<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03289819</url>
  </required_header>
  <id_info>
    <org_study_id>IFG-NIB-01</org_study_id>
    <secondary_id>2016-003102-14</secondary_id>
    <secondary_id>U1111-1188-3915</secondary_id>
    <nct_id>NCT03289819</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Pembrolizumab(Pbr)/Nab-Paclitaxel Followed by Pbr/Epirubicin/Cyclophosphamide in TNBC</brief_title>
  <acronym>NIB</acronym>
  <official_title>A Phase II One-arm Open-label Neoadjuvant Study of Pembrolizumab in Combination With Nab-paclitaxel Followed by Pembrolizumab in Combination With Epirubicin and Cyclophosphamide in Patients With Triple Negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut fuer Frauengesundheit</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Celgene Corporation</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut fuer Frauengesundheit</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite its aggressiveness and high incidence, to date, no targeted therapies exist for the&#xD;
      treatment of triple negative breast cancer (TNBC). Emerging evidence suggests a crucial role&#xD;
      of tumor immunology on outcome for this entity. Checkpoint inhibitors like pembrolizumab,&#xD;
      which target immune cells within the tumor, might therefore have an important impact on&#xD;
      therapy response and outcome in these high risk patients. We propose a phase II study&#xD;
      exploring pathological complete response and the safety of the combination of pembrolizumab&#xD;
      and nab-paclitaxel as well as the combination of pembrolizumab with epirubicin and&#xD;
      cyclophosphamide in the neoadjuvant setting for women with early TNBC. After completion of&#xD;
      this study an extension will be determined.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter, phase II, one-arm, open-label neoadjuvant study of pembrolizumab in&#xD;
      combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and&#xD;
      cyclophosphamide (E/C) in patients with TNBC. Pathological complete response rate at the time&#xD;
      of surgery is the primary objective of this study.&#xD;
&#xD;
      In approximately six large breast cancer centers in Germany 50 patients are planned to be&#xD;
      enrolled. All patients will undergo state of the art staging and tumor assessments prior to&#xD;
      study entry to assess eligibility for the present trial. Eligible and consented patients will&#xD;
      receive 12 cycles of weekly nab-paclitaxel i.v. 125 mg/m² BSA q1w in combination with 4&#xD;
      cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA&#xD;
      and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles pembrolizumab i.v.&#xD;
      200 mg q3w. After the 25th patient has started trial treatment, all further included patients&#xD;
      will receive 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy followed by 12 cycles of&#xD;
      weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination&#xD;
      with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90&#xD;
      mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of&#xD;
      pembrolizumab i.v. 200 mg q3w. Clinical and bioptic tumor assessment will be performed after&#xD;
      each treatment phase. Additional imaging, preferably with sonography, will be performed 6&#xD;
      weeks after initiation of taxane and anthracycline therapy to allow for early progress and&#xD;
      response monitoring.&#xD;
&#xD;
      Study treatment will be applied until state of the art surgery, onset of unacceptable&#xD;
      toxicities, progression or withdrawal of consent. A safety follow-up is planned 120 days&#xD;
      after administration of the last dose of trial treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 23, 2018</start_date>
  <completion_date type="Actual">January 22, 2021</completion_date>
  <primary_completion_date type="Actual">August 27, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pathological Complete Response (pCR) rate</measure>
    <time_frame>Pathological complete response will be assessed at final surgery for patients who received at least two cycles of Pembrolizumab. The rate will be assessed from 30 days until 120 days after last application of medication.</time_frame>
    <description>Pathological complete response (pCR) rate, defined as the complete absence of all tumor cells (ypT0/ypN0), absence of invasive tumor (ypT0/is ypN0) and regression grades after study treatment. Pathological complete response is the primary endpoint of this trial and correlates especially well with disease-free survival and overall survival in patients with TNBC. Pathological complete response also serves as a surrogate marker for prognosis in TNBC</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</measure>
    <time_frame>The adverse events will be assessed from first infusion until 120 days after last application of medication.</time_frame>
    <description>The safety endpoints for the study will include rate of AE/SAEs and fatal SAEs, causality and outcome of AE/SAEs, rate of treatment discontinuations and reasons, changes in vital signs, laboratory values etc. Grading of AE/SAEs will be based on NCI CTCAE v4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response</measure>
