type: DRUG

Given IV

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.

Group Type: EXPERIMENTAL

Doxorubicin

Intervention Type: DRUG

60 mg/m2 once every 2 weeks for 4 cycles.

Cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.

Paclitaxel

Intervention Type: DRUG

Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.

Carboplatin

Intervention Type: DRUG

carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.

Decitabine

Intervention Type: DRUG

Given IV

Pembrolizumab

Intervention Type: DRUG

Given IV

Interventions

Doxorubicin

60 mg/m2 once every 2 weeks for 4 cycles.

Intervention Type: DRUG

Cyclophosphamide

cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.

Intervention Type: DRUG

Paclitaxel

Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.

Intervention Type: DRUG

Carboplatin

carboplatin IV 1.5 area under curve (AUC) once weekly for 12 weeks.

Intervention Type: DRUG

Decitabine

Given IV

Intervention Type: DRUG

Pembrolizumab

Given IV

Intervention Type: DRUG

Other Intervention Names

Adriamycin; Rubex; Cytoxan; Neosar; Taxol; Onxol; Abraxane; Paraplatin; Dacogen; Deoxyazacytidine; Dezocitidine; Keytruda; Lambrolizumab

Eligibility Criteria

Inclusion Criteria

• Invasive adenocarcinoma of the breast diagnosed by core needle biopsy
• Breast cancer determined to be HER2-negative per current American Society of Clinical Oncologists/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) Guidelines (If IHC was performed, IHC 0 or 1+; if fluorescence in situ hybridization (FISH) or other in situ hybridization test, dual probe HER2/Chromosome 17 Centromere (CEP17) ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell)
• Breast cancer determined to be hormone receptor-positive or hormone receptor-negative defined as follows:

• Hormone receptor-positive: ≥ 10% staining by IHC for either estrogen receptor (ER) or progesterone receptor (PgR)
• Hormone receptor-negative: < 10% staining by IHC for both ER and PgR
• Locally advanced breast cancer defined as any of the following per American Joint Committee on Cancer (AJCC) Staging Criteria:

• T2 based on tumor measurements by physical examination or imaging and with clinically positive regional lymph nodes (cN1 or cN2), irrespective of hormone receptor status
• Hormone receptor-negative breast cancer patients with tumor size of 3-5 cm measured by physical examination or imaging with clinically negative regional lymph nodes (cN0)
• Any T3 based on tumor measurements by physical examination or imaging
• Any T4 (including inflammatory breast cancer), irrespective of hormone receptor status
• Ipsilateral axillary lymph nodes must be evaluated by MRI or ultrasound within 12 weeks prior to study registration to determine clinical nodal status. If imaging is suspicious or abnormal, a fine needle aspiration (FNA) or core biopsy of the questionable node(s) on imaging is required. Nodal status should be classified according to the following criteria:

• Nodal status - negative

• Imaging of the axilla is negative; OR
• Imaging of the axilla is suspicious or abnormal AND FNA or core biopsy is negative.
• Nodal status - positive

• FNA or core biopsy of node(s) is cytologically or histologically suspicious or positive
• Breast imaging performed prior to study registration as follows:
• Ipsilateral breast - within 12 weeks
• Contralateral breast - within 24 weeks
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate bone marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Hemoglobin ≥ 10.0 g/dL
• Adequate renal function as defined below:
• Serum creatinine ≤ upper limit of normal (ULN) for the lab or a calculated creatinine clearance ≥ 60 mL/min
• Adequate hepatic function as defined below:

• Total bilirubin ≤ ULN for the laboratory
• Aspartate aminotransferase (AST) ≤ 1.5 x ULN for the laboratory
• Alanine aminotransferase (ALT) ≤ 1.5 x ULN for the laboratory
• Alkaline phosphatase (ALP) ≤ 2.5 x ULN for the laboratory Note: If ALP is > 1.5 x ULN, imaging to rule out bone and liver metastasis is required.
• Left ventricular ejection fraction (LVEF) assessment (ie, 2-D echocardiogram or multigated acquisition (MUGA) scan) performed within 12 weeks prior to study registration indicates an LVEF ≥ 50% regardless of the cardiac imaging facility's lower limit of normal
• Women who are not postmenopausal or have not undergone hysterectomy must have a documented negative serum pregnancy test within 72 hours prior to initiating study treatment.

