<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/NCT04427293</url>
  </required_header>
  <id_info>
    <org_study_id>2020-0232</org_study_id>
    <nct_id>NCT04427293</nct_id>
  </id_info>
  <brief_title>Preoperative Lenvatinib Plus Pembrolizumab in Early-Stage Triple-Negative Breast Cancer (TNBC)</brief_title>
  <official_title>BRE-03: Window of Opportunity Trial of Preoperative Lenvatinib Plus Pembrolizumab in Early-Stage Triple-Negative Breast Cancer (TNBC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Illinois at Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Illinois at Chicago</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is single arm study of a window of opportunity in which participants with previously&#xD;
      untreated triple negative breast cancers (TNBC) who are candidates for potentially curative&#xD;
      surgery will receive lenvatinib 12 mg daily for 7 and pembrolizumab 200 mg IV on day 1 prior&#xD;
      to surgery&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single arm study of a window of opportunity study in which participants with&#xD;
      previously untreated triple negative breast cancers (TNBC) who are candidates for potentially&#xD;
      curative surgery will receive therapy prior to surgery, consisting of lenvatinib 12 mg daily&#xD;
      for 7 days and pembrolizumab 200 mg IV on day 1. Subjects will either have curative surgery&#xD;
      7-10 days after last dose of lenvatinib, and post-operative adjuvant therapy as per&#xD;
      institution guidelines or have a research core biopsy of the breast tumor 7-10 days after&#xD;
      last dose of lenvatinib, and standard of care neoadjuvant chemotherapy +/_ immune checkpoint&#xD;
      inhibitor therapy, then curative surgery, post-operative adjuvant therapy as per institution&#xD;
      guidelines&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 9, 2020</start_date>
  <completion_date type="Anticipated">July 2026</completion_date>
  <primary_completion_date type="Anticipated">July 2026</primary_completion_date>
  <phase>Phase 1</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>Evaluate the effectiveness of preoperative anti-vascular endothelial growth factor receptor (VEGFR) therapy and immune checkpoint blockade on infiltration of CD8+ tumor infiltrating lymphocytes (TILs) (CD45RA-/CD8+/FoxP3-) in primary tumors from patients</measure>
    <time_frame>2 years</time_frame>
    <description>Measuring the presence of a T-cell inflamed TME, characterized by infiltration of CD8+ TILs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluate clinical response to preoperative anti-VEGFR therapy and immune checkpoint blockade based on pathologic complete response and residual tumor burden in subjects receiving neoadjuvant chemotherapy and changes in the Ki-67 index in all patients.</measure>
    <time_frame>At the point of surgery</time_frame>
    <description>Reviewing pathology report</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate treatment tolerability of preoperative anti-VEGFR therapy and immune checkpoint blockade assessed by failure to completed planned course of neoadjuvant chemo-immune therapy and surgery in patients with early-stage TNBC</measure>
    <time_frame>30 days post treatment</time_frame>
    <description>Assessing for adverse events (e.g., infections) using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Evaluate quality of life in patients with early-stage TNBC treated with preoperative anti-VEGFR therapy and immune checkpoint blockade</measure>
    <time_frame>5 years</time_frame>
    <description>Reviewing questionnaires European Organization for Research, and Treatment of Cancer (EORTC) QLQ-C30 administered at screening, first post-op visit and final visit</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Triple Negative Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Open Label</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will receive lenvatinib 12mg daily for 7 days and pembrolizumab 200 mg IV on day 1 prior to surgery</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib</intervention_name>
    <description>Lenvatinib 12mg daily for 7 days prior to surgery</description>
    <arm_group_label>Open Label</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab 200 mg IV on day 1</description>
    <arm_group_label>Open Label</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years of age at time of consent&#xD;
&#xD;
          2. Histologically confirmed invasive breast carcinoma documented by core needle biopsy or&#xD;
             incisional biopsy (excisional biopsy is not allowed). AJCC 8th edition clinical stage&#xD;
             T1b-T3/N0-N3/M0 by physical exam or radiologic studies&#xD;
&#xD;
          3. Must be candidates for curative surgical resection&#xD;
&#xD;
          4. Have an FFPE diagnostic core biopsy specimen available that is determined by the study&#xD;
             pathologist to be adequate for planned analyses&#xD;
&#xD;
          5. Definitive surgical excision of the primary breast tumor (either partial mastectomy or&#xD;
             total mastectomy) and ipsilateral axillary lymph node sampling (sentinel lymph node&#xD;
             biopsy or axillary dissection) is planned following completion of preoperative&#xD;
             chemotherapy.&#xD;
&#xD;
          6. Estrogen Receptor (ER)- and Progesterone Receptor (PR)-negative as determined by&#xD;
             immunohistochemistry (IHC), and Human Epidermal Growth Factor Receptor (HER)2-negative&#xD;
             (triple-negative) cancer of the breast&#xD;
&#xD;
             Triple-negative tumors are defined as:&#xD;
&#xD;
               -  Less than or equal to 10% of tumor cells staining for ER and for PR by&#xD;
