<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/NCT01704716</url>
  </required_header>
  <id_info>
    <org_study_id>HR-NBL-1.8 / SIOPEN</org_study_id>
    <nct_id>NCT01704716</nct_id>
  </id_info>
  <brief_title>High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)</brief_title>
  <official_title>High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Anna Kinderkrebsforschung</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St. Anna Kinderkrebsforschung</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk&#xD;
      neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified&#xD;
      &gt; 12 months at diagnosis).&#xD;
&#xD;
      The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood&#xD;
      stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy&#xD;
      followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour&#xD;
      and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba&#xD;
      ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3&#xD;
      randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody&#xD;
      is recommended without scIL-2 as continuous infusion as standard of care outside of&#xD;
      controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba&#xD;
      ®).&#xD;
&#xD;
      In the induction phase, all patients receive Rapid COJEC following the result of the R3&#xD;
      randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned.&#xD;
&#xD;
      Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and&#xD;
      complete excision of the primary tumour will be attempted.&#xD;
&#xD;
      Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the&#xD;
      end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles.&#xD;
&#xD;
      After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged&#xD;
      12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without&#xD;
      segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop&#xD;
      treatment after induction therapy and surgery to the primary tumour.&#xD;
&#xD;
      Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by&#xD;
      peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.&#xD;
&#xD;
      The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days&#xD;
      ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin&#xD;
      (13-cis-RA) is closed.&#xD;
&#xD;
      The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total&#xD;
      dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin&#xD;
      (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC&#xD;
      approval.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this protocol the term high-risk neuroblastoma refers to children with either&#xD;
&#xD;
        -  disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age&#xD;
           of one or&#xD;
&#xD;
        -  INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and&#xD;
           20% of children with stage 3 and occasional patients with stage 2 disease are&#xD;
           characterized by amplification of the MycN gene in their tumours. This biological&#xD;
           characteristic has clearly been shown to be associated with a greater risk of relapse&#xD;
           and death from disease progression. These patients may benefit from very aggressive&#xD;
           treatment and, based on this hypothesis, they are included in this protocol. Infants (&lt;&#xD;
           12 months at diagnosis) with MYCN amplified tumors are included.&#xD;
&#xD;
      Children with this type of presentation and age represent the largest neuroblastoma subgroup.&#xD;
      Their prognosis remains poor in most cases and our ability to predict the clinical course and&#xD;
      the outcome of the individual patient is modest.&#xD;
&#xD;
      Primary objectives:&#xD;
&#xD;
      R0 randomization: R0 was opened with the study activation in February 2002 and closed in&#xD;
      November 2005. The randomized use of G-CSF during COJEC induction resulted in the&#xD;
      recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia&#xD;
      (Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic&#xD;
      granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with&#xD;
      high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul&#xD;
      20;3516-24).&#xD;
&#xD;
      R1 randomization: R1 was opened with the study activation in February 2002 and closed in&#xD;
      10/2010 following the results showing significant superiority of myeloablative therapy (MAT)&#xD;
      with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan&#xD;
      (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan&#xD;
      and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for&#xD;
      high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm,&#xD;
      open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).&#xD;
&#xD;
      R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric&#xD;
      ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization&#xD;
      tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2,&#xD;
      Proleukin®), following MAT and autologous stem cell transplantation, in addition to&#xD;
      differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with&#xD;
      high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr&#xD;
      10500)).&#xD;
&#xD;
      R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7&#xD;
      induction regimen will improve the metastatic response rates or event free survival (EFS) as&#xD;
      compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630&#xD;
      randomized patients as planned. There was no difference in event free survival rate between&#xD;
      both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade&#xD;
      3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard&#xD;
      induction treatment with G-CSF support based on the results of the R0 randomization open from&#xD;
      2002 top 2005 This change has been implemented in amendment 8 of the protocol.&#xD;
&#xD;
      R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI)&#xD;
      ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time&#xD;
      of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in&#xD;
      relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement&#xD;
      this more favorable immunotherapy dosing schedule for the time till the induction question R3&#xD;
      was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate&#xD;
      of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment&#xD;
      arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address&#xD;
      the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be&#xD;
      addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be&#xD;
      reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106&#xD;
      IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course&#xD;
