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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02957968
Recruitment Status : Recruiting
First Posted : November 8, 2016
Last Update Posted : August 20, 2020
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Tracking Information
First Submitted Date  ICMJE November 3, 2016
First Posted Date  ICMJE November 8, 2016
Last Update Posted Date August 20, 2020
Actual Study Start Date  ICMJE January 24, 2017
Estimated Primary Completion Date February 28, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
Increase in percent of tumor and stroma with infiltrating lymphocytes from baseline pre-treatment biopsy to post-immunotherapy biopsy following administration of decitabine followed by pembrolizumab. [ Time Frame: 29 days ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 3, 2016)
  • Percent of tumor and stroma with infiltrating lymphocytes from baseline pre-treatment biopsy to post-immunotherapy biopsy following administration of decitabine followed by pembrolizumab. [ Time Frame: 26 days ]
    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.
  • All adverse events (AEs) reported during and after immune treatment (ie, decitabine and pembrolizumab) [ Time Frame: 30 days after surgery ]
    To evaluate the safety and toxicity of sequential decitabine plus pembrolizumab followed by dose-dense AC, weekly paclitaxel (or paclitaxel plus carboplatin) administered as neoadjuvant therapy. Using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0), all adverse events (AEs) reported during and after immune treatment (ie, decitabine and pembrolizumab), serious adverse events (SAEs) and unanticipated problems (UPs) reported during neoadjuvant chemotherapy (ie, dose-dense AC, weekly paclitaxel plus carboplatin for patients in Cohort A [or paclitaxel without carboplatin for patients in Cohort B]), and UPs reported during and within 30 days after surgery.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • All adverse events (AEs) reported during and after immune treatment (ie, decitabine and pembrolizumab) [ Time Frame: 30 days after surgery ]
    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, 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.
  • Percentage of patients meeting criteria for lymphocyte-predominant breast cancer (LPBC) following treatment with decitabine and pembrolizumab compared to the percentage before treatment. [ Time Frame: 26 days ]
    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.)
  • Proportion of patients with pathologic complete response (pCR) in the breast and post-therapy lymph nodes. [ Time Frame: 30 days after surgery ]
    To determine the rate of pCR in the breast and lymph nodes (pCR breast and nodes). The proportion 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).
  • Proportion of patients with no or minimal residual disease in the resected breast and axillary specimen. [ Time Frame: 7 months ]
    To determine the rate of Residual Cancer Burden (RCB) Index value of 0-1 following all neoadjuvant therapy. The proportion of patients with no or minimal residual disease in the resected breast and axillary specimen defined as RCB Index value 0 or 1.
  • The proportion of patients with clinical complete response (cCR) [ Time Frame: 7 months ]
    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 [ Time Frame: 26 days ]
    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 CD8+ cytotoxic T cells, CD4+ helper T cells, FOXP3+ regulatory T Cells, 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 PD-L1 within tumor, stroma, and infiltrating immune cells at baseline and following immunotherapy. [ Time Frame: 36 days ]
    To evaluate the correlation of pre-existing and post-immunotherapy immune response signatures with response to neoadjuvant chemotherapy.
  • Correlation of intensity of PD-L1 expression by assay as it relates to pCR rates from chemotherapy. [ Time Frame: 30 days after surgery ]
    QualTek Molecular Laboratories will use tumor samples for proprietary PD-L1 staining.
  • Evaluation of myeloid-derived suppressor cells (MDSC) identified in blood samples post-decitabine and post-pembrolizumab compared to MDSC found in blood samples collected at baseline. [ Time Frame: 36 days ]
    To evaluate the level of circulating MDSC at baseline, following treatment with decitabine alone, and following treatment with pembrolizumab administered after decitabine.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 3, 2016)
  • Percentage of patients meeting criteria for LPBC following treatment with decitabine and pembrolizumab compared to the percentage before treatment. [ Time Frame: 26 days ]
    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.)
  • Proportion of patients with pCR in the breast and post-therapy lymph nodes. [ Time Frame: 30 days after surgery ]
    To determine the rate of pCR in the breast and lymph nodes (pCR breast and nodes). The proportion 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).
  • Proportion of patients with no or minimal residual disease in the resected breast and axillary specimen. [ Time Frame: 7 months ]
    To determine the rate of Residual Cancer Burden (RCB) Index value of 0-1 following all neoadjuvant therapy. The proportion of patients with no or minimal residual disease in the resected breast and axillary specimen defined as RCB Index value 0 or 1.
