<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/NCT01727206</url>
  </required_header>
  <id_info>
    <org_study_id>ECD-TCZ-01</org_study_id>
    <secondary_id>2012-003151-11</secondary_id>
    <secondary_id>GR-2009-1594586</secondary_id>
    <nct_id>NCT01727206</nct_id>
  </id_info>
  <brief_title>Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease</brief_title>
  <official_title>Open-label, Single-arm, Phase II, Prospective, Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ospedale San Raffaele</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ospedale San Raffaele</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study we propose is a pilot phase II, interventional, treatment, open-label, single-arm,&#xD;
      efficacy/safety clinical trial of a 6-month treatment with tocilizumab (8 mg/kg once monthly)&#xD;
      in adult patients with extraskeletal Erdheim-Chester disease (ECD). Efficacy will be assessed&#xD;
      as the effect of the treatment on the size of the measurable lesions, as evaluated by&#xD;
      bidimensional measurements, and by the impact of the treatment on symptom control and on&#xD;
      patient quality of life. Safety of the treatment will be determined by the analysis of&#xD;
      adverse events and of the relevant safety laboratory parameters.&#xD;
&#xD;
      Secondary objectives of the study will be:&#xD;
&#xD;
        1. to better characterize the mechanisms underlying such disease and the possible response&#xD;
           to the treatment. In particular: i) we will investigate the immunophenotypic and&#xD;
           histomorphologic features of ECD histiocytes; ii) we will gather gene expression data&#xD;
           from peripheral blood immune cells to better characterize their functional status, to&#xD;
           define their transcriptional fingerprints and their possible modulation as a result of&#xD;
           tocilizumab treatment; iii) we will assess the production of soluble mediators and the&#xD;
           expression of activation molecules by monocytes derived from ECD patients, as well as&#xD;
           after stimulation with selected inflammatory cytokines; iv) we will investigate the ex&#xD;
           vivo and in vitro impact of tocilizumab treatment on those markers, for possible use as&#xD;
           a predictor or indicator of response to treatment.&#xD;
&#xD;
        2. to investigate the metabolic pattern in ECD patients before and after tocilizumab&#xD;
           treatment as evaluated by fluoro-d-glucose positron emission tomography (FDG-PET) and to&#xD;
           verify if it can be an indicator of ECD activity.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">February 2015</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>Reduction in the dimensions of measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria</measure>
    <time_frame>6 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Functional improvement in measurable indexes</measure>
    <time_frame>6 months</time_frame>
    <description>Improvement in renal, hypophyseal, and respiratory function or of bone turnover, when altered at baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Variations of patient quality of life</measure>
    <time_frame>6 months</time_frame>
    <description>As evaluated by standard questionnaires (HAQ, Short Form (SF)-36)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of the adverse events and of the relevant safety laboratory parameters</measure>
    <time_frame>6 months</time_frame>
    <description>Monitoring of adverse events, variations in biochemical and hematological tests (full blood count, liver and renal function tests, lipid profile)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Variations in disease activity as evaluated by FDG-PET imaging</measure>
    <time_frame>0, 2 and 6 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of soluble factors, receptors and activation molecules involved the accumulation, activation and entrapment of histiocytes possibly associated to a response to the experimental treatment</measure>
    <time_frame>6 months</time_frame>
    <description>the levels of circulating cytokines and chemokines before, during and after tocilizumab treatment;&#xD;
the immunophenotype and the transcriptional fingerprints of circulating immune cells from ECD patients and their possible modulation as a result of tocilizumab treatment;&#xD;
the pathways involved in the production of interleukin (IL)-6 and IL-6-induced cytokines and chemokines by mononuclear cells obtained from ECD patients;&#xD;
the interference of tocilizumab in vitro on monocyte activation and ex vivo from treated patients, also to evaluate its effect on the profile of circulating cytokines and on the secretory potential of patient-derived monocytes</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Erdheim-Chester Disease</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tocilizumab 8 mg/kg intravenously every month for six months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <arm_group_label>Tocilizumab</arm_group_label>
    <other_name>Ro-Actemra</other_name>
    <other_name>Actemra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients &gt;= 18 years of age able to understand and sign an informed consent;&#xD;
&#xD;
          -  histologically proven diagnosis of Erdheim-Chester disease ;&#xD;
&#xD;
          -  an advanced disease not limited to the skeleton, with at least one measurable lesion;&#xD;
&#xD;
          -  if females of childbearing potential, a negative pregnancy test and willingness to&#xD;
             adhere to a highly effective contraceptive method of birth control for the duration of&#xD;
             the study;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  history of hypersensitivity to tocilizumab or to any of the excipients;&#xD;
&#xD;
             ￼- severe infections requiring hospitalization or antibiotic therapy in the 30 days&#xD;
             before the enrollment in the study;&#xD;
&#xD;
          -  active tuberculosis, listeriosis, histoplasmosis, sepsis, abscesses, opportunistic&#xD;
             infections; active hepatitis B or C virus infection;&#xD;
&#xD;
          -  past history of tuberculosis (as documented by a positive purified protein derivative&#xD;
             (PPD) skin test and/or a positive Quantiferon test and/or a chest X- ray), in the&#xD;
             absence of a documented and appropriate administration of a specific treatment for&#xD;
             latent tuberculosis;&#xD;
&#xD;
          -  history of human immunodeficiency virus (HIV) infection;&#xD;
&#xD;
          -  past history (&lt; 5 years before enrollment) of a lymphoproliferative disorder or of a&#xD;
             solid cancer (excluding cured basal cell or squamous cell carcinoma of the skin);&#xD;
&#xD;
          -  moderate or severe heart failure (NYHA class III/IV), uncontrolled diabetes mellitus&#xD;
             or other diseases that -according to the physician in charge of the protocol- may be&#xD;
             of harm to the patient, if he/she would enroll in the study;&#xD;
&#xD;
          -  history of alcohol and/or drug abuse;&#xD;
&#xD;
          -  prior treatment with alkylating drugs (chlorambucil, cyclophosphamide);&#xD;
&#xD;
          -  serum creatinine &gt; 1.6 mg/dL in female patients or &gt; 1.9 mg/dL in male patients,&#xD;
             aspartate aminotransferase and/or alanine aminotransferase &gt; 3 x upper limit of normal&#xD;
             ; platelet &lt; 100.000/fL; hemoglobin &lt; 8.5 g/dL; white blood cell count &lt; 1000/fL;&#xD;
             lymphocyte &lt; 500/fL; total bilirubin &gt; 2.0 mg/dL&#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>Lorenzo Dagna, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>San Raffaele Scientific Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>San Raffaele Hospital</name>
      <address>
        <city>Milano</city>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>November 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 15, 2012</study_first_posted>
  <last_update_submitted>February 9, 2016</last_update_submitted>
  <last_update_submitted_qc>February 9, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 10, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ospedale San Raffaele</investigator_affiliation>
    <investigator_full_name>Lorenzo Dagna</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Erdheim-Chester disease</keyword>
  <keyword>Tocilizumab</keyword>
  <keyword>Treatment</keyword>
  <keyword>Phase II</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Erdheim-Chester Disease</mesh_term>
  </condition_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/NCT01727206
org study id: ECD-TCZ-01
secondary id: 2012-003151-11
secondary id: GR-2009-1594586
nct id: NCT01727206
lead sponsor: 
has dmc: Yes
The study we propose is a pilot phase II, interventional, treatment, open-label, single-arm,
      efficacy/safety clinical trial of a 6-month treatment with tocilizumab (8 mg/kg once monthly)
      in adult patients with extraskeletal Erdheim-Chester disease (ECD). Efficacy will be assessed
      as the effect of the treatment on the size of the measurable lesions, as evaluated by
      bidimensional measurements, and by the impact of the treatment on symptom control and on
      patient quality of life. Safety of the treatment will be determined by the analysis of
      adverse events and of the relevant safety laboratory parameters.