      s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and&#xD;
      not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization&#xD;
      is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization.&#xD;
      For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as&#xD;
      continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of&#xD;
      controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing&#xD;
      authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>February 2002</start_date>
  <completion_date type="Anticipated">September 2026</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Event Free Survival (R1: MAT therapy)</measure>
    <time_frame>Up to three years</time_frame>
    <description>The primary endpoint was the event free survival (EFS) calculated from the date of the first R1 randomisation. The following was considered as event:&#xD;
disease progression or relapse&#xD;
death from any cause&#xD;
second neoplasm&#xD;
Patients lost to follow up without event were considered at the date of their last follow up evaluation.&#xD;
R1 has been closed in October 2010 following the results of R1 randomisation showing significant superiority for myeloablative therapy (MAT) with busulfan and melphalan (BuMel) in patients with high risk neuroblastoma over MAT with continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Event Free Survival (immunotherapy)</measure>
    <time_frame>Up to three years</time_frame>
    <description>R2 randomisation comparing immunotherapy with ch14.18/CHO and 13-cis retinoic acid versus 13-cis retinoic acid alone was activated in November 2006. It was amended in July 2009 and compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2). Immunotherapy randomisation has been amended in 2014 (R4 randomisation). The ch14.18/CHO antibody is given as continuous Infusion and the randomisation has lasted until the necessary number of patients for R3 randomisation was reached&#xD;
The primary endpoint is 3-year event free survival calculated from the date of the second randomisation. The following will be considered as events:&#xD;
disease progression or relapse&#xD;
death from any cause&#xD;
second neoplasm&#xD;
Patients lost to follow up without event will be censored at the date of their last follow-up evaluation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete metastatic response (R3: Induction therapy)</measure>
    <time_frame>Up to 95 days</time_frame>
    <description>R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.&#xD;
Complete metastatic response after induction is defined as:&#xD;
no skeletal uptake on mIBG&#xD;
Negative bone marrow aspirates (by cytomorphology) and trephines&#xD;
Absence of other metastatic sites</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Event free survival (R3: Induction therapy)</measure>
    <time_frame>Up to three years</time_frame>
    <description>R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.&#xD;
The primary endpoint is event free survival calculated from the date of the R3-randomisation. The following will be calculated as events:&#xD;
disease progression or relapse&#xD;
death from any cause&#xD;
second neoplasm&#xD;
Patients lost to follow up without event will be censored at the date of their last follow up evaluation</description>
  </primary_outcome>
  <number_of_arms>10</number_of_arms>
  <enrollment type="Anticipated">3300</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R1: BuMel MAT</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan.&#xD;
In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R1: CEM MAT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R2: ch14.18/CHO</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R2: ch14.18/CHO plus Aldesleukin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomised to receive ch14.18/CHO plus Aldesleukin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days:&#xD;
Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R3: Modified N7</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R4: cnt inf ch14.18/CHO</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R4: cnt inf ch14.18/CHO plus Aldesleukin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO.&#xD;
In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>given during Rapid COJEC and modified N7 therapy</description>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <arm_group_label>R3: Modified N7</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aldesleukin</intervention_name>
    <description>Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2</description>
    <arm_group_label>R2: ch14.18/CHO plus Aldesleukin</arm_group_label>
    <arm_group_label>R4: cnt inf ch14.18/CHO plus Aldesleukin</arm_group_label>
    <other_name>Interleukin 2, IL-2, IL2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ch14.18/CHO</intervention_name>
    <description>ch14.18/CHO antibody is given during MRD treatment</description>
    <arm_group_label>R2: ch14.18/CHO</arm_group_label>
    <arm_group_label>R2: ch14.18/CHO plus Aldesleukin</arm_group_label>
    <arm_group_label>R4: cnt inf ch14.18/CHO</arm_group_label>
    <arm_group_label>R4: cnt inf ch14.18/CHO plus Aldesleukin</arm_group_label>
    <other_name>anti GD2 antibody</other_name>
    <other_name>Dinutuximab beta EUSA</other_name>
    <other_name>Qarziba®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)</description>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <arm_group_label>R1: CEM MAT</arm_group_label>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <other_name>Paraplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Etoposide is given during Induction Treatment (both R3 randomisation arms)</description>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <arm_group_label>R1: CEM MAT</arm_group_label>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <arm_group_label>R3: Modified N7</arm_group_label>
    <other_name>VP16</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Cisplatin is given during Induction Treatment (both R3 randomisation arms)</description>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <arm_group_label>R3: Modified N7</arm_group_label>
    <other_name>CDDP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)</description>
    <arm_group_label>R0: COJEC</arm_group_label>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <arm_group_label>R3: COJEC Induction</arm_group_label>
    <arm_group_label>R3: Modified N7</arm_group_label>
    <other_name>Endoxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Doxorubicin is given during Induction Treatment (R3 arm modified N7)</description>
    <arm_group_label>R3: Modified N7</arm_group_label>
    <other_name>Adriamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>G-CSF</intervention_name>
    <description>G-CSF is given during Induction Treatment</description>
