<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/NCT02205762</url>
  </required_header>
  <id_info>
    <org_study_id>13-428</org_study_id>
    <secondary_id>2011-001699-20</secondary_id>
    <secondary_id>042011</secondary_id>
    <nct_id>NCT02205762</nct_id>
  </id_info>
  <brief_title>LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis</brief_title>
  <official_title>LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>North American Consortium for Histiocytosis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Histiocyte Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>North American Consortium for Histiocytosis</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The LCH-IV is an international, multicenter, prospective clinical study for pediatric&#xD;
      Langerhans Cell Histiocytosis LCH (age &lt; 18 years).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The international efforts of the past 20 years have shown that combination therapy with&#xD;
      vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous&#xD;
      prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in patients&#xD;
      with and without risk organ involvement. It also showed that prolonged treatment in the&#xD;
      latter group (treatment duration of 12 vs. 6 months) is superior in preventing disease&#xD;
      reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV&#xD;
      study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV&#xD;
      study seeks to tailor treatment based on features at presentation and on response to&#xD;
      treatment, leading to seven strata:&#xD;
&#xD;
        -  Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single&#xD;
           system (SS)-LCH with multifocal bone or &quot;Central Nervous System (CNS)-risk&quot; lesions&#xD;
           (Group 2)&#xD;
&#xD;
        -  Stratum II: Second-line treatment for non-risk patients (patients without risk organ&#xD;
           involvement who fail first-line therapy or have a reactivation after completion of&#xD;
           first-line therapy)&#xD;
&#xD;
        -  Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs&#xD;
           who fail first-line therapy)&#xD;
&#xD;
        -  Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk&#xD;
           organs who fail first-line therapy)&#xD;
&#xD;
        -  Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH&#xD;
&#xD;
        -  Stratum VI: Natural history and management of &quot;other&quot; SS-LCH (patients who do not need&#xD;
           systemic therapy at the time of diagnosis)&#xD;
&#xD;
        -  Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be&#xD;
           followed for reactivation or permanent consequences once complete disease resolution has&#xD;
           been achieved and the respective protocol treatment completed)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>November 2, 2016</start_date>
  <completion_date type="Anticipated">July 2025</completion_date>
  <primary_completion_date type="Anticipated">July 2025</primary_completion_date>
  <phase>Phase 2/Phase 3</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Patients with Reactivation Free Survival</measure>
    <time_frame>12 Months</time_frame>
    <description>Stratum I, II, VI</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Response Rate of Second Cycle</measure>
    <time_frame>9 weeks</time_frame>
    <description>Stratum III</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)</measure>
    <time_frame>3 Years</time_frame>
    <description>Stratum IV</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The cumulative incidence of radiological and clinical neurodegeneration in patients with isolated tumorous CNS-LCH, DI, anterior pituitary dysfunction, and those with CNS-risk lesions</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum V</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum V</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.</measure>
    <time_frame>2 Years</time_frame>
    <description>From all treatment stratum via long-term follow up in Stratum VII</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum I</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Serious and Non-Serious Adverse Events</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Permanent Consequences</measure>
    <time_frame>2 Years</time_frame>
    <description>All Stratum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of reactivations in risk organs</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to complete disease resolution</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum III</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate to the combination of prednisone, vincristine and cytarabine</measure>
    <time_frame>2 years</time_frame>
    <description>Stratum II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of treatment-related toxicities</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.</measure>
    <time_frame>2 years</time_frame>
    <description>Stratum II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The type of subsequent intensive and/or maintenance therapy utilized</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum III</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early and late mortality</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early and late toxicity</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum III</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>d+100 transplant related mortality</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum IV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with incidence of chronic GVHD</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum IV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy</measure>
    <time_frame>2 years</time_frame>
    <description>Stratum V</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response of isolated tumorous CNS-LCH to 2-CDA</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum V</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum V</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Methods of early identification of ND-CNS-LCH</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum V - Exploration of the value of neurochemistry, neurophysiology, and neuropsychology methods in early identification of ND-CNS-LCH and in assessing its severity, and comparison to MRI findings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for systemic therapy later during disease course</measure>
    <time_frame>2 Years</time_frame>
    <description>Stratum VI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify possible risk factors for permanent consequences (PC)</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Anticipated">1400</enrollment>
  <condition>Langerhans Cell Histiocytosis</condition>
  <arm_group>
    <arm_group_label>Stratum I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Stratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV).&#xD;
Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum II</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A uniform &quot;intensive&quot; 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms &quot;INDOMETHACIN&quot; and &quot;6-MP/MTX&quot; (mercaptopurine and Methotrexate).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum III</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Salvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy.&#xD;
The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum IV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>To determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum V</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Stratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH&#xD;
- Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum VI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Natural history and management of &quot;other&quot; SS-LCH not eligible for stratum I group 2.&#xD;
Treatment Options- Management (mostly &quot;wait &amp; see&quot; and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator.&#xD;
Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy.&#xD;
Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Stratum I</description>
    <arm_group_label>Stratum I</arm_group_label>
    <arm_group_label>Stratum II</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vinblastine</intervention_name>
    <description>Stratum I</description>
    <arm_group_label>Stratum I</arm_group_label>
    <arm_group_label>Stratum II</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
    <other_name>Velban®</other_name>
    <other_name>Vincaleukoblastine Sulfate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mercaptopurine</intervention_name>
    <description>Stratum I</description>
    <arm_group_label>Stratum I</arm_group_label>
    <arm_group_label>Stratum II</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
    <other_name>-Purinethol®</other_name>
    <other_name>-6-MP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>INDOMETHACIN</intervention_name>
    <description>Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.</description>
    <arm_group_label>Stratum II</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>fixed dose weekly orally for total treatment duration of 24 months.</description>
    <arm_group_label>Stratum II</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytosine Arabinoside</intervention_name>
    <arm_group_label>Stratum II</arm_group_label>
    <arm_group_label>Stratum V</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
    <other_name>Cytarabine, Ara-C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>2-chlorodeoxyadenosine</intervention_name>
    <arm_group_label>Stratum III</arm_group_label>
    <arm_group_label>Stratum V</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
    <other_name>2-CdA</other_name>
    <other_name>Cladribin®</other_name>
    <other_name>Leustatin®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>hematopoietic stem cell transplantation (RIC-HSCT)</intervention_name>
    <arm_group_label>Stratum IV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Intravenous immunoglobulin</intervention_name>
    <arm_group_label>Stratum V</arm_group_label>
    <arm_group_label>Stratum VI</arm_group_label>
    <other_name>IVIG</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stratum I&#xD;
&#xD;
               -  Patients must be less than 18 years of age at the time of diagnosis.&#xD;
&#xD;
               -  Patients must have histological verification of the diagnosis of Langerhans cell&#xD;
                  histiocytosis according to the criteria described in Section 6.1&#xD;
&#xD;
               -  Signed informed consent form&#xD;
&#xD;
          -  Stratum II&#xD;
&#xD;
               -  Patients of Stratum I who have:&#xD;
&#xD;
               -  Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course&#xD;
&#xD;
               -  AD intermediate or worse in non-risk organs or AD better in risk organs after 12&#xD;
                  weeks (Initial Course 2)&#xD;
&#xD;
               -  Disease progression (AD worse) in non-risk organs at any time during continuation&#xD;
                  treatment&#xD;
&#xD;
               -  Active disease at the end of Stratum I treatment&#xD;
&#xD;
               -  Disease reactivation in non-risk organs at any time after completion of Stratum I&#xD;
                  treatment&#xD;
&#xD;
          -  Stratum III&#xD;
&#xD;
               -  Patients from Stratum I who fulfill the following criteria:&#xD;
&#xD;
               -  AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD&#xD;
                  intermediate in risk organs after week 12 (after Initial Course 2).&#xD;
&#xD;
               -  Presence of unequivocally severe organ dysfunction at the above mentioned&#xD;
                  evaluation points (hematological dysfunction, liver dysfunction, or both of them)&#xD;
                  as&#xD;
&#xD;
                    -  Hb &lt;70 g/L (&lt;7.0 g/dl) and/or transfusion dependency&#xD;
&#xD;
                    -  PLT &lt;20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have&#xD;
                       to be fulfilled) AND/OR&#xD;
&#xD;
                    -  Liver dysfunction (or digestive involvement with protein loss)&#xD;
&#xD;
                    -  Total protein &lt;55 g/L or substitution dependency&#xD;
&#xD;
                    -  Albumin &lt;25 g/L or substitution dependency (at least one of the two criteria&#xD;
                       to be fulfilled)&#xD;
&#xD;
          -  Stratum IV&#xD;
&#xD;
               -  Patients from Stratum I or Stratum III who fulfill the following criteria:&#xD;
&#xD;
               -  AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD&#xD;
                  intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I&#xD;
                  OR&#xD;
&#xD;
               -  AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD&#xD;
                  intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND&#xD;
&#xD;
               -  Presence of unequivocally severe organ dysfunction at the above mentioned&#xD;
                  evaluation points (hematological dysfunction, liver dysfunction, or both of them)&#xD;
                  as defined in Table XI (see Section 10.3.1).&#xD;
&#xD;
               -  Informed consent: All patients or their legal guardians (if the patient is &lt;18&#xD;
                  years of age) must sign an Ethics or institutional Review Board approved consent&#xD;
                  form indicating their awareness of the investigational nature and the risks of&#xD;
                  this study. When appropriate, younger patients will be included in all&#xD;
                  discussions in order to obtain assent.&#xD;
&#xD;
               -  Adequate organ function: Patients should have adequate hepatic, renal, cardiac&#xD;
                  and pulmonary function to undergo reduced intensity HCT based upon local&#xD;
                  institutional guidelines, or at a minimum meet requirements noted in eligibility&#xD;
                  checklist Appendix A-VIII_1. However, significant hepatic and pulmonary&#xD;
                  dysfunction, if secondary to underlying LCH disease activity, will not exclude&#xD;
                  patients from protocol enrollment and should be discussed with the National PI&#xD;
                  Coordinator and the Coordinating Principal Investigator.&#xD;
&#xD;
          -  Stratum V&#xD;
&#xD;
               -  All patients with verified diagnosis of LCH and MRI findings consistent with&#xD;
                  ND-CNSLCH irrespective of previous treatments (also those not registered to other&#xD;
                  Strata ofLCH-IV).&#xD;
&#xD;
               -  Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion&#xD;
                  in the hypothalamus-pituitary axis). In patients with already established&#xD;
                  diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a&#xD;
                  biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion&#xD;
                  is needed for inclusion into the study&#xD;
&#xD;
          -  Stratum VI&#xD;
&#xD;
             -- Patients with newly diagnosed SS-LCH and localization other than &quot;multifocal&#xD;
             bone&quot;,isolated tumorous CNS lesion, or isolated &quot;CNS-risk&quot; lesion.&#xD;
&#xD;
          -  Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as&#xD;
             consent for longterm follow-up has not been withheld.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Stratum I&#xD;
&#xD;
               -  Pregnancy (patients of child-bearing age must be appropriately tested before&#xD;
                  chemotherapy)&#xD;
&#xD;
               -  LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,&#xD;
                  lung fibrosis, etc.) in the absence of active disease&#xD;
&#xD;
               -  Prior systemic therapy&#xD;
&#xD;
          -  Stratum II&#xD;
&#xD;
               -  Patients with progressive disease in risk organs&#xD;
&#xD;
               -  Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without&#xD;
                  evidence of active LCH in the same organ or in any other locations&#xD;
&#xD;
               -  No written consent of the patient or his/her parents or legal guardian&#xD;
&#xD;
          -  Stratum III&#xD;
&#xD;
               -  The presence of any of the following criteria will exclude the patient from the&#xD;
                  study:&#xD;
&#xD;
               -  Isolated sclerosing cholangitis without evidence of active hepatic LCH as the&#xD;
                  only evidence of risk organ involvement.&#xD;
&#xD;
               -  Inadequate renal function as defined by serum creatinine &gt; 3x normal for age&#xD;
&#xD;
          -  Stratum IV&#xD;
&#xD;
               -  Pulmonary failure (requiring mechanical ventilation) not due to active LCH.&#xD;
&#xD;
               -  Isolated liver sclerosis or pulmonary fibrosis, without active LCH.&#xD;
&#xD;
               -  Uncontrolled active life-threatening infection.&#xD;
&#xD;
               -  Decreased renal function with a GFR of less than 50ml/1.73m2/min.&#xD;
&#xD;
               -  Pregnancy or active breast feeding&#xD;
&#xD;
               -  Failure to provide signed informed consent&#xD;
&#xD;
          -  Stratum VI&#xD;
&#xD;
               -  Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible&#xD;
                  for Stratum V),&#xD;
&#xD;
               -  Patients with isolated &quot;CNS-risk&quot; or multifocal bone lesions (they are eligible&#xD;
                  for Stratum I, Group 2)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Milen Minkov, MD, Ph.D</last_name>
    <role>Study Chair</role>
    <affiliation>Children's Cancer Research Institute / St. Anna Children's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Carlos Rodriguez-Galindo, MD</last_name>
    <role>Study Chair</role>
    <affiliation>North American Consortium for Histiocytosis</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Heidi M Clough, BSN, RN</last_name>
    <phone>901-595-0362</phone>
    <email>Heidi.clough@stjude.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sara G Hastings, MBA</last_name>
    <email>Sara.Hastings@stjude.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Children's of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthew Kutny, MD</last_name>
      <phone>205-638-9285</phone>
      <email>mkutny@peds.uab.edu</email>
    </contact>
    <contact_backup>
      <last_name>Vicky L Poss</last_name>
      <phone>205-638-5430</phone>
      <email>vlposs@peds.uab.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Matthew Kutny, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Phoenix Children's Hospital</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85006</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Henry, MD</last_name>
      <email>mhenry@phoenixchildrens.com</email>
    </contact>
    <investigator>
      <last_name>Michael Henry, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Arkansas Children's Hospital</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kimo Stine, MD</last_name>
      <email>stinekimoc@uams.edu</email>
    </contact>
    <investigator>
      <last_name>Kimo Stine, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rima Jubran, MD</last_name>
      <email>rjubran@chla.usc.edu</email>
    </contact>
    <investigator>
      <last_name>Rima Jubran, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Valley Children's Healthcare</name>
      <address>
        <city>Madera</city>
        <state>California</state>
        <zip>93636</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Samuel, MD</last_name>
      <email>DSamuel@valleychildrens.org</email>
    </contact>
    <contact_backup>
      <last_name>Faisal Razzaqi, MD</last_name>
      <email>FRazzaqi@valleychildrens.org</email>
    </contact_backup>
    <investigator>
      <last_name>David Samuel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UCSF Benioff Children's Hospital of Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Robert Raphael, MD</last_name>
      <email>Robert.Raphael@ucsf.edu</email>
    </contact>
    <contact_backup>
      <last_name>Jennifer Michlitsch, MD</last_name>
      <email>Jennifer.Michlitsch@ucsf.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lilibeth Torno, MD</last_name>
      <phone>714-509-4348</phone>
      <email>ltorno@choc.org</email>
    </contact>
    <contact_backup>
      <last_name>Tina Templeman, RN</last_name>
      <phone>714-509-8646</phone>
      <email>ttempleman@choc.org</email>
    </contact_backup>
    <investigator>
      <last_name>Lilibeth Torno, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UCSF Helen Diller Family Cancer Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158-0106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michelle Hermiston, MD, PhD</last_name>
      <email>Michelle.Hermiston@ucsf.edu</email>
    </contact>
    <contact_backup>