    <time_frame>Every 6 weeks from date of first medication administration until the date of first documented progression, surgery or date of death from any cause, whichever came first, assessed up to 120 days after last dose.</time_frame>
    <description>To evaluate the efficacy of the treatment as measured by clinical response (objective response rate by 30 %) 6 weeks after the start of each sequential chemotherapy (nab-paclitaxel and E/C) and at the time of the surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ-BR23</measure>
    <time_frame>Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.</time_frame>
    <description>To evaluate changes in health related quality of life (QoL) assessments from baseline in all subjects using the EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ-C30</measure>
    <time_frame>Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.</time_frame>
    <description>To evaluate changes in health related quality of life (QoL) assessments from baseline in all subjects using Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Tumor infiltrating lymphocytes (TILs)</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Tumor microenvironment prior to and during study treatment. TILs (stroma and intratumoral) in percent as assessed in Denkert et al. 2015, JCO.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunohistochemistry</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>PD1 (Programmed cell death protein 1), PD-L1 (Programmed death-ligand 1), SPARC (Secreted protein acidic and rich in cysteine), Caveolin-1, TIM-3 (T-cell immunoglobulin mucin-3), Lag-3 (Lymphocyte-activation gene 3) will be assessed via immunohistochemistry in percentage of stained cells to total cell count and assesment of immunoreactive score (IRS) for each marker.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor Immunogenicity</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Tumor immunogenicity characteristic measured via FACS of the following markers (CD45, CD3, CD4, CD8, CD14, CD19, CD25, CD56, CD127, CD197, HLA-DR, CD45RA, Ki67) in percent of positive cells to total cell count.</description>
  </other_outcome>
  <other_outcome>
    <measure>Mutational load</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Mutational load assessed by Next Generation Sequencing of Germline- and Tumor-DNA in mutations per megabases</description>
  </other_outcome>
  <other_outcome>
    <measure>Neoepitope Detection</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Amount of tumor neoepitopes assessed by Next Generation Sequencing comparing Germline- and Tumor-DNA. Neoepitopes are defined as mutations that lead to aminoacid changes and are found in tumor DNA only.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cell-free RNA (cfRNA)</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Expression levels of specific tumor- and immune-related analytes in cfRNA will be measured by qPCR and possibly other methods and analyzed for correlations with subject outcomes.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immune Status</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Peripheral Blood Mononuclear Cells will be collected from whole peripheral blood and sorted into subsets of T cells and myeloid cells by flow cytometry and then subjected to transcriptomic profilling by deep sequencing.</description>
  </other_outcome>
  <other_outcome>
    <measure>Circulation Metabolites</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Circulating metabolites of host and bacterial metabolites will be assessed in plasma using a multiplex 43-panel ELISA assay.</description>
  </other_outcome>
  <other_outcome>
    <measure>Microbial burden</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Viral, bacterial, fungal, helminth and parasite microbial burden will be assessed by Shotgun Deep Sequencing of cell-free RNA and DNA fragments in plasma.</description>
  </other_outcome>
  <other_outcome>
    <measure>Microbiome</measure>
    <time_frame>Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.</time_frame>
    <description>Stool microbiome will be assessed by Shotgun Deep Sequencing and analyzed for correlations with clinical outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>pCR rate after initiation boost</measure>
    <time_frame>Pathological complete response will be assessed at final surgery for patients who received at least two cycles of Pembrolizumab. The rate will be assessed from 30 days until 120 days after last application of medication.</time_frame>
    <description>To compare pCR rate in patients receiving a combination of pembrolizumab with nab-paclitaxel and epirubicin/cyclophosphamide chemotherapy and patients receiving 1 cycle of pembrolizumab monotherapy during an initiation boost followed by a combination of pembrolizumab with nab-paclitaxel and epirubicin/cyclophosphamide chemotherapy</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">53</enrollment>