                  immunohistochemistry (IHC)&#xD;
&#xD;
               -  HER2-negative, as defined by ASCO/CAP guidelines55&#xD;
&#xD;
          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 30&#xD;
             days prior to study registration&#xD;
&#xD;
          8. Demonstrate adequate organ function as defined in the table below; all screening labs&#xD;
             to be obtained within 30 days prior to registration Hematological Leukocytes&#xD;
             ≥2,500/mm3 Platelet count ≥ 100,000/mm3 Absolute Neutrophil Count (ANC) ≥ 1,500/mm3&#xD;
             Hemoglobin (Hgb) ≥ 9.0 g/dL Renal Creatinine/Calculated creatinine clearance (CrCl) Cr&#xD;
             &lt; 1.5 x upper limit of normal (ULN) or CrCl ≥ 50 mL/min using the Cockcroft-Gault&#xD;
             formula Hepatic Bilirubin Bilirubin ≤ 1.5 × ULN. Subjects with Gilbert's syndrome may&#xD;
             have a bilirubin &gt; 1.5 × ULN, if no evidence of biliary obstruction exists Aspartate&#xD;
             aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN&#xD;
&#xD;
          9. No evidence of distant metastases (M0 as per AJCC staging guidelines)&#xD;
&#xD;
         10. Provided written informed consent and HIPAA authorization for release of personal&#xD;
             health information, approved by an Institutional Review Board (IRB)&#xD;
&#xD;
         11. NOTE: HIPAA authorization may be included in the informed consent or obtained&#xD;
             separately&#xD;
&#xD;
         12. Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A&#xD;
             negative serum or urine pregnancy test is required within 14 days of study&#xD;
             registration. If the urine test cannot be confirmed as negative, a serum pregnancy&#xD;
             test will be required&#xD;
&#xD;
         13. Women of childbearing potential (WOCP) must be willing to use two effective methods of&#xD;
             birth control such as an oral, implantable, injectable, or transdermal hormonal&#xD;
             contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,&#xD;
             sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total&#xD;
             abstinence for the course of the study until 120 days after the last dose of study&#xD;
             drug NOTE: Women are considered to be of childbearing potential unless they are&#xD;
             postmenopausal (≥45 years of age and has not had menses for greater than 12&#xD;
             consecutive months or bilateral oophorectomy) or surgically sterile (bilateral tubal&#xD;
             ligation or hysterectomy) or not heterosexually active for the duration of the study&#xD;
             and at least 120 days after the last dose of study drug&#xD;
&#xD;
         14. As determined by the enrolling physician or protocol designee, ability of the subject&#xD;
             to understand and comply with study procedures for the entire length of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Active infection requiring systemic therapy&#xD;
&#xD;
          2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the&#xD;
             mother is being treated on study)&#xD;
&#xD;
          3. Previous anti-cancer treatment (cytotoxic chemotherapy, immunotherapy, biologic&#xD;
             therapy, radiotherapy directed towards the primary breast tumor and/or ipsilateral&#xD;
             axillary lymph nodes or investigational agents) with therapeutic intent for the&#xD;
             current breast cancer&#xD;
&#xD;
          4. Previous treatment with lenvatinib or any immune checkpoint inhibitor within the past&#xD;
             2 years&#xD;
&#xD;
          5. Treatment with any investigational drug within 14 days prior to registration or within&#xD;
             5 half-lives of the investigational product, whichever is longer&#xD;
&#xD;
          6. Major surgery within 14 days prior to registration or has not recovered from major&#xD;
             side effects of a major surgery (tumor biopsy and placement of an indwelling venous&#xD;
             access device are not considered major surgery)&#xD;
&#xD;
          7. Any prior or concurrent malignancy whose natural history or treatment has the&#xD;
             potential to interfere with the safety or efficacy assessment of this investigational&#xD;
             regimen, as determined by the treating Medical Oncologist.&#xD;
&#xD;
          8. Known history of AIDS (HIV testing is not mandatory). HIV-positive individuals on&#xD;
             active HARRT therapy with virologic suppression (defined as an HIV-1 RNA level below&#xD;
             the lower limit of detection of the assay used) within 90 days of study enrollment and&#xD;
             a CD4 cell count &gt;500 cells/mm3 on the most recent determination are eligible for the&#xD;
             study&#xD;
&#xD;
          9. . Subjects with any of the following conditions:&#xD;
&#xD;
               -  History of abdominal fistula, gastrointestinal perforation, or intra- abdominal&#xD;
                  abscess within 28 days prior to registration&#xD;
&#xD;
               -  History of cerebrovascular accident (CVA) or transient ischemic attack within 6&#xD;
                  months prior to registration&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction, unstable&#xD;
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or&#xD;
                  symptomatic pericarditis within 6 months prior to registration&#xD;
&#xD;
               -  Symptomatic congestive heart failure (New York Heart Association III-IV) or&#xD;
                  documented current left ventricular (LV) systolic dysfunction with left&#xD;
                  ventricular ejection fraction (LVEF) &lt;50% on most recent assessment of LV&#xD;