      <last_name>Ben Huang, MD</last_name>
      <email>ben.huang@ucsf.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Connecticut Children's Medical Center</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrea Orsey, MD</last_name>
      <email>aorsey@connecticutchildrens.org</email>
    </contact>
    <investigator>
      <last_name>Andrea Orsey, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stephan Ladisch, MD</last_name>
      <email>sladisch@childrensnational.org</email>
    </contact>
    <contact_backup>
      <last_name>Jay Greenberg, MD</last_name>
      <email>jagreenb@childrensnational.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins All Children's Hospital</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33701</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Deepakbabu Chellapandian, MD</last_name>
      <phone>727-767-7040</phone>
      <email>dchella2@jhmi.edu</email>
    </contact>
    <contact_backup>
      <last_name>Kelsey Titus</last_name>
      <phone>727-767-3229</phone>
      <email>ktitus2@jhmi.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Deepakbabu Chellapandian, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta, Emory</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30342</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kathryn Sutton, MD</last_name>
      <phone>404-785-1651</phone>
      <email>Kathryn.Sutton@choa.org</email>
    </contact>
    <contact_backup>
      <last_name>Bradley George, MD</last_name>
      <email>Bradley.George@choa.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Ann &amp; Robert H. Lurie Children's Hospital of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611-2991</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joanna Weinstein, MD</last_name>
      <email>jweinstein@luriechildrens.org</email>
    </contact>
    <contact_backup>
      <last_name>Jenna Rossoff, MD</last_name>
      <email>jrossoff@luriechildrens.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Children's Mercy Hospitals</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>64108</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>J. Allyson Hays, MD</last_name>
      <email>jahays@cmh.edu</email>
    </contact>
    <contact_backup>
      <last_name>Joy Fulbright, MD</last_name>
      <email>JMfulbright@cmh.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Kentucky A.B.Chandler Medical Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tom C Badgett, MD, PhD</last_name>
      <email>tom.badgett@uky.edu</email>
    </contact>
    <contact_backup>
      <last_name>Vlad C Radulescu, MD</last_name>
      <email>vlad.radulescu@uky.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Louisville, Norton Children's Hospital</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kerry McGowan, MD</last_name>
      <phone>502-852-8450</phone>
      <email>kkpowe01@louisville.edu</email>
    </contact>
    <contact_backup>
      <last_name>Cynthia Lemmons</last_name>
      <phone>502-629-7164</phone>
      <email>Cynthia.lemmons@nortonhealthcare.org</email>
    </contact_backup>
    <investigator>
      <last_name>Kerry McGowan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elias Zambidis, MD</last_name>
      <email>EZambid1@jhmi.edu</email>
    </contact>
    <contact_backup>
      <last_name>Christine Pratilas, MD</last_name>
      <email>Cpratil1@jhmi.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary Huang, MD</last_name>
      <phone>617-726-2737</phone>
      <email>mshuang@partners.org</email>
    </contact>
    <investigator>
      <last_name>Mary Huang, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Barbara Degar, MD</last_name>
      <phone>617-632-6801</phone>
      <email>bdegar@partners.org</email>
    </contact>
    <investigator>
      <last_name>Barbara Degar, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55404</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Richards, MD</last_name>
      <email>Michael.richards@childrensmn.org</email>
    </contact>
    <contact_backup>
      <last_name>Nathan Gossai, MD</last_name>
      <email>nathan.gossai@childrensmn.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Hackensack University Medical Center</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Steven Diamond, MD</last_name>
      <email>Steven.Diamond@hackensackmeridian.org</email>
    </contact>
    <contact_backup>
      <last_name>Burton Appel, MD</last_name>
      <email>Burton.appel@hackensackmeridian.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Cohen Children's Medical Center</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carolyn Fein Levy, MD</last_name>
      <email>clevy4@northwell.edu</email>
    </contact>
    <contact_backup>
      <last_name>Jeffery Lipton, MD</last_name>
      <email>jlipton@northwell.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Victor</last_name>
      <email>michael.victor@mssm.edu</email>
    </contact>
    <investigator>
      <last_name>Gary Crouch, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Columbia University / Herbert Irving Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria Luis Sulis, MD</last_name>
      <email>mls95@cumc.columbia.edu</email>
    </contact>
    <contact_backup>
