<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/NCT01701479</url>
  </required_header>
  <id_info>
    <org_study_id>012010</org_study_id>
    <secondary_id>2009-018077-31</secondary_id>
    <nct_id>NCT01701479</nct_id>
  </id_info>
  <brief_title>Long Term Continuous Infusion ch14.18/CHO Plus s.c. Aldesleukin (IL-2)</brief_title>
  <acronym>LTI</acronym>
  <official_title>A Phase I/II Dose Schedule Finding Study of ch14.18/CHO Continuous Infusion Combined With Subcutaneous Aldesleukin (IL-2) in Patients With Primary Refractory or Relapsed Neuroblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Anna Kinderkrebsforschung</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Medicine Greifswald</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Anna Children's Hospital, Vienna</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Universitario La Fe</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Istituto Giannina Gaslini</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Gustave Roussy, Cancer Campus, Grand Paris</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Schneider Children's Medical Center, Israel</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Great Ormond Street Hospital for Children NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Toulouse</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Johann Wolfgang Goethe University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Jena University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's University Hospital, Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Tuebingen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alder Hey Children's NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospitals Bristol and Weston NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Newcastle-upon-Tyne Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leeds Teaching Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>NHS Greater Glasgow and Clyde</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical University of Graz</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical University Innsbruck</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre Leon Berard</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Infantil Universitario Niño Jesús, Madrid, Spain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Southampton NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut Curie</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Anna Kinderkrebsforschung</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main aim of this clinical trial is to find a way of giving ch14.18/CHO, in combination&#xD;
      with subcutaneous aldesleukin (IL-2) and oral isotretinoin (13-cis-RA), to children and young&#xD;
      people with primary refractory or relapsed neuroblastoma without intravenous morphine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although a lot of children and young people with neuroblastoma can be cured with current&#xD;
      standard chemotherapy, sometimes, particularly at relapse the disease no longer responds to&#xD;
      standard drugs. Therefore, there is a need to find new drug combinations which will act&#xD;
      against neuroblastoma which no longer responds to standard drugs.&#xD;
&#xD;
      Ch14.18/CHO has been shown to improve the outcome of patients with neuroblastoma. However,&#xD;
      one of the side effects of receiving ch14.18/CHO is severe pain. High doses of intravenous&#xD;
      morphine are needed to control the pain and this means that patients must stay in hospital.&#xD;
      Results from other clinical trials have shown that giving ch14.18/CHO over a longer time&#xD;
      reduces pain, yet the drug still works just as well to fight the neuroblastoma. The clinical&#xD;
      trial aims to give ch14.18/CHO over a longer time so that intravenous morphine is not needed&#xD;
      and that this treatment regimen can ultimately be given in an outpatient setting.&#xD;
&#xD;
      Ch14.18/CHO is a monoclonal antibody. Monoclonal antibodies are made in the laboratory and&#xD;
      are designed to bind to specific cancer cells. Ch14.18/CHO was designed to bind to&#xD;
      neuroblastoma cells and other cancer cells that express the GD-2 antigen. The GD-2 antigen is&#xD;
      expressed by virtually all neuroblastoma cells. An antigen is a substance that stimulates an&#xD;
      immune response in the body by producing antibodies. Thus, when ch14.18/CHO binds to the&#xD;
      neuroblastoma cells, the body's immune system is stimulated to attack and kill the&#xD;
      neuroblastoma cells. Ch14.18/CHO is called chimeric, because it was genetically engineered to&#xD;
      consist of 30% mouse-protein and of 70% human protein.&#xD;
&#xD;
      Ch14.18/CHO represents a new kind of cancer therapy that, unlike chemotherapy and radiation,&#xD;
      targets the destruction of cancer cells without destroying nearby healthy cells. There is&#xD;
      laboratory evidence to suggest that ch14.18/CHO can activate the body's own immune cells to&#xD;
      destroy cancer cells. These immune cells include killer cells that are activated or&#xD;
      stimulated by aldesleukin (IL-2). Therefore this treatment is a combination of ch14.18/CHO&#xD;
      and aldesleukin (IL-2).&#xD;
&#xD;
      Aldesleukin (IL-2) is a substance that is similar to a substance made by the body in all&#xD;
      individuals. Under normal circumstances, the body makes small amounts of aldesleukin (IL-2)&#xD;
      that help white blood cells fight infection. It is now possible to make aldesleukin (IL-2) in&#xD;