  <condition>Malignant Neoplasm of Breast</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab/Nab-Paclitaxel</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a phase II, one-arm, open label neoadjuvant study of pembrolizumab in combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and cyclophosphamide in patients with triple negative breast cancer.&#xD;
All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.&#xD;
After the 25th patient has started trial treatment, all further included patients will receive 1 additional cycle of pembrolizumab i.v. 200 mg q3w monotherapy before starting regular trial treatment.&#xD;
Clinical and bioptic tumor assessment will be performed after each treatment phase. Study treatment will be applied until state of the art surgery, onset of unacceptable toxicities, progression or withdrawal of consent.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w. After the 25th patient has started trial treatment, all further included patients will receive 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy followed by 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w.</description>
    <arm_group_label>Pembrolizumab/Nab-Paclitaxel</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>MK-3475</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nab-paclitaxel</intervention_name>
    <description>All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.</description>
    <arm_group_label>Pembrolizumab/Nab-Paclitaxel</arm_group_label>
    <other_name>nano-particle albumin bound (NAB) paclitaxel</other_name>
    <other_name>Abraxane</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epirubicin</intervention_name>
    <description>All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.</description>
    <arm_group_label>Pembrolizumab/Nab-Paclitaxel</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.</description>
    <arm_group_label>Pembrolizumab/Nab-Paclitaxel</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent prior to beginning of trial specific procedures.&#xD;
&#xD;
          2. Subject must be female and aged ≥ 18 years on day of signing informed consent.&#xD;
&#xD;
          3. ECOG(Eastern Cooperative Oncology Group) 0-1&#xD;
&#xD;
          4. Histologically confirmed, early TNBC determined by core biopsy of breast tumor lesion.&#xD;
             ER and PR negativity are defined as ≤ 1% of cells expressing hormonal receptors via&#xD;
             IHC (immuno-histochemistry) analysis. HER2(human epidermal growth factor receptor 2)&#xD;
             negativity is defined as either of the following by local laboratory assessment: In&#xD;
             situ hybridization (ISH) non-amplified (ratio ≤ 2.2), or IHC 0 or IHC 1+.&#xD;
&#xD;
          5. Measurable tumor lesion with a size of ≥ 1 cm assessed by sonography or magnetic&#xD;
             resonance imaging (MRI) within ≤ 21 days prior to entry. In case of inflammatory&#xD;
             disease the extent of inflammation will be measured.&#xD;
&#xD;
          6. Indication for chemotherapy.&#xD;
&#xD;
          7. Multicentric and/or multifocal disease, as well as synchronous bilateral breast&#xD;
             cancer, is eligible as long as one measurable lesion meets all inclusion criteria. The&#xD;
             investigator has to determine which lesion will be used for tumor evaluation before&#xD;
             initiation of treatment.&#xD;
&#xD;
          8. Complete staging work up within 8 weeks prior to entry with no evidence of distant&#xD;
             disease, including bilateral mammography, breast ultrasound, chest-X-ray (or chest&#xD;
             CT-scan), liver ultrasound (or liver CT-scan or liver MRI) and bone scan.&#xD;
&#xD;
          9. Subjects must provide a core biopsy from tumor lesion at 3 time points (before, after&#xD;
             first phase of treatment and at surgery) for central confirmation of TNBC status and&#xD;
             biomarker analyses.&#xD;
&#xD;
         10. Adequate organ function, defined as:&#xD;
&#xD;
             Absolute neutrophil count (ANC)≥ 1.5 x10³/μl, Hemoglobin ≥ 10.0 g/dl OR ≥ 6.2 mmol/l,&#xD;
             Platelets ≥ 100 x10³/μl, Creatinine ≤ 1.5 x ULN OR GFR ≥ 30 ml/min, Total bilirubin ≤&#xD;
             1.5 x ULN, AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN, Alkaline phosphatase ≤ 2.5 x ULN,&#xD;
             International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN, Activated&#xD;
             partial thromboplastin time (aPTT) ≤ 1.5 x ULN,&#xD;
&#xD;
         11. Female subjects of childbearing potential must have a negative urine pregnancy test&#xD;
             within 72 hours prior to study entry and be willing to use an adequate method of&#xD;
             contraception for the course of the study through 120 days after the last dose of&#xD;
             study medication. Abstinence is acceptable if this is the usual lifestyle and&#xD;
             preferred contraception for the subject.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Concurrent participation in a study with an investigational agent/device or within 14&#xD;
             days of study entry.&#xD;
&#xD;
          2. Prior chemotherapy, radiation therapy or small molecule therapy for any reason.&#xD;
&#xD;
          3. Previous malignant disease being disease-free for less than 3 years (except in situ&#xD;
             carcinoma of the cervix and basal cell carcinoma of the skin).&#xD;
&#xD;
          4. Pregnancy or lactation.&#xD;
&#xD;
          5. Prior therapy with an anti-PD1, anti-PD L1, anti-PD-L2 agent or with an agent directed&#xD;
             to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).&#xD;
&#xD;
          6. Active infection requiring systemic therapy.&#xD;
&#xD;
          7. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.&#xD;
&#xD;
          8. Active autoimmune disease or other diseases that requires systemic treatment with&#xD;
             corticosteroids or immunosuppressive drugs (physiologic corticosteroid replacement&#xD;
             therapy for adrenal or pituitary insufficiency is allowed).&#xD;
&#xD;
          9. History of primary or acquired immunodeficiency (including allogenic organ&#xD;
             transplant).&#xD;
&#xD;
         10. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,&#xD;
             ulcerative colitis).&#xD;
&#xD;
         11. Known history of following infections:&#xD;
&#xD;
               1. Human immunodeficiency virus (HIV)&#xD;
&#xD;
               2. History of acute or chronic Hepatitis B or Hepatitis C&#xD;
&#xD;
               3. Has received a live-virus vaccination within 30 days of planned treatment start.&#xD;
                  Seasonal flu vaccines that do not contain live virus are permitted&#xD;
&#xD;
         12. Known congestive heart failure &gt;NYHA I (New York Heart Association) and/or coronary&#xD;
             heart disease, angina pectoris, previous history of myocardial infarction,&#xD;
             uncontrolled or poorly controlled arterial hypertension (e.g. blood pressure &gt;160/90&#xD;
             mmHg under treatment with two or more antihypertensive drugs), rhythm disorders with&#xD;
             clinically significant valvular heart disease.&#xD;
&#xD;
         13. Preexisting motor or sensory neuropathy of a severity grade ≥ 2 by NCI CTCAE v4.0.&#xD;
&#xD;
         14. Known, pathogenic BRCA (breast cancer susceptibility gene) mutation. Note: testing is&#xD;
             not mandatory for trial participation.&#xD;
&#xD;
         15. Any other condition in opinion of the investigator that would interfere with applied&#xD;
             systemic treatment or other trial procedures.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter A Fasching, MD, Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Gynecology and Obstetrics, Erlangen University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Gynecology, Tübingen University Hospital</name>
      <address>
        <city>Tübingen</city>
        <state>Baden-Württemberg</state>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Gynecology and Obstetrics, Erlangen University Hospital</name>
      <address>
        <city>Erlangen</city>
        <state>Bavaria</state>
        <zip>91054</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department for Gynecology and Obstetrics, Marienhospital Bottrop gGmbH</name>
      <address>
        <city>Bottrop</city>
        <state>North Rhine-Westphalia</state>
        <zip>46236</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Gynecology and Obstetrics, HELIOS Hospital Berlin Buch GmbH</name>
      <address>
        <city>Berlin</city>
        <zip>13125</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>October 11, 2016</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <last_update_submitted>April 3, 2021</last_update_submitted>
  <last_update_submitted_qc>April 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>TNBC</keyword>
  <keyword>neoadjuvant chemotherapy</keyword>
  <keyword>triple negative breast cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Albumin-Bound Paclitaxel</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Epirubicin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 9, 2021</submitted>
    <returned>January 7, 2022</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03289819
org study id: IFG-NIB-01
secondary id: 2016-003102-14
secondary id: U1111-1188-3915
nct id: NCT03289819
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Despite its aggressiveness and high incidence, to date, no targeted therapies exist for the
      treatment of triple negative breast cancer (TNBC). Emerging evidence suggests a crucial role
      of tumor immunology on outcome for this entity. Checkpoint inhibitors like pembrolizumab,
      which target immune cells within the tumor, might therefore have an important impact on
      therapy response and outcome in these high risk patients. We propose a phase II study
      exploring pathological complete response and the safety of the combination of pembrolizumab
      and nab-paclitaxel as well as the combination of pembrolizumab with epirubicin and
      cyclophosphamide in the neoadjuvant setting for women with early TNBC. After completion of
      this study an extension will be determined.
