<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/NCT02250118</url>
  </required_header>
  <id_info>
    <org_study_id>IC 2014-02</org_study_id>
    <secondary_id>2014-000654-11</secondary_id>
    <nct_id>NCT02250118</nct_id>
  </id_info>
  <brief_title>Intrapleural Bevacizumab After Pleural Drainage in the Context of Breast Cancer</brief_title>
  <acronym>BEVAP</acronym>
  <official_title>Phase I Study to Determine the Maximum Tolerated Dose and Evaluate the Pharmacokinetics of Intrapleural Bevacizumab After Pleural Drainage in Patients With Symptomatic Malignant Pleural Effusion in the Context of Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Curie</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Henri Mondor University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut Curie</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Metastatic pleural effusion is a common complication of late-stage cancer and reduces the&#xD;
      quality of life and survival of patients. The survival of patients with recurrent pleurisy by&#xD;
      uncontrolled local or systemic treatment is less than 6 months. It is important to develop&#xD;
      specific therapies to improve the quality of life and survival of patients with metastatic&#xD;
      pleurisy.&#xD;
&#xD;
      Bevacizumab is a monoclonal anti vascular endothelial growth factor (VEGF) which has proven&#xD;
      effective in many indications in oncology. Vascular endothelial growth factor (VEGF) is an&#xD;
      angiogenic factor which increases endothelial permeability. It plays a central role in many&#xD;
      tumors of epithelial origin. In this context, it is legitimate to ask whether an&#xD;
      antiangiogenic targeting VEGF may be effective in patients with metastatic pleurisy by&#xD;
      decreasing local blood supply and over-permeability.&#xD;
&#xD;
      No study has been interested in the intra-pleural pharmacokinetics of monoclonal antibodies&#xD;
      and there are no predictive or prognostic biomarkers for metastatic pleural effusions.&#xD;
&#xD;
      The investigators believe that intrapleural administration of bevacizumab will reduce the&#xD;
      pleural vasculature permeability. It will neutralize VEGF present in pleural fluid and reduce&#xD;
      the replenishment of effusion due to its prolonged half-life of 21 days.&#xD;
&#xD;
      The investigators therefore propose a phase I study to determine the maximum tolerated dose&#xD;
      and the recommended dose for phases II, studying the pharmacokinetics of intrapleural&#xD;
      bevacizumab administered by an implantable device after evacuating a symptomatic metastatic&#xD;
      pleurisy as part of a mammary carcinoma. The VEGF intrapleural levels and serum will be study&#xD;
      and the time until a new puncture. Dyspnea will be evaluated as well as its impact on quality&#xD;
      of life.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Insufficient Recruitment&#xD;
  </why_stopped>
  <start_date type="Actual">December 9, 2014</start_date>
  <completion_date type="Actual">October 17, 2017</completion_date>
  <primary_completion_date type="Actual">April 12, 2017</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>To determine the maximum tolerated dose (MTD)</measure>
    <time_frame>90 days after intrapleural injection</time_frame>
    <description>Maximum tolerated dose (MTD) according to safety of intrapleural bevacizumab at dose levels of 1 mg/kg, 3 mg/kg and 5 mg/kg administered by pleural catheter after drainage of symptomatic malignant pleural effusion in a context of breast cancer.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Study of the pleural and serum pharmacokinetics</measure>
    <time_frame>90 days</time_frame>
    <description>Pharmacokinetics of bevacizumab just before administration and 1 hour after treatment on Day 1, and at D15, D30, D60 and D90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study of pleural and serum Vascular Endothelial Growth Factor (VEGF) levels</measure>
    <time_frame>90 days</time_frame>
    <description>Pleural and serum VEGF levels just before administration and 1 hour after treatment on Day 1, and at D15, D30, D60 and D90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of time until new punction or death</measure>
    <time_frame>2 years</time_frame>
    <description>Response to treatment assessed by the time to new puncture</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of pleural drainage procedures</measure>
    <time_frame>90 days</time_frame>
    <description>Measure of the total number of pleural drainage procedures at D15, D30, D60 and D90.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Drainage-free survival and overall survival</measure>
    <time_frame>2 years</time_frame>
    <description>Drainage-free survival and overall survival Evaluation of survival without punction and overall survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of dyspnoea</measure>
    <time_frame>90 days</time_frame>
    <description>Measure by dyspnoea scale and peak flow at D15, D30, D60 and D90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of quality of life</measure>
    <time_frame>2 years</time_frame>
    <description>Quality of life (QLQ-C30) questionnaire according to European Organisation for Research and Treatment of Cancer (EORTC) and FACIT questionnaire Dyspnoea 10 Short Form at D15, D30, D60 and D90 and every 6 month during 2 years</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Pleural Effusion, Malignant</condition>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Bevacizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intrapleural use: range 0.5 - 5 mg/kg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Intrapleural Bevacizumab</description>