  • The proportion of patients with cCR [ Time Frame: 7 months ]
    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 [ Time Frame: 26 days ]
    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 CD8+ cytotoxic T cells, CD4+ helper T cells, FOXP3+ regulatory T Cells, 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 PD-L1 within tumor, stroma, and infiltrating immune cells at baseline and following immunotherapy. [ Time Frame: 36 days ]
    To evaluate the correlation of pre-existing and post-immunotherapy immune response signatures with response to neoadjuvant chemotherapy.
  • Correlation of intensity of PD-L1 expression by assay as it relates to pCR rates from chemotherapy. [ Time Frame: 30 days after surgery ]
    QualTek Molecular Laboratories will use tumor samples for proprietary PD-L1 staining.
  • Evaluation of MDSC identified in blood samples post-decitabine and post-pembrolizumab compared to MDSC found in blood samples collected at baseline. [ Time Frame: 36 days ]
    To evaluate the level of circulating MDSC at baseline, following treatment with decitabine alone, and following treatment with pembrolizumab administered after decitabine.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
Official Title  ICMJE 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
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. Efficacy will be evaluated in 2 cohorts based on hormone receptor status.
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 dose-dense AC followed by 12 doses of weekly paclitaxel. Paclitaxel will be combined with carboplatin for Cohort A (TNBC). The primary safety objective will be to evaluate the safety and toxicity of sequential decitabine plus pembrolizumab followed by dose-dense AC, weekly paclitaxel (or paclitaxel plus carboplatin) administered as neoadjuvant therapy. If the breast tumor is resectable following completion of all protocol therapy, breast-conserving surgery or mastectomy and axillary surgical staging (either sentinel node biopsy and/or axillary dissection) will be performed.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Adenocarcinoma
  • Estrogen Receptor- Negative Breast Cancer
  • Estrogen Receptor-positive Breast Cancer
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Progesterone Receptor Negative
  • Progesterone Receptor Positive Tumor
  • Stage II Breast Cancer
  • Stage IIA Breast Cancer
  • Stage IIB Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Triple-negative Breast Carcinoma
Intervention  ICMJE
  • Drug: Doxorubicin
    60 mg/m2 once every 2 weeks for 4 cycles.
    Other Names:
    • Adriamycin
    • Rubex
  • Drug: Cyclophosphamide
    cyclophosphamide 600 mg/m2 (AC) once every 2 weeks for 4 cycles.
    Other Names:
    • Cytoxan
    • Neosar
  • Drug: Paclitaxel
    Paclitaxel 80 mg/m2 IV once weekly for 12 weeks.
    Other Names:
    • Taxol
    • Onxal
    • Abraxane
  • Drug: Carboplatin
    carboplatin AUC 1.5 once weekly for 12 weeks.
    Other Name: Paraplatin
  • Drug: Decitabine
    Given IV
    Other Names:
    • Dacogen
    • Deoxyazacytidine
    • Dezocitidine
  • Drug: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
Study Arms  ICMJE
  • Experimental: 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.
    Interventions:
    • Drug: Doxorubicin
    • Drug: Cyclophosphamide
    • Drug: Paclitaxel
    • Drug: Carboplatin
    • Drug: Decitabine
    • Drug: Pembrolizumab
  • Experimental: 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.
    Interventions:
    • Drug: Doxorubicin
    • Drug: Cyclophosphamide
    • Drug: Paclitaxel
    • Drug: Decitabine
    • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 12, 2019)
32
Original Estimated Enrollment  ICMJE
 (submitted: November 3, 2016)
50
Estimated Study Completion Date  ICMJE February 28, 2023
Estimated Primary Completion Date February 28, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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) 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/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 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 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.
  • LVEF assessment (ie, 2-D echocardiogram or 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 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-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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katherine Thompson, RN 804-628-0960 masseysiit@vcu.edu
Contact: Harry D. Bear, M.D., Ph.D. 804-828-9325 harry.bear@vcuhealth.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02957968
Other Study ID Numbers  ICMJE MCC-15-11083
NCI-2016-01980 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016059 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Virginia Commonwealth University
Study Sponsor  ICMJE Virginia Commonwealth University
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Harry D. Bear, M.D., Ph.D. Massey Cancer Center
PRS Account Virginia Commonwealth University
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP