<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/NCT03237572</url>
  </required_header>
  <id_info>
    <org_study_id>19900</org_study_id>
    <nct_id>NCT03237572</nct_id>
  </id_info>
  <brief_title>Focused Ultrasound and Pembrolizumab in Metastatic Breast Cancer</brief_title>
  <acronym>Breast-48</acronym>
  <official_title>Focused Ultrasound Therapy to Augment Antigen Presentation and Immune-Specificity of Checkpoint Inhibitor Therapy With Pembrolizumab in Metastatic Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Patrick Dillon, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Virginia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot study evaluates the use of high-intensity focused ultrasound (HIFU) combined with&#xD;
      pembrolizumab in patients with metastatic breast cancer. One-half of participants will be&#xD;
      randomized to receive the first dose of pembrolizumab after HIFU and one-half of participants&#xD;
      will be randomized to receive their first dose of pembrolizumab before HIFU.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low rate of enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">September 25, 2017</start_date>
  <completion_date type="Actual">June 17, 2022</completion_date>
  <primary_completion_date type="Actual">June 1, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Pilot, 2-arm randomized study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in tumor infiltrating lymphocytes</measure>
    <time_frame>baseline and week 4</time_frame>
    <description>Change in proportion of CD8+ tumor infiltrating lymphocytes (ration CD8+/CD4+) in the primary ablation zone</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse event profile of pembrolizumab and HIFU</measure>
    <time_frame>From date of randomization through 30 days following cessation of treatment</time_frame>
    <description>Toxicities from the combination of pembrolizumab and HIFU</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A: 1st dose of pembrolizumab after HIFU</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab (200 mg) administered intravenously, days 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: 1st dose of pembrolizumab before HIFU</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab (200 mg) intravenously, days 1, 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab (200 mg)</description>
    <arm_group_label>Arm A: 1st dose of pembrolizumab after HIFU</arm_group_label>
    <arm_group_label>Arm B: 1st dose of pembrolizumab before HIFU</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>High-intensity focused ultrasound (HIFU)</intervention_name>
    <description>Ablation will target 50% of the tumor, up to 3 cubic centimeters</description>
    <arm_group_label>Arm A: 1st dose of pembrolizumab after HIFU</arm_group_label>
    <arm_group_label>Arm B: 1st dose of pembrolizumab before HIFU</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria (summary):&#xD;
&#xD;
          -  Histologically confirmed metastatic or unresectable breast cancer&#xD;
&#xD;
          -  Any receptor status (estrogen receptor, progesterone receptor, HER2 receptor).&#xD;
             Patients who are HR+ should also no longer be candidates for hormonal-based therapy.&#xD;
             Patients who are HER2+ should have progressed on or no longer be candidates for&#xD;
             available HER2 directed therapy. Hormonal therapy must be stopped prior to day 1 of&#xD;
             treatment.&#xD;
&#xD;
          -  Patients must have had at least one prior line of therapy for breast cancer in the&#xD;
             metastatic setting.&#xD;
&#xD;
          -  Patients must have an accessible lesion in the breast/chest wall/axilla which has not&#xD;
             been previously thermally ablated. Prior breast irradiation is acceptable if the&#xD;
             lesion has recurred or grown following radiation.&#xD;
&#xD;
          -  Patients must agree to use an adequate method of contraception for the course of the&#xD;
             study through 120 days after the last dose of study medication.&#xD;
&#xD;
          -  Patients must have at least one target lesion in breast/chest wall/axilla which is&#xD;
             amenable to application of high intensity focused ultrasound:&#xD;
&#xD;
          -  Patients must be willing to provide tissue from a newly obtained core or excisional&#xD;
             biopsy of a tumor lesion.&#xD;
&#xD;
          -  Performance status of 0 or 1 on the ECOG Performance Scale.&#xD;
&#xD;
          -  Adequate organ function&#xD;
&#xD;
        Exclusion Criteria (summary):&#xD;
&#xD;
          -  Patients currently participating and receiving study therapy or patients who have&#xD;
             participated in a study of an investigational agent and received study therapy or used&#xD;