    <arm_group_label>R0: COJEC plus G-CSF</arm_group_label>
    <other_name>Filgrastim</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Busulfan</intervention_name>
    <description>In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.</description>
    <arm_group_label>R1: BuMel MAT</arm_group_label>
    <other_name>Busilvex</other_name>
    <other_name>Myleran</other_name>
    <other_name>Busulphan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melphalan</intervention_name>
    <description>Melphalan is given during MAT treatment</description>
    <arm_group_label>R1: BuMel MAT</arm_group_label>
    <arm_group_label>R1: CEM MAT</arm_group_label>
    <other_name>Alkeran</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  • Established diagnosis of neuroblastoma according to the International Neuroblastoma&#xD;
             Staging System (INSS).&#xD;
&#xD;
               -  Age below 21 years.&#xD;
&#xD;
               -  High risk neuroblastoma defined as either:&#xD;
&#xD;
                    1. INSS stage 2, 3, 4, and 4s with MYCN amplification, or&#xD;
&#xD;
                    2. INSS stage 4 without MYCN amplification aged &gt; 12 months at diagnosis&#xD;
&#xD;
               -  Patients who have received no previous chemotherapy except for one cycle of&#xD;
                  etoposide and carboplatin (VP16/Carbo). In this situation patients will receive&#xD;
                  Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the&#xD;
                  first cycle VP16/Carbo (etoposide / carboplatin).&#xD;
&#xD;
               -  Written informed consent, including agreement of parents or legal guardian for&#xD;
                  minors, to enter a randomised study if the criteria for randomisation are met.&#xD;
&#xD;
               -  Tumour cell material available for determination of biological prognostic&#xD;
                  factors.&#xD;
&#xD;
               -  Females of childbearing potential must have a negative pregnancy test. Patients&#xD;
                  of childbearing potential must agree to use an effective birth control method.&#xD;
                  Female patients who are lactating must agree to stop breast-feeding.&#xD;
&#xD;
               -  Registration of all eligibility criteria with the data centre within 6 weeks from&#xD;
                  diagnosis.&#xD;
&#xD;
               -  Provisional follow up of 5 years.&#xD;
&#xD;
               -  National and local ethical committee approval.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Any negative answer concerning the inclusion criteria of the study&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ruth L Ladenstein, MD, MBA, cPM</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Anna Kinderkrebsforschung</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ruth L Ladenstein, MD, MBA, cPM</last_name>
    <phone>0043140470</phone>
    <phone_ext>4750</phone_ext>
    <email>ruth.ladenstein@ccri.at</email>
  </overall_contact>
  <location>
    <facility>
      <name>Women and Children´s Hospital</name>
      <address>
        <city>Adelaide</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Lady Cilento Children´s Hospital</name>
      <address>
        <city>Brisbane</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>John Hunter Children's Hospital</name>
      <address>
        <city>Newcastle</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Royal Children's Hospital Melbourne</name>
      <address>
        <city>Parkville</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Sydney Children's Hospital</name>
      <address>
        <city>Sydney</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Children´s Hospital Westmead</name>
      <address>
        <city>Westmead</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>St. Anna Kinderspital</name>
      <address>
        <city>Vienna</city>
        <state>Austra</state>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ruth Ladenstein, MD, MBA, cPM</last_name>
      <phone>0043140470</phone>
      <phone_ext>4750</phone_ext>
      <email>ruth.ladenstein@ccri.at</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Univ.-Klinik für Kinder- und Jugendheilkunde Graz</name>
      <address>
        <city>Graz</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck</name>
      <address>
        <city>Innsbruck</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Landes- Kinderklinik Linz</name>
      <address>
        <city>Linz</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>St. Johanns Spital LKH Salzburg</name>
      <address>
        <city>Salzburg</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Cliniques universitaires St-Luc</name>
      <address>
        <city>Brussels</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hôpital des Enfants</name>
      <address>
        <city>Brussels</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital Gent</name>
      <address>
        <city>Gent</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>UZ Gasthuisberg</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHR Citadelle</name>
      <address>
        <city>Lüttich</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinique de l'Espérance</name>
      <address>
        <city>Montegnee</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital Motol</name>
      <address>
        <city>Prague</city>
        <country>Czechia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Aarhus Universitetshospital</name>
      <address>
        <city>Aarhus</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>National State Hospital</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital of Odense</name>
      <address>
        <city>Odense</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Skejby Hospital</name>
      <address>
        <city>Skejby</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hopital d'Enfants Dijon</name>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHU de Grenoble</name>
      <address>
        <city>Grenoble</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHR Pellegrin</name>
      <address>
        <city>Le Pellerin</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Centre Oscar Lambret de Lille</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hopitaux de Marseille La Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHR de Nantes</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hôpital Trousseau Paris</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hôpital American Memorial Hospital</name>
      <address>
        <city>Reims</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHU-Saint Etienne</name>
      <address>
