<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/NCT03042429</url>
  </required_header>
  <id_info>
    <org_study_id>UCologne</org_study_id>
    <nct_id>NCT03042429</nct_id>
  </id_info>
  <brief_title>Combination Chemotherapy Followed by Stem Cell Transplant in High-risk Neuroblastoma Patients</brief_title>
  <acronym>NB2004-HR</acronym>
  <official_title>Combination Chemotherapy Followed by Stem Cell Transplant and Isotretinoin in Treating Young Patients With High-risk Neuroblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cologne</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Cologne</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Improvement of event free survival of high-risk neuroblastoma patients by introduction of two&#xD;
      additional topotecan containing chemotherapy cycles into the multimodal standard treatment&#xD;
      (induction chemotherapy, myeloablative therapy, radiation, surgery as indicated, and&#xD;
      consolidation therapy).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Experimental intervention (6 weeks + duration of the control intervention):&#xD;
&#xD;
      2 x N8 cycle (topotecan, cyclophosphamide, and etoposide) followed by standard arm treatment&#xD;
      (i.e., control intervention)&#xD;
&#xD;
      Control intervention (total duration 70-76 weeks):&#xD;
&#xD;
      3 x N5 cycle (cisplatin, etoposide, and vindesine) 3 x N6 cycle (vincristine, dacarbacine,&#xD;
      ifosfamide, and doxorubicine), myeloablative chemotherapy with autologous stem cell&#xD;
      transplantation (melphalan, carboplatin, etoposide) 9 x retinoic acid cycles (6 months, 3&#xD;
      months break, 3 months) supportive care (PCP/fungal prophylaxis, transfusions, antibiotics,&#xD;
      G-CSF)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2007</start_date>
  <completion_date type="Actual">December 31, 2016</completion_date>
  <primary_completion_date type="Actual">December 31, 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Randomized, multi-center, non-blinded, prospective, controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>no masking</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Event free survival</measure>
    <time_frame>up to 9 years</time_frame>
    <description>days from diagnosis to Event or last follow-up</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>up to 9 years</time_frame>
    <description>days from diagnosis to death or last follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>early response</measure>
    <time_frame>up to 3 months</time_frame>
    <description>remission status (INRG) measured after 2 chemotherapy cycles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>late response</measure>
    <time_frame>up to 9 months</time_frame>
    <description>remission status (INRG) measured before stem cell transplant</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">360</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>experimental arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: Cycles N8, N5, and N6 Drug: topotecan, cyclophosphamide, and etoposide (N8 cycle) followed by Drug: cisplatin, etoposide, and vindesine (N5 cycle) and Drug: vincristine, dacarbacine, ifosfamide, and doxorubicine (N6 cycle) followed by myeloablative chemotherapy with autologous stem cell transplantation (melphalan, carboplatin, etoposide) and by 9 x retinoic acid cycles (6 months, 3 months break, 3 months)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>standard arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Drug: Cycles N5 and N6 Drug: cisplatin, etoposide, and vindesine (N5 cycle) and Drug: vincristine, dacarbacine, ifosfamide, and doxorubicine (N6 cycle) followed by myeloablative chemotherapy with autologous stem cell transplantation (melphalan, carboplatin, etoposide) and by 9 x retinoic acid cycles (6 months, 3 months break, 3 months)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cycles N8, N5 and N6</intervention_name>
    <description>two chemotherapy cycles N8 followed by standard arm therapy</description>
    <arm_group_label>experimental arm</arm_group_label>
    <other_name>topotecan, cyclophosphamide, etoposide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cycles N5 and N6</intervention_name>
    <description>Standard arm six chemotherapy cycles (3xN5 and 3x N6) followed by myeloablative therapy with stem cell support and isotretinoin</description>
    <arm_group_label>standard arm</arm_group_label>
    <other_name>cisplatin, vindesine, ifosfamide, dacarbacine, doxorubicine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  neuroblastoma&#xD;
&#xD;
          -  stage 4 neuroblastoma and age ≥1 - 21 years or MYCN amplification and age ≥6 months -&#xD;
             21 years&#xD;
&#xD;
          -  informed consent obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participation in other trials&#xD;
&#xD;
          -  Pregnancy, lactation, or insufficient contraception for girls in childbearing age,&#xD;
&#xD;
          -  Any concomitant non-protocol anticancer therapy,&#xD;
&#xD;
          -  Incomplete initial staging.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frank Berthold, Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>University of Cologne</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Cologne</name>
      <address>
        <city>Koln</city>
        <zip>50924</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <results_reference>
    <citation>Berthold F, Hero B, Kremens B, Handgretinger R, Henze G, Schilling FH, Schrappe M, Simon T, Spix C. Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett. 2003 Jul 18;197(1-2):11-7. doi: 10.1016/s0304-3835(03)00076-4.</citation>
    <PMID>12880954</PMID>
  </results_reference>
  <results_reference>
    <citation>Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, Klingebiel T, Kremens B, Schilling FH, Schrappe M, Simon T, Hero B. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 2005 Sep;6(9):649-58. doi: 10.1016/S1470-2045(05)70291-6.</citation>
    <PMID>16129365</PMID>
  </results_reference>
  <results_reference>
    <citation>Langler A, Christaras A, Abshagen K, Krauth K, Hero B, Berthold F. Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood - a phase-II-study. Klin Padiatr. 2002 Jul-Aug;214(4):153-6. doi: 10.1055/s-2002-33175.</citation>
    <PMID>12165894</PMID>
  </results_reference>
  <results_reference>
    <citation>Berthold F, Hero B. Neuroblastoma: current drug therapy recommendations as part of the total treatment approach. Drugs. 2000 Jun;59(6):1261-77. doi: 10.2165/00003495-200059060-00006.</citation>
    <PMID>10882162</PMID>
  </results_reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>February 1, 2017</study_first_submitted>
  <study_first_submitted_qc>February 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 3, 2017</study_first_posted>
  <last_update_submitted>February 3, 2017</last_update_submitted>
  <last_update_submitted_qc>February 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cologne</investigator_affiliation>
    <investigator_full_name>Frank Berthold</investigator_full_name>
    <investigator_title>Prof. Dr.</investigator_title>
  </responsible_party>
  <keyword>neuroblastoma</keyword>
  <keyword>chemotherapy</keyword>
  <keyword>autologous stem cell transplantation</keyword>
  <keyword>radiotherapy</keyword>
  <keyword>mIBG</keyword>
  <keyword>tumor resection</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>Cyclophosphamide</mesh_term>
    <mesh_term>Ifosfamide</mesh_term>
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Topotecan</mesh_term>
    <mesh_term>Vindesine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03042429
org study id: UCologne
nct id: NCT03042429
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Improvement of event free survival of high-risk neuroblastoma patients by introduction of two
      additional topotecan containing chemotherapy cycles into the multimodal standard treatment
      (induction chemotherapy, myeloablative therapy, radiation, surgery as indicated, and
      consolidation therapy).
Experimental intervention (6 weeks + duration of the control intervention):