This is a multicenter, phase II, one-arm, open-label neoadjuvant study of pembrolizumab in
      combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and
      cyclophosphamide (E/C) in patients with TNBC. Pathological complete response rate at the time
      of surgery is the primary objective of this study.

      In approximately six large breast cancer centers in Germany 50 patients are planned to be
      enrolled. All patients will undergo state of the art staging and tumor assessments prior to
      study entry to assess eligibility for the present trial. Eligible and consented patients will
      receive 12 cycles of weekly nab-paclitaxel i.v. 125 mg/m² BSA q1w in combination with 4
      cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA
      and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles pembrolizumab i.v.
      200 mg q3w. After the 25th patient has started trial treatment, all further included patients
      will receive 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy followed by 12 cycles of
      weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination
      with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90
      mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of
      pembrolizumab i.v. 200 mg q3w. Clinical and bioptic tumor assessment will be performed after
      each treatment phase. Additional imaging, preferably with sonography, will be performed 6
      weeks after initiation of taxane and anthracycline therapy to allow for early progress and
      response monitoring.

      Study treatment will be applied until state of the art surgery, onset of unacceptable
      toxicities, progression or withdrawal of consent. A safety follow-up is planned 120 days
      after administration of the last dose of trial treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pathological Complete Response (pCR) rate
time frame: Pathological complete response will be assessed at final surgery for patients who received at least two cycles of Pembrolizumab. The rate will be assessed from 30 days until 120 days after last application of medication.
description: Pathological complete response (pCR) rate, defined as the complete absence of all tumor cells (ypT0/ypN0), absence of invasive tumor (ypT0/is ypN0) and regression grades after study treatment. Pathological complete response is the primary endpoint of this trial and correlates especially well with disease-free survival and overall survival in patients with TNBC. Pathological complete response also serves as a surrogate marker for prognosis in TNBC
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
time frame: The adverse events will be assessed from first infusion until 120 days after last application of medication.
description: The safety endpoints for the study will include rate of AE/SAEs and fatal SAEs, causality and outcome of AE/SAEs, rate of treatment discontinuations and reasons, changes in vital signs, laboratory values etc. Grading of AE/SAEs will be based on NCI CTCAE v4.0.
measure: Clinical Response
time frame: Every 6 weeks from date of first medication administration until the date of first documented progression, surgery or date of death from any cause, whichever came first, assessed up to 120 days after last dose.
description: To evaluate the efficacy of the treatment as measured by clinical response (objective response rate by 30 %) 6 weeks after the start of each sequential chemotherapy (nab-paclitaxel and E/C) and at the time of the surgery
measure: EORTC QLQ-BR23
time frame: Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.
description: To evaluate changes in health related quality of life (QoL) assessments from baseline in all subjects using the EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23)
measure: EORTC QLQ-C30
time frame: Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.
description: To evaluate changes in health related quality of life (QoL) assessments from baseline in all subjects using Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
measure: Tumor infiltrating lymphocytes (TILs)
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Tumor microenvironment prior to and during study treatment. TILs (stroma and intratumoral) in percent as assessed in Denkert et al. 2015, JCO.
measure: Immunohistochemistry
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: PD1 (Programmed cell death protein 1), PD-L1 (Programmed death-ligand 1), SPARC (Secreted protein acidic and rich in cysteine), Caveolin-1, TIM-3 (T-cell immunoglobulin mucin-3), Lag-3 (Lymphocyte-activation gene 3) will be assessed via immunohistochemistry in percentage of stained cells to total cell count and assesment of immunoreactive score (IRS) for each marker.