        <city>Saint Etienne</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hôpital de Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hôpital D'Enfants de Toulouse</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>&quot;A&amp;P Kyriakou&quot; Children's Hospital</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Aghia Sophia Children's Hospital</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>MITERA Hospital</name>
      <address>
        <city>Heraklion</city>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>PEPAGNH University Hospital</name>
      <address>
        <city>Heraklion</city>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Madarász Children Hospital Budapest</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Semmelweis University of Budapest</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Debrecen</name>
      <address>
        <city>Debrecen</city>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Pecs</name>
      <address>
        <city>Pécs</city>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Szeged</name>
      <address>
        <city>Szeged</city>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Dublin: OLHSC</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Centre</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Schneider Children's Medical Center of Israel</name>
      <address>
        <city>Petah Tiqwa</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Sheba Medical Center</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale G. Salesi</name>
      <address>
        <city>Ancona</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Universitŕ degli studi di Bari</name>
      <address>
        <city>Bari</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedali Riuniti</name>
      <address>
        <city>Bergamo</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale S. Orsola</name>
      <address>
        <city>Bologna</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale Regionale per le Microcitemie</name>
      <address>
        <city>Cagliari</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera di Cosenza</name>
      <address>
        <city>Cosenza</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera A. Meyer</name>
      <address>
        <city>Firenze</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Istituto Giannina Gaslini</name>
      <address>
        <city>Genua</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori di Milano</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedal. Univ. di Modena</name>
      <address>
        <city>Modena</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Sec. Univ. degli Studi di Napoli - Policlinico</name>
      <address>
        <city>Napoli</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Clinica di Oncoematologia Pediatrica Padova</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale dei Bambini, Palermo</name>
      <address>
        <city>Palermo</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica</name>
      <address>
        <city>Parma</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Policlinico San Matteo</name>
      <address>
        <city>Pavia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale Civile Spirito Santo</name>
      <address>
        <city>Pescara</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale &quot;Infermi &quot;</name>
      <address>
        <city>Rimini</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Policlinico Borgo Roma</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ospedale Bambino Gesu</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Casa Sollievo della Sofferenza</name>
      <address>
        <city>San Giovanni Rotondo</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>O.I.R.M. - S. Anna</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Istituto per l'Infanzia &quot;Burlo Garofolo&quot;</name>
      <address>
        <city>Trieste</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Haukeland University Hospital</name>
      <address>
        <city>Bergen</city>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Rikshospitalet</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital of North-Norway</name>
      <address>
        <city>Tromso</city>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Medical University of Bialystok</name>
      <address>
        <city>Bialystok</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Medical University of Bydgoszcz</name>
      <address>
        <city>Bydgoszcz</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Childrens' Hospital in Chorzów</name>
      <address>
        <city>Chorzów</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Medical University in Gdansk</name>
      <address>
        <city>Gdansk</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Upper Silesian Centre of Child and Mother's Care</name>
      <address>
        <city>Katowice</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Children's University Hospital in Lublin</name>
      <address>
        <city>Lublin</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Medical Sciences Poznan</name>
      <address>
        <city>Poznan</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Institute Mother and Child</name>
      <address>
        <city>Warschau</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Wroclaw Medical University</name>
      <address>
        <city>Wroclaw</city>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ipofg-Crl</name>
      <address>
        <city>Lissabon</city>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital F. D. Roosevelt</name>
      <address>
        <city>Banská Bystrica</city>
        <country>Slovakia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital Ljubljana</name>
      <address>
        <city>Ljubljana</city>
        <zip>10000</zip>
        <country>Slovenia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>H. General de Alicante</name>
      <address>
        <city>Alicante</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital de Cruces</name>
      <address>
        <city>Bilbao</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario de Jaen</name>
      <address>
        <city>Jaen</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H . Materno-Infantil Teresa Herrera</name>
      <address>
        <city>La Coruna</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H. Monteprincipe</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H Central de Asturias</name>
      <address>
        <city>Oviedo</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H. C. U. de Salamanca</name>
      <address>
        <city>Salamanca</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H. de Donostia Ntra. Sra. de Aranzazu</name>
      <address>
        <city>San Sebastián</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H. General de Galicia</name>
      <address>