      the laboratory and give humans much higher doses than their own body makes. There is evidence&#xD;
      in the laboratory and in animals that aldesleukin (IL-2) increases the anti-cancer effect of&#xD;
      monoclonal antibodies like ch14.18/CHO. We wish to study whether aldesleukin (IL-2) can help&#xD;
      improve the effectiveness of ch14.18/CHO in humans.&#xD;
&#xD;
      In addition to ch14.18/CHO and aldesleukin (IL-2), isotretinoin (13-cis-RA) will also be&#xD;
      given. Isotretinoin (13-cis-RA) is considered standard treatment for patients with&#xD;
      neuroblastoma and works by induction of neuroblastoma cell death.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>January 2012</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The patients will be randomised to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Event free survival</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>The primary endpoint is event free survival calculated from the date of randomisation. The following will be considered as events:&#xD;
disease progression or relapse&#xD;
death from any cause&#xD;
second neoplasm</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain-toxicity endpoint</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>assessment of pain intensity and relief by appropriate medication with a validated self-report tool (Wong-Baker Faces Pain Rating Scale, FPS-R)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy endpoint</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>validation of the correlation between activated NK cells and ch14.18/CHO level with ADCC by using serum and MNC from patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic immune modulation/response</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2) in the standard treatment arm.</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of pharmacokinetics of ch14.18/CHO by assessing blood levels of ch14.18/CHO via ELISA (Enzyme-linked-Immunosorbent Assay)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>determination of the pharmacokinetics of ch14.18/CHO (ELISA analysis of ch14.18/CHO blood levels)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of anti-tumour response in patients with measureable disease</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Bone marrow, skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site as measured by immunocytology, mIBG, CT and/or MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of impact of KIR/KIRL mismatch and Fc receptor polymorphisms on EFS (PCR sequence-specific primer technique)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>Immunomodulation induced by the treatment will be complemented by a whole blood assay. Fc Receptor polymorphisms and KIR/KIR Ligand mismatch analysis will be done via KIR genotyping on patient DNA samples by PCR sequence-specific primer technique</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">288</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>Experimental arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subcutaneous aldesleukin (IL-2) will be given at a dose of 6 x 106 IU/m2/day in two 5 day blocks (days 1-5 and 8-12).&#xD;
A continuous infusion of ch14.18/CHO is started on day 8. The duration of the infusion is dependent on the assigned infusion schedule. The duration will range from 10 to 21 days. Three dose levels will be considered with respect to daily dose (7 mg/m2, 10 mg/m2, 15 mg/m2), which relates to total doses of 100 mg/m2,150 mg/m2 and 210 mg/m2.&#xD;
Patients will receive isotretinoin (13-cis-RA) 160 mg/m²/day divided into two equal doses given orally twice a day for 14 days after the completion of the ch14.18/CHO infusion. The starting day is dependent on the duration of ch14.18/CHO infusion and may be either day 19, 23, 24 or 30.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Comparator arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A continuous infusion of ch14.18/CHO is started on day 8. The duration of the infusion is dependent on the assigned infusion schedule. The duration will range from 10 to 21 days. Three dose levels will be considered with respect to daily dose (7 mg/m2, 10 mg/m2, 15 mg/m2), which relates to total doses of 100 mg/m2,150 mg/m2 and 210 mg/m2.&#xD;
Patients will receive isotretinoin (13-cis-RA) 160 mg/m²/day divided into two equal doses given orally twice a day for 14 days after the completion of the ch14.18/CHO infusion. The starting day is dependent on the duration of ch14.18/CHO infusion and may be either day 19, 23, 24 or 30.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ch14.18/CHO</intervention_name>
    <arm_group_label>Comparator arm</arm_group_label>
    <arm_group_label>Experimental arm</arm_group_label>
    <other_name>Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cells</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aldesleukin</intervention_name>
    <arm_group_label>Experimental arm</arm_group_label>
    <other_name>Proleukin</other_name>
    <other_name>Interleukin-2</other_name>
    <other_name>IL-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotretinoin</intervention_name>
    <arm_group_label>Comparator arm</arm_group_label>
    <arm_group_label>Experimental arm</arm_group_label>
    <other_name>13-cis-Retinoic acid</other_name>
    <other_name>13-cis-RA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At study entry patients must be &gt; 1 year but &lt;= 21 years of age. NOTE: Patients &gt;21&#xD;
             years but &lt;= 45 years of age, fulfilling the remaining criteria, may be enrolled in&#xD;
