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

NCT02957968 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 3 other identifiers: MCC-15-11083NCI-2016-01980P30CA016059
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 4

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)

Conditions

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

Keywords

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• The Percentage of Increase in Tumor and Stroma With Infiltrating Lymphocytes (TIL) From Baseline Pre-treatment Biopsy to Post-immunotherapy Biopsy Following Administration of Decitabine Followed by Pembrolizumab.

  To determine and quantify if treatment with neoadjuvant decitabine followed by pembrolizumab increases lymphocyte infiltration into tumor and/or stroma in patients with locally advanced, HER2-negative breast cancer.

  Baseline pre-treatment biopsy to post-immunotherapy biopsy following administration of decitabine followed by pembrolizumab, 3-7 day window after Day 22 medication administration, about one month

Secondary Outcomes (12)

• 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.

• 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

• 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

• Number of Patients With no or Minimal Residual Disease in the Resected Breast and Axillary Specimen.

  End of therapy surgery

• The Number of Patients With Clinical Complete Response (cCR)

  End of therapy surgery

Study Arms (3)

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.

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.

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.

Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Carboplatin; Drug: Decitabine; Drug: Pembrolizumab

Interventions

Doxorubicin DRUG

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

Also known as: Adriamycin, Rubex

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

Cyclophosphamide DRUG

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

Also known as: Cytoxan, Neosar

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

Paclitaxel DRUG

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

Also known as: Taxol, Onxol, Abraxane

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

Carboplatin DRUG

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

Also known as: Paraplatin

Cohort A2: Triple Negative Breast Cancer (TNBC) with Extended Pembrolizumab; Cohort A: Triple Negative Breast Cancer (TNBC)

Decitabine DRUG

Given IV

Also known as: Dacogen, Deoxyazacytidine, Dezocitidine

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

Pembrolizumab DRUG

Given IV

Also known as: Keytruda, Lambrolizumab

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Virginia Commonwealth University: lead
• Merck Sharp & Dohme LLC: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (4)

St. Elizabeth Healthcare

Edgewood, Kentucky, 41017, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

Related Publications (1)

• 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.

  PMID: 40021215 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

Doxorubicin; Cyclophosphamide; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Decitabine; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Coordination Complexes; Azacitidine; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Limitations and Caveats

Adequate paired biopsy specimens for Tumor and Stroma With Infiltrating Lymphocytes (TIL) and protein Programmed Death-Ligand 1 (PD-L1) analysis were not obtained for all of the enrolled and treated patients due to insufficient tissue amounts.

Results Point of Contact

• Title: Massey CTO Breast Team
• Organization: Virginia Commonwealth University Massey Cancer Center

masseyctbrst@vcu.edu

804-628-6430

Study Officials

• Harry D. Bear, M.D., Ph.D.

  Massey Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2016
• First Posted: November 8, 2016
• Study Start: January 24, 2017
• Primary Completion: August 4, 2022
• Study Completion (Estimated): March 31, 2027
• Last Updated: April 21, 2026
• Results First Posted: November 9, 2023

Record last verified: 2026-03

Locations

US (4)