             an investigational device within 4 weeks of the first dose of treatment.&#xD;
&#xD;
          -  Patients with a diagnosis of immunodeficiency, patients receiving systemic steroid&#xD;
             therapy or, patients who have received any other form of immunosuppressive therapy&#xD;
             within 7 days prior to the first dose of trial treatment.&#xD;
&#xD;
          -  Patients with a known history of active Tuberculosis&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients&#xD;
&#xD;
          -  Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1.&#xD;
             Patients who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier are excluded.&#xD;
&#xD;
          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2&#xD;
             weeks prior to study Day 1. Patients who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent.&#xD;
&#xD;
          -  Known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in the past 2 years.&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis.&#xD;
&#xD;
          -  Active infection requiring systemic therapy.&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent within the prior 24&#xD;
             weeks.&#xD;
&#xD;
          -  Known history of Human Immunodeficiency Virus (HIV)&#xD;
&#xD;
          -  Receipt of a live vaccine within 30 days of planned start of study therapy.&#xD;
&#xD;
          -  HIFU must not be applied to a breast with an implant. A region outside of the breast&#xD;
             may be targeted as long as the targeted area is at least 10mm away from an implant.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Patrick Dillon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Virginia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>July 31, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>September 7, 2022</last_update_submitted>
  <last_update_submitted_qc>September 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Virginia</investigator_affiliation>
    <investigator_full_name>Patrick Dillon, MD</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>breast cancer</keyword>
  <keyword>pembrolizumab</keyword>
  <keyword>focused ultrasound</keyword>
  <keyword>immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 15, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03237572/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03237572
org study id: 19900
nct id: NCT03237572
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is unapproved device: Yes
This pilot study evaluates the use of high-intensity focused ultrasound (HIFU) combined with
      pembrolizumab in patients with metastatic breast cancer. One-half of participants will be
      randomized to receive the first dose of pembrolizumab after HIFU and one-half of participants
      will be randomized to receive their first dose of pembrolizumab before HIFU.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Pilot, 2-arm randomized study
primary purpose: Treatment
masking: None (Open Label)
measure: Change in tumor infiltrating lymphocytes
time frame: baseline and week 4
description: Change in proportion of CD8+ tumor infiltrating lymphocytes (ration CD8+/CD4+) in the primary ablation zone
measure: Adverse event profile of pembrolizumab and HIFU
time frame: From date of randomization through 30 days following cessation of treatment
description: Toxicities from the combination of pembrolizumab and HIFU
arm group label: Arm A: 1st dose of pembrolizumab after HIFU
arm group type: Experimental
description: Pembrolizumab (200 mg) administered intravenously, days 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters.
arm group label: Arm B: 1st dose of pembrolizumab before HIFU
arm group type: Experimental
description: Pembrolizumab (200 mg) intravenously, days 1, 22, 43, 64, followed by day 1 of each ensuing 3 -week cycle. Focused ultrasound tumor ablation day 15. High-intensity focused ultrasound ablation will target 50% of the tumor, up to 3 cubic centimeters.
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab (200 mg)
arm group label: Arm A: 1st dose of pembrolizumab after HIFU
arm group label: Arm B: 1st dose of pembrolizumab before HIFU
other name: Keytruda
intervention type: Device
intervention name: High-intensity focused ultrasound (HIFU)
description: Ablation will target 50% of the tumor, up to 3 cubic centimeters
arm group label: Arm A: 1st dose of pembrolizumab after HIFU
arm group label: Arm B: 1st dose of pembrolizumab before HIFU
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Patrick Dillon, MD
role: Principal Investigator
affiliation: University of Virginia
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Virginia
investigator full name: Patrick Dillon, MD
investigator title: Associate Professor
mesh term: Breast Neoplasms
mesh term: Pembrolizumab
provided document: 