             the study. These patients will be analysed separately and will not be included in the&#xD;
             dose finding schedule algorithm. The purpose for inclusion of the older patients is to&#xD;
             enable the collection of tolerability data.&#xD;
&#xD;
          -  Patients must be diagnosed with neuroblastoma according to the INSS criteria.&#xD;
&#xD;
          -  Must have received at least one previous high dose treatment followed by stem cell&#xD;
             rescue after conventional therapy.&#xD;
&#xD;
          -  Must fulfil one of the following criteria:&#xD;
&#xD;
          -  Patients with stage 4 neuroblastoma on the current high-risk SIOPEN trial&#xD;
             (HR-NBL-1/SIOPEN) either with primary refractory disease having had more than two&#xD;
             front-line treatments or patients ineligible for the R2 randomization due to major&#xD;
             delays after completed high-dose treatments.&#xD;
&#xD;
          -  Treated and responding relapse after primary stage 4 disease, without signs of&#xD;
             progression at study entry&#xD;
&#xD;
          -  Treated and responding disseminated relapse after primary localized neuroblastoma&#xD;
             without signs of progression at study entry.&#xD;
&#xD;
          -  Patients must have a performance status greater or equal 70% (Lansky Score or&#xD;
             Karnofsky, see Appendix 1: performance Scales , page 91)&#xD;
&#xD;
          -  Patients must have an estimated life expectancy of at least 12 weeks.&#xD;
&#xD;
          -  Patients must consent to the placement of a central venous line, if one has not&#xD;
             already been placed.&#xD;
&#xD;
          -  Patients must be off any standard or experimental treatments for at least two weeks&#xD;
             prior to study entry and be fully recovered from the short term major toxic effects.&#xD;
&#xD;
          -  Patients must have no immediate requirements for palliative chemotherapy, radiotherapy&#xD;
             or surgery.&#xD;
&#xD;
          -  At least 4 weeks after major surgery (e.g. laporotomy or thoracotomy) and fully&#xD;
             recovered from any post-surgical complications.&#xD;
&#xD;
          -  HIV and Hepatitis B negative.&#xD;
&#xD;
          -  Females of childbearing potential must have a negative pregnancy test. Patients of&#xD;
             childbearing potential must agree to use an effective birth control method. Female&#xD;
             patients who are lactating must agree to stop breast-feeding.&#xD;
&#xD;
          -  Patients may have had prior CNS metastasis providing the following criteria are all&#xD;
             met:&#xD;
&#xD;
          -  the patient's CNS disease has been previously treated,&#xD;
&#xD;
          -  the patient's CNS disease has been clinically stable for four weeks prior to starting&#xD;
             this study (assessment must be made clinically and by CT or MRI scan),&#xD;
&#xD;
          -  the patient is off steroids for CNS disease for four weeks prior to starting on study&#xD;
             and during the course of the study.&#xD;
&#xD;
          -  Patients with seizure disorders may be enrolled if on anticonvulsants and are well&#xD;
             controlled.&#xD;
&#xD;
          -  All patients and/or their parents or legal guardians must sign a written informed&#xD;
             consent&#xD;
&#xD;
          -  All institutional and national requirements for human studies must be met.&#xD;
&#xD;
          -  Laboratory Testing:&#xD;
&#xD;
          -  Patients should have a shortening fraction of &gt;= 30 % by Echocardiogram.&#xD;
&#xD;
          -  Patients should have FEV1 and FVC &gt;60% of the predicted by pulmonary function tests.&#xD;
             Children unable to do PFTs should have no dyspnea at rest and a pulse oximetry &gt;94% on&#xD;
             room air.&#xD;
&#xD;
          -  All patients must have adequate bone marrow function as defined by ANC &gt;1 10^9/L,&#xD;
             platelets &gt;= 50 10^9/L and haemoglobin &gt; 9.0 g/dL.&#xD;
&#xD;
          -  Patients must have adequate liver function, as defined by an ALT or AST &lt; 5 x normal&#xD;
             and a total bilirubin &lt; 1.0 mg/dL.&#xD;
&#xD;
          -  Patients must have adequate renal function, as defined by a serum creatinine &lt;1.5&#xD;
             mg/dL or a creatinine clearance or radioisotope GFR of &gt; 60 mL/minute/1.73m2.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with progressive disease&#xD;
&#xD;
          -  Patients who have previously received treatment with ch14.18/SP2/0 and/or ch14.18/CHO.&#xD;
&#xD;
          -  Platelet transfusion dependent.&#xD;
&#xD;
          -  Patients with significant intercurrent illnesses and/or any of the following:&#xD;
&#xD;
          -  Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm&#xD;
             disturbance.&#xD;
&#xD;
          -  Patients with significant psychiatric disabilities or uncontrolled seizure disorders.&#xD;
&#xD;
          -  Patients with active infections.&#xD;
&#xD;
          -  Patients with a clinically significant neurologic deficit or objective peripheral&#xD;
             neuropathy (Grade &gt;2) are ineligible.&#xD;
&#xD;
          -  Patients with clinically significant, symptomatic, pleural effusions.&#xD;
&#xD;
          -  Patients who require, or are likely to require, corticosteroid or other&#xD;
             immunosuppressive drugs.&#xD;
&#xD;