    <arm_group_label>Bevacizumab</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient with histologically documented pleural effusion in a type of breast carcinoma&#xD;
             in exudate or with no other identified cause. In the absence of positive cytology,&#xD;
             will ensure that there is no other cause of the patient's history may explain the&#xD;
             effusion.&#xD;
&#xD;
          2. Unilateral or bilateral malignant pleural effusion but requiring drainage on only one&#xD;
             side.&#xD;
&#xD;
          3. Patient presenting an indication for pleural implantable device, means that requiring&#xD;
             at least one pleural drainage.&#xD;
&#xD;
          4. Patient aged 18 years old or more and without measure of legal protection&#xD;
&#xD;
          5. Subject female or male&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2&#xD;
&#xD;
          7. Expected life span &gt; 2 months&#xD;
&#xD;
          8. Corticosteroids authorized if started less than 15 days before enrollment and no dose&#xD;
             modification will be allowed during treatment&#xD;
&#xD;
          9. Adequate biological functions 14 days before inclusion:&#xD;
&#xD;
               -  Haemoglobin ≥ 8 g/dl (transfusion authorized)&#xD;
&#xD;
               -  Neutrophil count (ANC) ≥ 1000/mm3&#xD;
&#xD;
               -  Platelet count ≥ 100 000/mm3&#xD;
&#xD;
               -  International Normalized Ratio (INR) ≤ 1.5 and/or Prothrombin Ratio (TR) ≥ 70 %&#xD;
                  and Partial Thromboplastin Time (PTT) ≤ 1.5&#xD;
&#xD;
               -  Aspartate Aminotransferase Test (AST), Alanine Aminotransferase Test (ALT),&#xD;
                  Gamma-Glutamyl Transpeptidase (GGT), Alk Phos ≤ 3 times Unit Line Number (ULN),&#xD;
                  bilirubin ≤ 40 μmol/L&#xD;
&#xD;
               -  Lactate Dehydrogenase (LDH) ≤ 1,5 times ULN&#xD;
&#xD;
               -  Albumin ≥ 28 g/dL&#xD;
&#xD;
               -  Creatinine clearance ≥ 45 mL/min according to the Modification of the Diet in&#xD;
                  Renal Disease formula (MDRD)&#xD;
&#xD;
               -  Proteinuria ≤ 1g/dL in the absence of tract infection&#xD;
&#xD;
         10. Cardiac Function satisfactory: Left Ventricular Ejection Fraction (LVEF) determined by&#xD;
             myocardial scintigraphy or echocardiography&#xD;
&#xD;
         11. Females of childbearing potential must take acceptable methods of birth control during&#xD;
             the complete duration of treatment and serum pregnancy tests must be negative at the&#xD;
             inclusion. Men must agree to use a condom if his partner is of child bearing potential&#xD;
&#xD;
         12. Patient receiving a social security system&#xD;
&#xD;
         13. Signed inform consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or lactating women or childbearing potential refusing methods of birth&#xD;
             control&#xD;
&#xD;
          2. Transudative pleural effusion: pleural protein &lt; 30 g/L and/or Light's criteria when&#xD;
             pleural protein is not indicative. Light's criteria are as follows (for diagnosis of&#xD;
             transudative):&#xD;
&#xD;
               -  Pleural protein/serum protein ratio &lt; 0.5&#xD;
&#xD;
               -  Pleural LDH/serum LDH ratio &lt; 0.6&#xD;
&#xD;
               -  Pleural LDH &lt; two-thirds the upper limit of normal of serum LDH&#xD;
&#xD;
          3. Purulent pleural effusion.&#xD;
&#xD;
          4. Macroscopically haemorrhagic pleural effusion.&#xD;
&#xD;
          5. Bilateral metastasis pleurisy requiring punctures on both sides.&#xD;
&#xD;
          6. Any co morbidity considered to be incompatible with participation in the study,&#xD;
             according to the investigator, particularly: untreated infectious disease, chronic&#xD;
             respiratory insufficiency, chronic renal insufficiency, Child Pugh B or C,&#xD;
             hepatocellular insufficiency; chronic heart failure not controlled by appropriate&#xD;
             medical treatment.&#xD;
&#xD;
          7. Contraindications to intrapleural administration of bevacizumab:&#xD;
&#xD;
               -  Non-controlled arterial or venous thromboembolism&#xD;
&#xD;
               -  Major surgery during the previous month or planned after study&#xD;
&#xD;
               -  Known, non treated brain metastases&#xD;
&#xD;
               -  Known hypersensitivity to bevacizumab or one of its excipients&#xD;
&#xD;
               -  Hypersensitivity to Chinese hamster ovary cell (CHO) products or other human&#xD;
                  recombinant or humanized antibodies&#xD;
&#xD;
               -  Intravenous administration of bevacizumab planned or underway in the usual cancer&#xD;
                  treatment (≥ 3 weeks wash out from the intrapleural injection)&#xD;
&#xD;
               -  Radiotherapy including lung field concerned since the administration of the&#xD;
                  product until the end of the study.&#xD;
&#xD;
          8. Diagnosis of any second malignancy within the last 5 years, except for basal cell or&#xD;
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast)&#xD;
             unless the subject has been free of the disease for &gt; 3 years.&#xD;
&#xD;
          9. Patients can't participate in another clinical trial with another experimental&#xD;
             anti-cancer drug therapy simultaneously for 90 days. No exclusion period is required&#xD;