                  function&#xD;
&#xD;
               -  Clinically significant cardiac ventricular arrhythmias (e.g. sustained&#xD;
                  ventricular tachycardia/ventricular fibrillation) or high-grade AV block (e.g.&#xD;
                  bifascicular block, Mobitz type II and third-degree AV block) unless a pacemaker&#xD;
                  is in place&#xD;
&#xD;
               -  Any concurrent severe and/or uncontrolled medical condition that would, in the&#xD;
                  investigator's judgment, cause unacceptable safety risks, contraindicate subject&#xD;
                  participation in the clinical study or compromise compliance with the protocol&#xD;
&#xD;
         10. Any condition that, in the opinion of the investigator, might jeopardize the safety of&#xD;
             the patient or interfere with protocol compliance&#xD;
&#xD;
         11. Any mental or medical condition that prevents the patient from giving informed consent&#xD;
             or participating in the trial&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Women</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Oana Danciu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Illinois at Chicago</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Oana Danciu, MD</last_name>
    <phone>312-996-1581</phone>
    <email>ocdanciu@uic.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Prathmika Jha, BS</last_name>
    <phone>312-413-2746</phone>
    <email>pjha7@uic.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Illinois</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Oana Danciu, MD</last_name>
      <phone>312-996-1581</phone>
      <email>ocdanciu@uic.edu</email>
    </contact>
    <contact_backup>
      <last_name>Prathmika Jha, BS</last_name>
      <phone>312-413-2746</phone>
      <email>pjha7@uic.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Illinois at Chicago</investigator_affiliation>
    <investigator_full_name>Oana Danciu</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Lenvatinib</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04427293
org study id: 2020-0232
nct id: NCT04427293
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is single arm study of a window of opportunity in which participants with previously
      untreated triple negative breast cancers (TNBC) who are candidates for potentially curative
      surgery will receive lenvatinib 12 mg daily for 7 and pembrolizumab 200 mg IV on day 1 prior
      to surgery
This is a single arm study of a window of opportunity study in which participants with
      previously untreated triple negative breast cancers (TNBC) who are candidates for potentially
      curative surgery will receive therapy prior to surgery, consisting of lenvatinib 12 mg daily
      for 7 days and pembrolizumab 200 mg IV on day 1. Subjects will either have curative surgery
      7-10 days after last dose of lenvatinib, and post-operative adjuvant therapy as per
      institution guidelines or have a research core biopsy of the breast tumor 7-10 days after
      last dose of lenvatinib, and standard of care neoadjuvant chemotherapy +/_ immune checkpoint
      inhibitor therapy, then curative surgery, post-operative adjuvant therapy as per institution
      guidelines
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Evaluate the effectiveness of preoperative anti-vascular endothelial growth factor receptor (VEGFR) therapy and immune checkpoint blockade on infiltration of CD8+ tumor infiltrating lymphocytes (TILs) (CD45RA-/CD8+/FoxP3-) in primary tumors from patients
time frame: 2 years
description: Measuring the presence of a T-cell inflamed TME, characterized by infiltration of CD8+ TILs
measure: Evaluate clinical response to preoperative anti-VEGFR therapy and immune checkpoint blockade based on pathologic complete response and residual tumor burden in subjects receiving neoadjuvant chemotherapy and changes in the Ki-67 index in all patients.
time frame: At the point of surgery
description: Reviewing pathology report
measure: Evaluate treatment tolerability of preoperative anti-VEGFR therapy and immune checkpoint blockade assessed by failure to completed planned course of neoadjuvant chemo-immune therapy and surgery in patients with early-stage TNBC
time frame: 30 days post treatment
description: Assessing for adverse events (e.g., infections) using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5
measure: Evaluate quality of life in patients with early-stage TNBC treated with preoperative anti-VEGFR therapy and immune checkpoint blockade
time frame: 5 years
description: Reviewing questionnaires European Organization for Research, and Treatment of Cancer (EORTC) QLQ-C30 administered at screening, first post-op visit and final visit
arm group label: Open Label
arm group type: Experimental
description: All participants will receive lenvatinib 12mg daily for 7 days and pembrolizumab 200 mg IV on day 1 prior to surgery
intervention type: Drug
intervention name: Lenvatinib
description: Lenvatinib 12mg daily for 7 days prior to surgery
arm group label: Open Label
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab 200 mg IV on day 1
arm group label: Open Label
criteria: 
gender: Female
gender based: Yes
gender description: Women
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Oana Danciu, MD
role: Principal Investigator
affiliation: University of Illinois at Chicago
last name: Oana Danciu, MD
phone: 312-996-1581
email: ocdanciu@uic.edu
last name: Prathmika Jha, BS
phone: 312-413-2746
email: pjha7@uic.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Illinois at Chicago
investigator full name: Oana Danciu
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Pembrolizumab
mesh term: Lenvatinib