          -  Concurrent treatment with any non-trial anticancer therapies.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Holger Lode, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medicine Greifswald</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St. Anna Kinderspital</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Paris</city>
        <zip>75248</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital</name>
      <address>
        <city>Greifswald</city>
        <zip>17475</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Schneider Children's Medical Centre of Israel</name>
      <address>
        <city>Petach Tikvah</city>
        <zip>49202</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gaslini Children's Hospital</name>
      <address>
        <city>Genova</city>
        <zip>16147</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La Fe</name>
      <address>
        <city>Valencia</city>
        <zip>46009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Birmingham Children's Hospital NHS Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <zip>B4 6NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Bristol NHS Foundation Trust</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8BJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leeds Teaching Hospitals NHS Trust</name>
      <address>
        <city>Leeds</city>
        <zip>LS1 3EX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alder Hey Children's NHS Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <zip>L12 2AP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College Hospitals NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW1 2BU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Ormond Street Hospital for Children NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>WC1N 3JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Newcastle upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle</city>
        <zip>NE1 4LP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>France</country>
    <country>Germany</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Spain</country>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.kinderkrebsforschung.at/</url>
    <description>Related Info</description>
  </link>
  <link>
    <url>https://www.siopen-r-net.org/</url>
    <description>Related Info</description>
  </link>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>October 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <last_update_submitted>July 9, 2020</last_update_submitted>
  <last_update_submitted_qc>July 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Neuroblastoma</keyword>
  <keyword>Refractory neuroblastoma</keyword>
  <keyword>Relapsed neuroblastoma</keyword>
  <keyword>ch14.18/CHO</keyword>
  <keyword>Aldesleukin (IL-2)</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>Interleukin-2</mesh_term>
    <mesh_term>Dinutuximab</mesh_term>
    <mesh_term>Isotretinoin</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/NCT01701479
org study id: 012010
secondary id: 2009-018077-31
nct id: NCT01701479
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has dmc: Yes
The main aim of this clinical trial is to find a way of giving ch14.18/CHO, in combination
      with subcutaneous aldesleukin (IL-2) and oral isotretinoin (13-cis-RA), to children and young
      people with primary refractory or relapsed neuroblastoma without intravenous morphine.
Although a lot of children and young people with neuroblastoma can be cured with current
      standard chemotherapy, sometimes, particularly at relapse the disease no longer responds to
      standard drugs. Therefore, there is a need to find new drug combinations which will act
      against neuroblastoma which no longer responds to standard drugs.

      Ch14.18/CHO has been shown to improve the outcome of patients with neuroblastoma. However,
      one of the side effects of receiving ch14.18/CHO is severe pain. High doses of intravenous
      morphine are needed to control the pain and this means that patients must stay in hospital.
      Results from other clinical trials have shown that giving ch14.18/CHO over a longer time
      reduces pain, yet the drug still works just as well to fight the neuroblastoma. The clinical
      trial aims to give ch14.18/CHO over a longer time so that intravenous morphine is not needed
      and that this treatment regimen can ultimately be given in an outpatient setting.

      Ch14.18/CHO is a monoclonal antibody. Monoclonal antibodies are made in the laboratory and
      are designed to bind to specific cancer cells. Ch14.18/CHO was designed to bind to
      neuroblastoma cells and other cancer cells that express the GD-2 antigen. The GD-2 antigen is
      expressed by virtually all neuroblastoma cells. An antigen is a substance that stimulates an
      immune response in the body by producing antibodies. Thus, when ch14.18/CHO binds to the
      neuroblastoma cells, the body's immune system is stimulated to attack and kill the
      neuroblastoma cells. Ch14.18/CHO is called chimeric, because it was genetically engineered to
      consist of 30% mouse-protein and of 70% human protein.

      Ch14.18/CHO represents a new kind of cancer therapy that, unlike chemotherapy and radiation,
      targets the destruction of cancer cells without destroying nearby healthy cells. There is
      laboratory evidence to suggest that ch14.18/CHO can activate the body's own immune cells to
      destroy cancer cells. These immune cells include killer cells that are activated or
      stimulated by aldesleukin (IL-2). Therefore this treatment is a combination of ch14.18/CHO
      and aldesleukin (IL-2).