        <city>Santiago De Compostela</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital Virgen del Rocio</name>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Carlos Haya</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital Infantil La Fe</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>H Clinico-Universitario</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Queen Silvia's Children's Hospital</name>
      <address>
        <city>Göteburg</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Childrens Hospital Linkoping</name>
      <address>
        <city>Linkoping</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital</name>
      <address>
        <city>Geneva</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CHUV</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Aberdeen: Royal Aberdeen Children's Hospital</name>
      <address>
        <city>Aberdeen</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Royal Belfast Hospital for Sick Children</name>
      <address>
        <city>Belfast</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Birmingham Children's Hospital</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Bristol Royal Hospital for Children</name>
      <address>
        <city>Bristol</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's NHS Trust</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Llandough Hospital</name>
      <address>
        <city>Cardiff</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Edinburgh Royal Hospital for Sick Children</name>
      <address>
        <city>Edinburgh</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Glasgow Royal Hospital for Sick Children</name>
      <address>
        <city>Glasgow</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Leeds: St James's University Hospital</name>
      <address>
        <city>Leeds</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Leicester Royal Infirmary</name>
      <address>
        <city>Leicester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Liverpool: Alder Hey Children's Hospital</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Great Ormond Street Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>St Bartholomew's Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>UCLH University College London Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Royal Manchester Children's Hospital</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Newcastle: Royal Victoria Infirmary</name>
      <address>
        <city>Newcastle</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Nottingham: Queen's Medical Centre</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Oxford: John Radcliffe Hospital</name>
      <address>
        <city>Oxford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Sheffield Children's Hospital</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Southampton General Hospital</name>
      <address>
        <city>Southhampton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital</name>
      <address>
        <city>Sutton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Czechia</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>Ireland</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Slovakia</country>
    <country>Slovenia</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
  </removed_countries>
  <results_reference>
    <citation>Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, Malis J, Papadakis V, Lacerda A, Ruud E, Kogner P, Garami M, Balwierz W, Schroeder H, Beck-Popovic M, Schreier G, Machin D, Potschger U, Pearson A. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;28(21):3516-24. doi: 10.1200/JCO.2009.27.3524. Epub 2010 Jun 21.</citation>
    <PMID>20567002</PMID>
  </results_reference>
  <results_reference>
    <citation>Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):500-514. doi: 10.1016/S1470-2045(17)30070-0. Epub 2017 Mar 2.</citation>
    <PMID>28259608</PMID>
  </results_reference>
  <results_reference>
    <citation>Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629. doi: 10.1016/S1470-2045(18)30578-3. Epub 2018 Nov 12.</citation>
    <PMID>30442501</PMID>
  </results_reference>
  <results_reference>
    <citation>Morgenstern DA, Potschger U, Moreno L, Papadakis V, Owens C, Ash S, Pasqualini C, Luksch R, Garaventa A, Canete A, Elliot M, Wieczorek A, Laureys G, Kogner P, Malis J, Ruud E, Beck-Popovic M, Schleiermacher G, Valteau-Couanet D, Ladenstein R. Risk stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer. 2018 Nov;65(11):e27363. doi: 10.1002/pbc.27363. Epub 2018 Jul 17.</citation>
    <PMID>30015396</PMID>
  </results_reference>
  <results_reference>
    <citation>Berbegall AP, Bogen D, Potschger U, Beiske K, Bown N, Combaret V, Defferrari R, Jeison M, Mazzocco K, Varesio L, Vicha A, Ash S, Castel V, Coze C, Ladenstein R, Owens C, Papadakis V, Ruud E, Amann G, Sementa AR, Navarro S, Ambros PF, Noguera R, Ambros IM. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. Br J Cancer. 2018 May;118(11):1502-1512. doi: 10.1038/s41416-018-0098-6. Epub 2018 May 14.</citation>
    <PMID>29755120</PMID>
  </results_reference>
  <results_reference>
    <citation>Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S, Brock P, Garaventa A, Valteau-Couanet D, Janzek E, Hosten N, Zinke A, Barthlen W, Varol E, Loibner H, Ladenstein R, Lode HN. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs. 2018 Jan;10(1):55-61. doi: 10.1080/19420862.2017.1402997. Epub 2017 Dec 5.</citation>
    <PMID>29120699</PMID>
  </results_reference>
  <results_reference>
    <citation>Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Ash S, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chi Fung Chan G, Ruud E, Schroeder H, Beck-Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers (Basel). 2020 Jan 28;12(2):309. doi: 10.3390/cancers12020309.</citation>
    <PMID>32013055</PMID>
  </results_reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>October 5, 2012</study_first_submitted>
  <study_first_submitted_qc>October 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 11, 2012</study_first_posted>
  <last_update_submitted>October 21, 2020</last_update_submitted>
  <last_update_submitted_qc>October 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 23, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>neuroblastoma</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>MAT</keyword>
  <keyword>antibody treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aldesleukin</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Melphalan</mesh_term>
    <mesh_term>Busulfan</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
    <mesh_term>Dinutuximab</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/NCT01704716
org study id: HR-NBL-1.8 / SIOPEN
nct id: NCT01704716
lead sponsor: 
has dmc: Yes
This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk
      neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified
      > 12 months at diagnosis).