      <last_name>Julia Glade Bender, MD</last_name>
      <email>jg589@cumc.columbia.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christopher Forlenza, MD</last_name>
      <phone>212-639-5226</phone>
      <email>forlenzc@mskcc.org</email>
    </contact>
    <contact_backup>
      <last_name>Ira Dunkel, MD</last_name>
      <email>dunkeli@mskcc.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>SUNY Upstate Medical University</name>
      <address>
        <city>Syracuse</city>
        <state>New York</state>
        <zip>13210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melanie Comito, MD</last_name>
      <email>comitom@upstate.edu</email>
    </contact>
    <contact_backup>
      <last_name>Andrea Dvorak, MD</last_name>
      <email>dvoraka@upstate.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Carolinas Medical Center, Levine Children's Hospital</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28203</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chad Jacobsen, MD</last_name>
      <phone>704-381-9900</phone>
      <email>Chad.jacobsen@carolinashealthcare.org</email>
    </contact>
    <contact_backup>
      <last_name>Ashley Hinson, MD</last_name>
      <email>Ashley.hinson@carolinashealthcare.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Jordan, MD</last_name>
      <phone>513-636-1773</phone>
      <email>Michael.jordan@cchmc.org</email>
    </contact>
    <contact_backup>
      <last_name>Ashish Kumar, MD</last_name>
      <phone>513-803-1631</phone>
      <email>ashish.kumar@cchmc.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Rainbow Babies &amp; Children's Hospital, University Hospitals</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Irina Pateva, MD</last_name>
      <phone>216-844-3345</phone>
      <email>Irina.pateva@uhhospitals.org</email>
    </contact>
    <contact_backup>
      <last_name>Mary Hislop, CCRP</last_name>
      <phone>216-844-7444</phone>
      <email>mary.hislop1@uhhospitals.org</email>
    </contact_backup>
    <investigator>
      <last_name>Irina Pateva, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Toledo Hospital, Toledo Children's Hospital</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43606</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jamie Dargart, MD</last_name>
      <phone>414-291-9525</phone>
      <email>Jamie.Dargart@promedica.org</email>
    </contact>
    <contact_backup>
      <last_name>Anthony Palmer, MD</last_name>
      <email>Anthony.palmermd@promedica.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>UPMC Children's Hospital of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15224</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alex Berkebile, BS</last_name>
      <email>berkebileak@upmc.edu</email>
    </contact>
    <investigator>
      <last_name>Steven Allen, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Medical University of South Carolina (MUSC)</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jacqueline Kraveka, DO</last_name>
      <phone>843-792-2957</phone>
      <email>Kravekjm@musc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Abbey Moore</last_name>
      <phone>843-792-6078</phone>
      <email>mooreabi@musc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Jacqueline Kraveka, DO</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Greenville Health System BI-LO Charities Children's Cancer Center</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <zip>29605</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aniket Saha, MD</last_name>
      <email>Aniket.Saha@prismahealth.org</email>
    </contact>
    <contact_backup>
      <last_name>Nichole L. Bryant, MD</last_name>
      <email>Nichole.Bryant@prismahealth.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>St. Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrick Campbell, MD</last_name>
      <email>patrick.campbell@stjude.org</email>
    </contact>
    <investigator>
      <last_name>Patrick Campbell, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Medical Center Dallas, UT Southwestern</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrick Leavey, MD</last_name>
      <phone>214-648-8605</phone>
      <email>Patrick.Leavey@UTSouthwestern.edu</email>
    </contact>
    <contact_backup>
      <last_name>Princess Iroh-Rodgers, MS</last_name>
      <phone>214-456-2664</phone>
      <email>princess.iroh-rodgers@childrens.com</email>
    </contact_backup>
    <investigator>
      <last_name>Patrick Leavey, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Providence Sacred Heart Children's Hospital</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99204</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefanos Intzes, MD</last_name>
      <email>stefanos.intzes@providence.org</email>
    </contact>
    <contact_backup>
      <last_name>Judy Felgenhauer, MD</last_name>
      <email>judy.felgenhauer@providence.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Madigan Army Medical Center</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98431</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melissa A Forouhar, MD</last_name>
      <phone>253-968-6144</phone>
      <email>Melissa.a.forouhar.mil@mail.mil</email>
    </contact>
    <contact_backup>