Note: Postmenopausal is defined as any of the following:

• Age ≥ 60 years
• Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range
• Bilateral oophorectomy

• A female patient who is a woman of child-bearing potential (WCBP) and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of immunotherapy and neoadjuvant chemotherapy and until after completion of breast surgery or, for patients who do not receive neoadjuvant chemotherapy, for a minimum of 6 months following the last dose of pembrolizumab or decitabine
• Ability to understand and willingness to sign the consent form

Exclusion Criteria

• Breast cancer treatment for the currently diagnosed breast cancer including radiation therapy, chemotherapy, targeted therapy, or endocrine therapy prior to study registration
• Administration of a live vaccine within 30 days prior to initiating study treatment Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are permitted; however, intranasal influenza vaccines (eg, Flu-Mist) are live attenuated vaccines, and are not allowed.
• Administration of a monoclonal antibody within 4 weeks prior to initiating study treatment or has not recovered (ie, ≤ grade 1 or at baseline) from adverse events (AEs) due to a monoclonal antibody administered more than 4 weeks earlier
• Administration of any investigational agent within 4 weeks prior to initiating study treatment
• Evidence of metastatic disease that is extensive enough to preclude consideration of subsequent definitive surgery for the primary tumor
• History of ipsilateral invasive breast cancer or ipsilateral ductal carcinoma in situ (DCIS) Note: Patients with history of ipsilateral lobular carcinoma in situ (LCIS) are eligible.
• History of solid organ or allogeneic stem cell transplant
• Previous therapy for any malignancy with an anthracycline or taxane for Cohorts A and B and carboplatin for Cohort A
• Cardiac disease that would preclude administration of the drugs included in the study treatment regimen including, but not limited to:

• Angina pectoris that requires the current use of anti-anginal medication
• Ventricular arrhythmias except for benign premature ventricular contractions
• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
• Conduction abnormality requiring a pacemaker
• Valvular disease with documented compromise in cardiac function; and symptomatic pericarditis
• Nervous system disorder (ie, paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ grade 2, per CTCAE v5.0
• Administration of or condition requiring administration of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating study treatment Exception: Patients with conditions that can be managed with steroids equivalent to or less than an oral prednisone dose of 10 mg daily would not be excluded from the study.
• Previous therapy for this cancer with an anti-anti-programmed death-1 (PD-1), anti-PD-L1, anti-PD-L2 agent, or any other immunomodulatory agent
• Known or presumed hypersensitivity to decitabine or pembrolizumab (or any of their excipients)
• Diagnosed immunodeficiency, eg, human immunodeficiency virus (HIV)
• Active autoimmune disease requiring systemic treatment within the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents Note: Patients with the conditions or medical history listed below are NOT excluded from this study.

• Vitiligo
• Resolved childhood asthma/atopy
• Requirement for intermittent use of bronchodilators or local steroid injections or topical steroids
• Hypothyroidism stable on hormone replacement
• Sjogren's Syndrome
• Known history or evidence of interstitial lung disease or active, non-infectious pneumonitis
• Known history of active bacillus tuberculosis (TB)
• Active infection requiring systemic therapy
• Known active Hepatitis B or C
• Pregnancy or breastfeeding
• Diagnosis or treatment for another malignancy within 5 years prior to study registration, with the following exceptions: complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, and low-risk prostate cancer after curative therapy
• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Virginia Commonwealth University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Harry D. Bear, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Massey Cancer Center

Locations

St. Elizabeth Healthcare

Edgewood, Kentucky, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 40021215 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

NCI-2016-01980

Identifier Type: REGISTRY

Identifier Source: secondary_id

P30CA016059

Identifier Type: NIH

Identifier Source: secondary_id

View Link

MCC-15-11083

Identifier Type: -

Identifier Source: org_study_id