      The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood
      stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy
      followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour
      and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba
      ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3
      randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody
      is recommended without scIL-2 as continuous infusion as standard of care outside of
      controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba
      ®).

      In the induction phase, all patients receive Rapid COJEC following the result of the R3
      randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned.

      Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and
      complete excision of the primary tumour will be attempted.

      Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the
      end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles.

      After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged
      12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without
      segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop
      treatment after induction therapy and surgery to the primary tumour.

      Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by
      peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.

      The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days
      ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin
      (13-cis-RA) is closed.

      The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total
      dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin
      (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC
      approval.
In this protocol the term high-risk neuroblastoma refers to children with either

        -  disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age
           of one or

        -  INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and
           20% of children with stage 3 and occasional patients with stage 2 disease are
           characterized by amplification of the MycN gene in their tumours. This biological
           characteristic has clearly been shown to be associated with a greater risk of relapse
           and death from disease progression. These patients may benefit from very aggressive
           treatment and, based on this hypothesis, they are included in this protocol. Infants (<
           12 months at diagnosis) with MYCN amplified tumors are included.

      Children with this type of presentation and age represent the largest neuroblastoma subgroup.
      Their prognosis remains poor in most cases and our ability to predict the clinical course and
      the outcome of the individual patient is modest.

      Primary objectives:

      R0 randomization: R0 was opened with the study activation in February 2002 and closed in
      November 2005. The randomized use of G-CSF during COJEC induction resulted in the
      recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia
      (Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic
      granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with
      high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul
      20;3516-24).

      R1 randomization: R1 was opened with the study activation in February 2002 and closed in
      10/2010 following the results showing significant superiority of myeloablative therapy (MAT)
      with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan
      (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan
      and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for
      high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm,
      open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).

      R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric
      ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization
      tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2,
      Proleukin®), following MAT and autologous stem cell transplantation, in addition to
      differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with
      high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr
      10500)).

      R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7
      induction regimen will improve the metastatic response rates or event free survival (EFS) as
      compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630
      randomized patients as planned. There was no difference in event free survival rate between
      both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade
      3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard
      induction treatment with G-CSF support based on the results of the R0 randomization open from
      2002 top 2005 This change has been implemented in amendment 8 of the protocol.