      <last_name>Kirsten Van Houte, RN</last_name>
      <phone>253-968-1862</phone>
      <email>Kirstin.l.vanhoute.civ@mail.mil</email>
    </contact_backup>
    <investigator>
      <last_name>Melissa A Forouhar, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>American Family Children's Hospital University of Wisconsin</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Diane Puccetti, MD</last_name>
      <phone>608-890-8070</phone>
      <email>PedsHemOncResearch@lists.wisc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Jenny Weiland, CCRP</last_name>
      <phone>608-890-8070</phone>
      <email>PedsHemOncResearch@lists.wisc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Diane Pucettie, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Canada</country>
  </removed_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 31, 2014</study_first_posted>
  <last_update_submitted>March 21, 2023</last_update_submitted>
  <last_update_submitted_qc>March 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Langerhans cell histiocytosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Histiocytosis, Langerhans-Cell</mesh_term>
    <mesh_term>Histiocytosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Indomethacin</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Mercaptopurine</mesh_term>
    <mesh_term>Vinblastine</mesh_term>
    <mesh_term>Cladribine</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
    <mesh_term>gamma-Globulins</mesh_term>
    <mesh_term>Rho(D) Immune Globulin</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/NCT02205762
org study id: 13-428
secondary id: 2011-001699-20
secondary id: 042011
nct id: NCT02205762
lead sponsor: 
collaborator: 
has dmc: Yes
The LCH-IV is an international, multicenter, prospective clinical study for pediatric
      Langerhans Cell Histiocytosis LCH (age < 18 years).
The international efforts of the past 20 years have shown that combination therapy with
      vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous
      prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in patients
      with and without risk organ involvement. It also showed that prolonged treatment in the
      latter group (treatment duration of 12 vs. 6 months) is superior in preventing disease
      reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV
      study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV
      study seeks to tailor treatment based on features at presentation and on response to
      treatment, leading to seven strata:

        -  Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single
           system (SS)-LCH with multifocal bone or "Central Nervous System (CNS)-risk" lesions
           (Group 2)

        -  Stratum II: Second-line treatment for non-risk patients (patients without risk organ
           involvement who fail first-line therapy or have a reactivation after completion of
           first-line therapy)

        -  Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs
           who fail first-line therapy)

        -  Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk
           organs who fail first-line therapy)

        -  Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH

        -  Stratum VI: Natural history and management of "other" SS-LCH (patients who do not need
           systemic therapy at the time of diagnosis)

        -  Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be
           followed for reactivation or permanent consequences once complete disease resolution has
           been achieved and the respective protocol treatment completed)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Patients with Reactivation Free Survival
time frame: 12 Months
description: Stratum I, II, VI
measure: Response Rate of Second Cycle
time frame: 9 weeks
description: Stratum III
measure: Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)
time frame: 3 Years
description: Stratum IV
measure: The cumulative incidence of radiological and clinical neurodegeneration in patients with isolated tumorous CNS-LCH, DI, anterior pituitary dysfunction, and those with CNS-risk lesions
time frame: 2 Years
description: Stratum V
measure: The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH
time frame: 2 Years
description: Stratum V
measure: Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.
time frame: 2 Years
description: From all treatment stratum via long-term follow up in Stratum VII
measure: Overall Survival
time frame: 2 Years
description: Stratum I
measure: Number of Participants with Serious and Non-Serious Adverse Events
time frame: 2 Years
measure: Incidence of Permanent Consequences
time frame: 2 Years
description: All Stratum
measure: Cumulative incidence of reactivations in risk organs
time frame: 2 Years
measure: Time to complete disease resolution
time frame: 2 Years
description: Stratum III
measure: Response rate to the combination of prednisone, vincristine and cytarabine
time frame: 2 years
description: Stratum II
measure: The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)
time frame: 2 Years
description: Stratum II
measure: Percentage of treatment-related toxicities
time frame: 2 Years
description: Stratum II
measure: Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.
