Clinical Trials /

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

NCT02957968

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadj Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
  • 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

Clinical Trial IDs

  • ORG STUDY ID: MCC-15-11083
  • SECONDARY ID: NCI-2016-01980
  • NCT ID: NCT02957968

Conditions

  • Locally Advanced Breast Cancer
  • Invasive Adenocarcinoma of the Breast
  • Breast Cancer Stage II
  • Breast Cancer Stage III
  • Breast Cancer Stage IV

Interventions

DrugSynonymsArms
DoxorubicinAdriamycin, RubexCohort A: Triple Negative Breast Cancer (TNBC)
CyclophosphamideCytoxan, NeosarCohort A: Triple Negative Breast Cancer (TNBC)
PaclitaxelTaxol, OnxalCohort A: Triple Negative Breast Cancer (TNBC)
CarboplatinParaplatinCohort A: Triple Negative Breast Cancer (TNBC)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort A: Triple Negative Breast Cancer (TNBC)ExperimentalBoth 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 doxorubicin and cyclophosphamide (AC) followed by 12 doses of weekly paclitaxel. Paclitaxel will be combined with carboplatin for Cohort A, TNBC.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Carboplatin
Cohort B: HER2-negative hormone receptor-positive tumorsExperimentalBoth 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 doxorubicin and cyclophosphamide (AC) followed by 12 doses of weekly paclitaxel. Paclitaxel without carboplatin for patients in Cohort B, HER2-negative hormone receptor-positive tumors.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel

    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) 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 (ie, ≥ 1% estrogen receptor [ER] and/or progesterone receptor [PgR] staining by IHC) or hormone receptor-negative (ie, < 1% ER and PgR staining by IHC)

    - Locally advanced breast cancer defined as any of the following per American Joint Committee on Cancer (AJCC) Staging Criteria:

    - T2 with clinically positive regional lymph nodes (cN1 or cN2)

    - Any T3

    - Any T4 (including inflammatory breast cancer)

    - Ipsilateral axillary lymph nodes must be evaluated by MRI within 12 weeks prior to study registration to determine clinical nodal status. If imaging is suspicious or abnormal, an 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) ≤ 1.5 x ULN for the laboratory Note: If AST, ALT, and/or ALP are > 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 4 months following the last dose of pembrolizumab

    - 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 agents 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.

    - 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 v4.0

    - 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

    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Measure:Percentage of patients meeting criteria for LPBC following treatment with decitabine and pembrolizumab compared to the percentage before treatment.
    Time Frame:26 days
    Safety Issue:
    Description: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.)
    Measure:Proportion of patients with pCR in the breast and post-therapy lymph nodes.
    Time Frame:30 days after surgery
    Safety Issue:
    Description: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).
    Measure:Proportion of patients with no or minimal residual disease in the resected breast and axillary specimen.
    Time Frame:7 months
    Safety Issue:
    Description: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.
    Measure:The proportion of patients with cCR
    Time Frame:7 months
    Safety Issue:
    Description: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.
    Measure:Enumeration of T cells and immune cell subsets
    Time Frame:26 days
    Safety Issue:
    Description: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.
    Measure:Evaluation of expression of PD-L1 within tumor, stroma, and infiltrating immune cells at baseline and following immunotherapy.
    Time Frame:36 days
    Safety Issue:
    Description:To evaluate the correlation of pre-existing and post-immunotherapy immune response signatures with response to neoadjuvant chemotherapy.
    Measure:Correlation of intensity of PD-L1 expression by assay as it relates to pCR rates from chemotherapy.
    Time Frame:30 days after surgery
    Safety Issue:
    Description:QualTek Molecular Laboratories will use tumor samples for proprietary PD-L1 staining.
    Measure: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
    Safety Issue:
    Description:To evaluate the level of circulating MDSC at baseline, following treatment with decitabine alone, and following treatment with pembrolizumab administered after decitabine.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Virginia Commonwealth University

    Trial Keywords

    • Breast Cancer
    • Invasive adenocarcinoma
    • HER2-negative

    Last Updated

    December 19, 2016