      2 x N8 cycle (topotecan, cyclophosphamide, and etoposide) followed by standard arm treatment
      (i.e., control intervention)

      Control intervention (total duration 70-76 weeks):

      3 x N5 cycle (cisplatin, etoposide, and vindesine) 3 x N6 cycle (vincristine, dacarbacine,
      ifosfamide, and doxorubicine), myeloablative chemotherapy with autologous stem cell
      transplantation (melphalan, carboplatin, etoposide) 9 x retinoic acid cycles (6 months, 3
      months break, 3 months) supportive care (PCP/fungal prophylaxis, transfusions, antibiotics,
      G-CSF)
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: Randomized, multi-center, non-blinded, prospective, controlled trial
primary purpose: Treatment
masking: None (Open Label)
masking description: no masking
measure: Event free survival
time frame: up to 9 years
description: days from diagnosis to Event or last follow-up
measure: Overall survival
time frame: up to 9 years
description: days from diagnosis to death or last follow-up
measure: early response
time frame: up to 3 months
description: remission status (INRG) measured after 2 chemotherapy cycles
measure: late response
time frame: up to 9 months
description: remission status (INRG) measured before stem cell transplant
arm group label: experimental arm
arm group type: Experimental
description: Drug: Cycles N8, N5, and N6 Drug: topotecan, cyclophosphamide, and etoposide (N8 cycle) followed by Drug: cisplatin, etoposide, and vindesine (N5 cycle) and Drug: vincristine, dacarbacine, ifosfamide, and doxorubicine (N6 cycle) followed by myeloablative chemotherapy with autologous stem cell transplantation (melphalan, carboplatin, etoposide) and by 9 x retinoic acid cycles (6 months, 3 months break, 3 months)
arm group label: standard arm
arm group type: Active Comparator
description: Drug: Cycles N5 and N6 Drug: cisplatin, etoposide, and vindesine (N5 cycle) and Drug: vincristine, dacarbacine, ifosfamide, and doxorubicine (N6 cycle) followed by myeloablative chemotherapy with autologous stem cell transplantation (melphalan, carboplatin, etoposide) and by 9 x retinoic acid cycles (6 months, 3 months break, 3 months)
intervention type: Drug
intervention name: Cycles N8, N5 and N6
description: two chemotherapy cycles N8 followed by standard arm therapy
arm group label: experimental arm
other name: topotecan, cyclophosphamide, etoposide
intervention type: Drug
intervention name: Cycles N5 and N6
description: Standard arm six chemotherapy cycles (3xN5 and 3x N6) followed by myeloablative therapy with stem cell support and isotretinoin
arm group label: standard arm
other name: cisplatin, vindesine, ifosfamide, dacarbacine, doxorubicine
criteria: 
gender: All
minimum age: 6 Months
maximum age: 21 Years
healthy volunteers: No
last name: Frank Berthold, Prof.
role: Study Chair
affiliation: University of Cologne
facility: 
country: Germany
citation: Berthold F, Hero B, Kremens B, Handgretinger R, Henze G, Schilling FH, Schrappe M, Simon T, Spix C. Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett. 2003 Jul 18;197(1-2):11-7. doi: 10.1016/s0304-3835(03)00076-4.
PMID: 12880954
citation: Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, Klingebiel T, Kremens B, Schilling FH, Schrappe M, Simon T, Hero B. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 2005 Sep;6(9):649-58. doi: 10.1016/S1470-2045(05)70291-6.
PMID: 16129365
citation: Langler A, Christaras A, Abshagen K, Krauth K, Hero B, Berthold F. Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood - a phase-II-study. Klin Padiatr. 2002 Jul-Aug;214(4):153-6. doi: 10.1055/s-2002-33175.
PMID: 12165894
citation: Berthold F, Hero B. Neuroblastoma: current drug therapy recommendations as part of the total treatment approach. Drugs. 2000 Jun;59(6):1261-77. doi: 10.2165/00003495-200059060-00006.
PMID: 10882162
responsible party type: Principal Investigator
investigator affiliation: University of Cologne
investigator full name: Frank Berthold
investigator title: Prof. Dr.
mesh term: Neuroblastoma
mesh term: Cyclophosphamide
mesh term: Ifosfamide
mesh term: Cisplatin
mesh term: Doxorubicin
mesh term: Etoposide
mesh term: Topotecan
mesh term: Vindesine
sharing ipd: No