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 Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant 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
  • SECONDARY ID: P30CA016059
  • NCT ID: NCT02957968

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

Interventions

DrugSynonymsArms
DoxorubicinAdriamycin, RubexCohort A: Triple Negative Breast Cancer (TNBC)
CyclophosphamideCytoxan, NeosarCohort A: Triple Negative Breast Cancer (TNBC)
PaclitaxelTaxol, Onxal, AbraxaneCohort A: Triple Negative Breast Cancer (TNBC)
CarboplatinParaplatinCohort A: Triple Negative Breast Cancer (TNBC)
DecitabineDacogen, Deoxyazacytidine, DezocitidineCohort A: Triple Negative Breast Cancer (TNBC)
PembrolizumabKeytruda, LambrolizumabCohort 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)ExperimentalTriple 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.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Carboplatin
  • Decitabine
  • Pembrolizumab
Cohort B: HER2-negative hormone receptor-positive tumorsExperimentalHER2-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.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Decitabine
  • Pembrolizumab

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

Primary Outcome Measures

Measure: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
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:All adverse events (AEs) reported during and after immune treatment (ie, decitabine and pembrolizumab)
Time Frame:30 days after surgery
Safety Issue:
Description: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.
Measure: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
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 pathologic complete response (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 clinical complete response (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 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
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:Recruiting
Lead Sponsor:Virginia Commonwealth University

Trial Keywords

  • Breast Cancer

Last Updated

March 2, 2021