measure: Tumor Immunogenicity
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Tumor immunogenicity characteristic measured via FACS of the following markers (CD45, CD3, CD4, CD8, CD14, CD19, CD25, CD56, CD127, CD197, HLA-DR, CD45RA, Ki67) in percent of positive cells to total cell count.
measure: Mutational load
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Mutational load assessed by Next Generation Sequencing of Germline- and Tumor-DNA in mutations per megabases
measure: Neoepitope Detection
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Amount of tumor neoepitopes assessed by Next Generation Sequencing comparing Germline- and Tumor-DNA. Neoepitopes are defined as mutations that lead to aminoacid changes and are found in tumor DNA only.
measure: Cell-free RNA (cfRNA)
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Expression levels of specific tumor- and immune-related analytes in cfRNA will be measured by qPCR and possibly other methods and analyzed for correlations with subject outcomes.
measure: Immune Status
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Peripheral Blood Mononuclear Cells will be collected from whole peripheral blood and sorted into subsets of T cells and myeloid cells by flow cytometry and then subjected to transcriptomic profilling by deep sequencing.
measure: Circulation Metabolites
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Circulating metabolites of host and bacterial metabolites will be assessed in plasma using a multiplex 43-panel ELISA assay.
measure: Microbial burden
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Viral, bacterial, fungal, helminth and parasite microbial burden will be assessed by Shotgun Deep Sequencing of cell-free RNA and DNA fragments in plasma.
measure: Microbiome
time frame: Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.
description: Stool microbiome will be assessed by Shotgun Deep Sequencing and analyzed for correlations with clinical outcome.
measure: pCR rate after initiation boost
time frame: Pathological complete response will be assessed at final surgery for patients who received at least two cycles of Pembrolizumab. The rate will be assessed from 30 days until 120 days after last application of medication.
description: To compare pCR rate in patients receiving a combination of pembrolizumab with nab-paclitaxel and epirubicin/cyclophosphamide chemotherapy and patients receiving 1 cycle of pembrolizumab monotherapy during an initiation boost followed by a combination of pembrolizumab with nab-paclitaxel and epirubicin/cyclophosphamide chemotherapy
arm group label: Pembrolizumab/Nab-Paclitaxel
arm group type: Experimental
description: This is a phase II, one-arm, open label neoadjuvant study of pembrolizumab in combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and cyclophosphamide in patients with triple negative breast cancer.
All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.
After the 25th patient has started trial treatment, all further included patients will receive 1 additional cycle of pembrolizumab i.v. 200 mg q3w monotherapy before starting regular trial treatment.
Clinical and bioptic tumor assessment will be performed after each treatment phase. Study treatment will be applied until state of the art surgery, onset of unacceptable toxicities, progression or withdrawal of consent.
intervention type: Drug
intervention name: Pembrolizumab
description: All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w. After the 25th patient has started trial treatment, all further included patients will receive 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy followed by 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w.
arm group label: Pembrolizumab/Nab-Paclitaxel
other name: Keytruda
other name: MK-3475
intervention type: Drug
intervention name: nab-paclitaxel
description: All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.
arm group label: Pembrolizumab/Nab-Paclitaxel
other name: nano-particle albumin bound (NAB) paclitaxel
other name: Abraxane
intervention type: Drug
intervention name: Epirubicin
description: All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.
arm group label: Pembrolizumab/Nab-Paclitaxel
intervention type: Drug
intervention name: Cyclophosphamide
description: All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.
arm group label: Pembrolizumab/Nab-Paclitaxel
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Peter A Fasching, MD, Prof.
role: Study Chair
affiliation: Department of Gynecology and Obstetrics, Erlangen University Hospital
facility: 
facility: 
facility: 
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Breast Neoplasms
mesh term: Paclitaxel
mesh term: Albumin-Bound Paclitaxel
mesh term: Cyclophosphamide
mesh term: Pembrolizumab
mesh term: Epirubicin
sharing ipd: No
submitted: December 9, 2021
returned: January 7, 2022