time frame: 2 years
description: Stratum II
measure: The type of subsequent intensive and/or maintenance therapy utilized
time frame: 2 Years
description: Stratum III
measure: Early and late mortality
time frame: 2 Years
description: Stratum II
measure: Early and late toxicity
time frame: 2 Years
description: Stratum III
measure: d+100 transplant related mortality
time frame: 2 Years
description: Stratum IV
measure: Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT
time frame: 2 Years
measure: Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD
time frame: 2 Years
description: Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH
measure: Percentage of Participants with incidence of chronic GVHD
time frame: 2 Years
description: Stratum IV
measure: Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy
time frame: 2 years
description: Stratum V
measure: Response of isolated tumorous CNS-LCH to 2-CDA
time frame: 2 Years
description: Stratum V
measure: Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH
time frame: 2 Years
description: Stratum V
measure: Methods of early identification of ND-CNS-LCH
time frame: 2 Years
description: Stratum V - Exploration of the value of neurochemistry, neurophysiology, and neuropsychology methods in early identification of ND-CNS-LCH and in assessing its severity, and comparison to MRI findings.
measure: Need for systemic therapy later during disease course
time frame: 2 Years
description: Stratum VI
measure: Identify possible risk factors for permanent consequences (PC)
time frame: 2 Years
arm group label: Stratum I
arm group type: Experimental
description: Stratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV).
Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.
arm group label: Stratum II
arm group type: Experimental
description: A uniform "intensive" 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms "INDOMETHACIN" and "6-MP/MTX" (mercaptopurine and Methotrexate).
arm group label: Stratum III
arm group type: Experimental
description: Salvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy.
The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.
arm group label: Stratum IV
arm group type: Experimental
description: To determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).
arm group label: Stratum V
arm group type: Experimental
description: Stratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH
- Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.
arm group label: Stratum VI
arm group type: Experimental
description: Natural history and management of "other" SS-LCH not eligible for stratum I group 2.
Treatment Options- Management (mostly "wait & see" and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator.
Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy.
Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.
intervention type: Drug
intervention name: Prednisone
description: Stratum I
arm group label: Stratum I
arm group label: Stratum II
arm group label: Stratum VI
intervention type: Drug
intervention name: Vinblastine
description: Stratum I
arm group label: Stratum I
arm group label: Stratum II
arm group label: Stratum VI
other name: Velban®
other name: Vincaleukoblastine Sulfate
intervention type: Drug
intervention name: mercaptopurine
description: Stratum I
arm group label: Stratum I
arm group label: Stratum II
arm group label: Stratum VI
other name: -Purinethol®
other name: -6-MP
intervention type: Drug
intervention name: INDOMETHACIN
description: Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.
arm group label: Stratum II
intervention type: Drug
intervention name: Methotrexate
description: fixed dose weekly orally for total treatment duration of 24 months.
arm group label: Stratum II
intervention type: Drug
intervention name: Cytosine Arabinoside
arm group label: Stratum II
arm group label: Stratum V
arm group label: Stratum VI
other name: Cytarabine, Ara-C
intervention type: Drug
intervention name: 2-chlorodeoxyadenosine
arm group label: Stratum III
arm group label: Stratum V
arm group label: Stratum VI
other name: 2-CdA
other name: Cladribin®
other name: Leustatin®
intervention type: Procedure
intervention name: hematopoietic stem cell transplantation (RIC-HSCT)
arm group label: Stratum IV
intervention type: Biological
intervention name: Intravenous immunoglobulin
arm group label: Stratum V
arm group label: Stratum VI
other name: IVIG
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: Milen Minkov, MD, Ph.D
role: Study Chair
affiliation: Children's Cancer Research Institute / St. Anna Children's Hospital
last name: Carlos Rodriguez-Galindo, MD
role: Study Chair
affiliation: North American Consortium for Histiocytosis
last name: Heidi M Clough, BSN, RN
phone: 901-595-0362
email: Heidi.clough@stjude.org
last name: Sara G Hastings, MBA
email: Sara.Hastings@stjude.org
facility: 
status: Recruiting
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country: United States
country: Canada
responsible party type: Sponsor
mesh term: Histiocytosis, Langerhans-Cell
mesh term: Histiocytosis
mesh term: Cytarabine
mesh term: Prednisone
mesh term: Indomethacin
mesh term: Methotrexate
mesh term: Mercaptopurine
mesh term: Vinblastine
mesh term: Cladribine
mesh term: Immunoglobulins
mesh term: Immunoglobulins, Intravenous
mesh term: gamma-Globulins
mesh term: Rho(D) Immune Globulin