      R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI)
      ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time
      of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in
      relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement
      this more favorable immunotherapy dosing schedule for the time till the induction question R3
      was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate
      of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment
      arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address
      the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be
      addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be
      reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106
      IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course
      s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and
      not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization
      is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization.
      For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as
      continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of
      controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing
      authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Event Free Survival (R1: MAT therapy)
time frame: Up to three years
description: The primary endpoint was the event free survival (EFS) calculated from the date of the first R1 randomisation. The following was considered as event:
disease progression or relapse
death from any cause
second neoplasm
Patients lost to follow up without event were considered at the date of their last follow up evaluation.
R1 has been closed in October 2010 following the results of R1 randomisation showing significant superiority for myeloablative therapy (MAT) with busulfan and melphalan (BuMel) in patients with high risk neuroblastoma over MAT with continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT.
measure: Event Free Survival (immunotherapy)
time frame: Up to three years
description: R2 randomisation comparing immunotherapy with ch14.18/CHO and 13-cis retinoic acid versus 13-cis retinoic acid alone was activated in November 2006. It was amended in July 2009 and compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2). Immunotherapy randomisation has been amended in 2014 (R4 randomisation). The ch14.18/CHO antibody is given as continuous Infusion and the randomisation has lasted until the necessary number of patients for R3 randomisation was reached
The primary endpoint is 3-year event free survival calculated from the date of the second randomisation. The following will be considered as events:
disease progression or relapse
death from any cause
second neoplasm
Patients lost to follow up without event will be censored at the date of their last follow-up evaluation.
measure: Complete metastatic response (R3: Induction therapy)
time frame: Up to 95 days
description: R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.
Complete metastatic response after induction is defined as:
no skeletal uptake on mIBG
Negative bone marrow aspirates (by cytomorphology) and trephines
Absence of other metastatic sites
measure: Event free survival (R3: Induction therapy)
time frame: Up to three years
description: R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.
The primary endpoint is event free survival calculated from the date of the R3-randomisation. The following will be calculated as events:
disease progression or relapse
death from any cause
second neoplasm
Patients lost to follow up without event will be censored at the date of their last follow up evaluation
arm group label: R0: COJEC plus G-CSF
arm group type: Experimental
description: Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose.
arm group label: R0: COJEC
arm group type: Active Comparator
description: Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF
arm group label: R1: BuMel MAT
arm group type: Active Comparator
description: The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan.
In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex)
arm group label: R1: CEM MAT
arm group type: Experimental
description: The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course
arm group label: R2: ch14.18/CHO
arm group type: Active Comparator
description: ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses
arm group label: R2: ch14.18/CHO plus Aldesleukin
arm group type: Experimental
description: Patients randomised to receive ch14.18/CHO plus Aldesleukin
arm group label: R3: COJEC Induction
arm group type: Active Comparator
description: Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days:
Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide
arm group label: R3: Modified N7
arm group type: Experimental
description: The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E).
arm group label: R4: cnt inf ch14.18/CHO
arm group type: Active Comparator
description: ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO
arm group label: R4: cnt inf ch14.18/CHO plus Aldesleukin
arm group type: Experimental
description: ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO.
In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion
intervention type: Drug
intervention name: Vincristine
description: given during Rapid COJEC and modified N7 therapy
arm group label: R0: COJEC
arm group label: R3: COJEC Induction
arm group label: R3: Modified N7
intervention type: Drug
intervention name: Aldesleukin