             after the end of the trial visit.&#xD;
&#xD;
         10. Impossibility to follow the calendar of exams because of geographic, social or&#xD;
             psychological reasons.&#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>Maya Gutierrez, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Curie - Hôpital René Huguenin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut Curie - Hôpital René Huguenin</name>
      <address>
        <city>Saint-Cloud</city>
        <zip>92210</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>September 8, 2014</study_first_submitted>
  <study_first_submitted_qc>September 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 2014</study_first_posted>
  <last_update_submitted>November 2, 2017</last_update_submitted>
  <last_update_submitted_qc>November 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pleural</keyword>
  <keyword>effusion</keyword>
  <keyword>breast</keyword>
  <keyword>cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Pleural Effusion, Malignant</mesh_term>
    <mesh_term>Pleural Effusion</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</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/NCT02250118
org study id: IC 2014-02
secondary id: 2014-000654-11
nct id: NCT02250118
lead sponsor: 
collaborator: 
has dmc: Yes
Metastatic pleural effusion is a common complication of late-stage cancer and reduces the
      quality of life and survival of patients. The survival of patients with recurrent pleurisy by
      uncontrolled local or systemic treatment is less than 6 months. It is important to develop
      specific therapies to improve the quality of life and survival of patients with metastatic
      pleurisy.

      Bevacizumab is a monoclonal anti vascular endothelial growth factor (VEGF) which has proven
      effective in many indications in oncology. Vascular endothelial growth factor (VEGF) is an
      angiogenic factor which increases endothelial permeability. It plays a central role in many
      tumors of epithelial origin. In this context, it is legitimate to ask whether an
      antiangiogenic targeting VEGF may be effective in patients with metastatic pleurisy by
      decreasing local blood supply and over-permeability.

      No study has been interested in the intra-pleural pharmacokinetics of monoclonal antibodies
      and there are no predictive or prognostic biomarkers for metastatic pleural effusions.

      The investigators believe that intrapleural administration of bevacizumab will reduce the
      pleural vasculature permeability. It will neutralize VEGF present in pleural fluid and reduce
      the replenishment of effusion due to its prolonged half-life of 21 days.

      The investigators therefore propose a phase I study to determine the maximum tolerated dose
      and the recommended dose for phases II, studying the pharmacokinetics of intrapleural
      bevacizumab administered by an implantable device after evacuating a symptomatic metastatic
      pleurisy as part of a mammary carcinoma. The VEGF intrapleural levels and serum will be study
      and the time until a new puncture. Dyspnea will be evaluated as well as its impact on quality
      of life.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To determine the maximum tolerated dose (MTD)
time frame: 90 days after intrapleural injection
description: Maximum tolerated dose (MTD) according to safety of intrapleural bevacizumab at dose levels of 1 mg/kg, 3 mg/kg and 5 mg/kg administered by pleural catheter after drainage of symptomatic malignant pleural effusion in a context of breast cancer.
measure: Study of the pleural and serum pharmacokinetics
time frame: 90 days
description: Pharmacokinetics of bevacizumab just before administration and 1 hour after treatment on Day 1, and at D15, D30, D60 and D90.
measure: Study of pleural and serum Vascular Endothelial Growth Factor (VEGF) levels
time frame: 90 days
description: Pleural and serum VEGF levels just before administration and 1 hour after treatment on Day 1, and at D15, D30, D60 and D90.
measure: Determination of time until new punction or death
time frame: 2 years
description: Response to treatment assessed by the time to new puncture
measure: Total number of pleural drainage procedures
time frame: 90 days
description: Measure of the total number of pleural drainage procedures at D15, D30, D60 and D90.
measure: Drainage-free survival and overall survival
time frame: 2 years
description: Drainage-free survival and overall survival Evaluation of survival without punction and overall survival
measure: Evaluation of dyspnoea
time frame: 90 days
description: Measure by dyspnoea scale and peak flow at D15, D30, D60 and D90
measure: Evaluation of quality of life
time frame: 2 years
description: Quality of life (QLQ-C30) questionnaire according to European Organisation for Research and Treatment of Cancer (EORTC) and FACIT questionnaire Dyspnoea 10 Short Form at D15, D30, D60 and D90 and every 6 month during 2 years
arm group label: Bevacizumab
arm group type: Experimental
description: Intrapleural use: range 0.5 - 5 mg/kg
intervention type: Drug
intervention name: Bevacizumab
description: Intrapleural Bevacizumab
arm group label: Bevacizumab
other name: Avastin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Maya Gutierrez, MD
role: Principal Investigator
affiliation: Institut Curie - Hôpital René Huguenin
facility: 
country: France
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Pleural Effusion, Malignant
mesh term: Pleural Effusion
mesh term: Bevacizumab