      Secondary objectives of the study will be:

        1. to better characterize the mechanisms underlying such disease and the possible response
           to the treatment. In particular: i) we will investigate the immunophenotypic and
           histomorphologic features of ECD histiocytes; ii) we will gather gene expression data
           from peripheral blood immune cells to better characterize their functional status, to
           define their transcriptional fingerprints and their possible modulation as a result of
           tocilizumab treatment; iii) we will assess the production of soluble mediators and the
           expression of activation molecules by monocytes derived from ECD patients, as well as
           after stimulation with selected inflammatory cytokines; iv) we will investigate the ex
           vivo and in vitro impact of tocilizumab treatment on those markers, for possible use as
           a predictor or indicator of response to treatment.

        2. to investigate the metabolic pattern in ECD patients before and after tocilizumab
           treatment as evaluated by fluoro-d-glucose positron emission tomography (FDG-PET) and to
           verify if it can be an indicator of ECD activity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Reduction in the dimensions of measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria
time frame: 6 months
measure: Functional improvement in measurable indexes
time frame: 6 months
description: Improvement in renal, hypophyseal, and respiratory function or of bone turnover, when altered at baseline
measure: Variations of patient quality of life
time frame: 6 months
description: As evaluated by standard questionnaires (HAQ, Short Form (SF)-36)
measure: Analysis of the adverse events and of the relevant safety laboratory parameters
time frame: 6 months
description: Monitoring of adverse events, variations in biochemical and hematological tests (full blood count, liver and renal function tests, lipid profile)
measure: Variations in disease activity as evaluated by FDG-PET imaging
time frame: 0, 2 and 6 months
measure: Evaluation of soluble factors, receptors and activation molecules involved the accumulation, activation and entrapment of histiocytes possibly associated to a response to the experimental treatment
time frame: 6 months
description: the levels of circulating cytokines and chemokines before, during and after tocilizumab treatment;
the immunophenotype and the transcriptional fingerprints of circulating immune cells from ECD patients and their possible modulation as a result of tocilizumab treatment;
the pathways involved in the production of interleukin (IL)-6 and IL-6-induced cytokines and chemokines by mononuclear cells obtained from ECD patients;
the interference of tocilizumab in vitro on monocyte activation and ex vivo from treated patients, also to evaluate its effect on the profile of circulating cytokines and on the secretory potential of patient-derived monocytes
arm group label: Tocilizumab
arm group type: Experimental
description: Tocilizumab 8 mg/kg intravenously every month for six months
intervention type: Drug
intervention name: Tocilizumab
arm group label: Tocilizumab
other name: Ro-Actemra
other name: Actemra
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lorenzo Dagna, MD
role: Principal Investigator
affiliation: San Raffaele Scientific Institute
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Ospedale San Raffaele
investigator full name: Lorenzo Dagna
investigator title: Professor
mesh term: Erdheim-Chester Disease