description: Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
arm group label: R2: ch14.18/CHO plus Aldesleukin
arm group label: R4: cnt inf ch14.18/CHO plus Aldesleukin
other name: Interleukin 2, IL-2, IL2
intervention type: Drug
intervention name: ch14.18/CHO
description: ch14.18/CHO antibody is given during MRD treatment
arm group label: R2: ch14.18/CHO
arm group label: R2: ch14.18/CHO plus Aldesleukin
arm group label: R4: cnt inf ch14.18/CHO
arm group label: R4: cnt inf ch14.18/CHO plus Aldesleukin
other name: anti GD2 antibody
other name: Dinutuximab beta EUSA
other name: Qarziba®
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
arm group label: R0: COJEC
arm group label: R0: COJEC plus G-CSF
arm group label: R1: CEM MAT
arm group label: R3: COJEC Induction
other name: Paraplatin
intervention type: Drug
intervention name: Etoposide
description: Etoposide is given during Induction Treatment (both R3 randomisation arms)
arm group label: R0: COJEC
arm group label: R0: COJEC plus G-CSF
arm group label: R1: CEM MAT
arm group label: R3: COJEC Induction
arm group label: R3: Modified N7
other name: VP16
intervention type: Drug
intervention name: Cisplatin
description: Cisplatin is given during Induction Treatment (both R3 randomisation arms)
arm group label: R0: COJEC
arm group label: R0: COJEC plus G-CSF
arm group label: R3: COJEC Induction
arm group label: R3: Modified N7
other name: CDDP
intervention type: Drug
intervention name: Cyclophosphamide
description: Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
arm group label: R0: COJEC
arm group label: R0: COJEC plus G-CSF
arm group label: R3: COJEC Induction
arm group label: R3: Modified N7
other name: Endoxan
intervention type: Drug
intervention name: Doxorubicin
description: Doxorubicin is given during Induction Treatment (R3 arm modified N7)
arm group label: R3: Modified N7
other name: Adriamycin
intervention type: Drug
intervention name: G-CSF
description: G-CSF is given during Induction Treatment
arm group label: R0: COJEC plus G-CSF
other name: Filgrastim
intervention type: Drug
intervention name: Busulfan
description: In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
arm group label: R1: BuMel MAT
other name: Busilvex
other name: Myleran
other name: Busulphan
intervention type: Drug
intervention name: Melphalan
description: Melphalan is given during MAT treatment
arm group label: R1: BuMel MAT
arm group label: R1: CEM MAT
other name: Alkeran
criteria: 
gender: All
minimum age: 1 Month
maximum age: 21 Years
healthy volunteers: No
last name: Ruth L Ladenstein, MD, MBA, cPM
role: Principal Investigator
affiliation: St. Anna Kinderkrebsforschung
last name: Ruth L Ladenstein, MD, MBA, cPM
phone: 0043140470
phone ext: 4750
email: ruth.ladenstein@ccri.at
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country: Australia
country: Austria
country: Belgium
country: Czechia
country: Denmark
country: France
country: Greece
country: Hungary
country: Ireland
country: Israel
country: Italy
country: Norway
country: Poland
country: Portugal
country: Slovakia
country: Slovenia
country: Spain
country: Sweden
country: Switzerland
country: United Kingdom
country: Czech Republic
citation: Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, Malis J, Papadakis V, Lacerda A, Ruud E, Kogner P, Garami M, Balwierz W, Schroeder H, Beck-Popovic M, Schreier G, Machin D, Potschger U, Pearson A. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;28(21):3516-24. doi: 10.1200/JCO.2009.27.3524. Epub 2010 Jun 21.
PMID: 20567002
citation: Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):500-514. doi: 10.1016/S1470-2045(17)30070-0. Epub 2017 Mar 2.
PMID: 28259608
citation: Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629. doi: 10.1016/S1470-2045(18)30578-3. Epub 2018 Nov 12.
PMID: 30442501
citation: Morgenstern DA, Potschger U, Moreno L, Papadakis V, Owens C, Ash S, Pasqualini C, Luksch R, Garaventa A, Canete A, Elliot M, Wieczorek A, Laureys G, Kogner P, Malis J, Ruud E, Beck-Popovic M, Schleiermacher G, Valteau-Couanet D, Ladenstein R. Risk stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer. 2018 Nov;65(11):e27363. doi: 10.1002/pbc.27363. Epub 2018 Jul 17.
PMID: 30015396
citation: Berbegall AP, Bogen D, Potschger U, Beiske K, Bown N, Combaret V, Defferrari R, Jeison M, Mazzocco K, Varesio L, Vicha A, Ash S, Castel V, Coze C, Ladenstein R, Owens C, Papadakis V, Ruud E, Amann G, Sementa AR, Navarro S, Ambros PF, Noguera R, Ambros IM. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. Br J Cancer. 2018 May;118(11):1502-1512. doi: 10.1038/s41416-018-0098-6. Epub 2018 May 14.
PMID: 29755120
citation: Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S, Brock P, Garaventa A, Valteau-Couanet D, Janzek E, Hosten N, Zinke A, Barthlen W, Varol E, Loibner H, Ladenstein R, Lode HN. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs. 2018 Jan;10(1):55-61. doi: 10.1080/19420862.2017.1402997. Epub 2017 Dec 5.
PMID: 29120699
citation: Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Ash S, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chi Fung Chan G, Ruud E, Schroeder H, Beck-Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers (Basel). 2020 Jan 28;12(2):309. doi: 10.3390/cancers12020309.
PMID: 32013055
responsible party type: Sponsor
mesh term: Neuroblastoma
mesh term: Aldesleukin
mesh term: Cyclophosphamide
mesh term: Melphalan
mesh term: Busulfan
mesh term: Carboplatin
mesh term: Doxorubicin
mesh term: Etoposide
mesh term: Vincristine
mesh term: Interleukin-2
mesh term: Dinutuximab