      Aldesleukin (IL-2) is a substance that is similar to a substance made by the body in all
      individuals. Under normal circumstances, the body makes small amounts of aldesleukin (IL-2)
      that help white blood cells fight infection. It is now possible to make aldesleukin (IL-2) in
      the laboratory and give humans much higher doses than their own body makes. There is evidence
      in the laboratory and in animals that aldesleukin (IL-2) increases the anti-cancer effect of
      monoclonal antibodies like ch14.18/CHO. We wish to study whether aldesleukin (IL-2) can help
      improve the effectiveness of ch14.18/CHO in humans.

      In addition to ch14.18/CHO and aldesleukin (IL-2), isotretinoin (13-cis-RA) will also be
      given. Isotretinoin (13-cis-RA) is considered standard treatment for patients with
      neuroblastoma and works by induction of neuroblastoma cell death.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The patients will be randomised to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2).
primary purpose: Treatment
masking: None (Open Label)
measure: Event free survival
time frame: through study completion, an average of 1 year
description: The primary endpoint is event free survival calculated from the date of randomisation. The following will be considered as events:
disease progression or relapse
death from any cause
second neoplasm
measure: Pain-toxicity endpoint
time frame: through study completion, an average of 1 year
description: assessment of pain intensity and relief by appropriate medication with a validated self-report tool (Wong-Baker Faces Pain Rating Scale, FPS-R)
measure: Efficacy endpoint
time frame: through study completion, an average of 1 year
description: validation of the correlation between activated NK cells and ch14.18/CHO level with ADCC by using serum and MNC from patients
measure: Systemic immune modulation/response
time frame: through study completion, an average of 1 year
description: repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA)
measure: Assessment of absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2) in the standard treatment arm.
time frame: through study completion, an average of 1 year
measure: Determination of pharmacokinetics of ch14.18/CHO by assessing blood levels of ch14.18/CHO via ELISA (Enzyme-linked-Immunosorbent Assay)
time frame: through study completion, an average of 1 year
description: determination of the pharmacokinetics of ch14.18/CHO (ELISA analysis of ch14.18/CHO blood levels)
measure: Evaluation of anti-tumour response in patients with measureable disease
time frame: through study completion, an average of 1 year
description: Bone marrow, skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site as measured by immunocytology, mIBG, CT and/or MRI
measure: Evaluation of impact of KIR/KIRL mismatch and Fc receptor polymorphisms on EFS (PCR sequence-specific primer technique)
time frame: through study completion, an average of 1 year
description: Immunomodulation induced by the treatment will be complemented by a whole blood assay. Fc Receptor polymorphisms and KIR/KIR Ligand mismatch analysis will be done via KIR genotyping on patient DNA samples by PCR sequence-specific primer technique
arm group label: Experimental arm
arm group type: Experimental
description: Subcutaneous aldesleukin (IL-2) will be given at a dose of 6 x 106 IU/m2/day in two 5 day blocks (days 1-5 and 8-12).
A continuous infusion of ch14.18/CHO is started on day 8. The duration of the infusion is dependent on the assigned infusion schedule. The duration will range from 10 to 21 days. Three dose levels will be considered with respect to daily dose (7 mg/m2, 10 mg/m2, 15 mg/m2), which relates to total doses of 100 mg/m2,150 mg/m2 and 210 mg/m2.
Patients will receive isotretinoin (13-cis-RA) 160 mg/m²/day divided into two equal doses given orally twice a day for 14 days after the completion of the ch14.18/CHO infusion. The starting day is dependent on the duration of ch14.18/CHO infusion and may be either day 19, 23, 24 or 30.
arm group label: Comparator arm
arm group type: Active Comparator
description: A continuous infusion of ch14.18/CHO is started on day 8. The duration of the infusion is dependent on the assigned infusion schedule. The duration will range from 10 to 21 days. Three dose levels will be considered with respect to daily dose (7 mg/m2, 10 mg/m2, 15 mg/m2), which relates to total doses of 100 mg/m2,150 mg/m2 and 210 mg/m2.
Patients will receive isotretinoin (13-cis-RA) 160 mg/m²/day divided into two equal doses given orally twice a day for 14 days after the completion of the ch14.18/CHO infusion. The starting day is dependent on the duration of ch14.18/CHO infusion and may be either day 19, 23, 24 or 30.
intervention type: Drug
intervention name: ch14.18/CHO
arm group label: Comparator arm
arm group label: Experimental arm
other name: Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cells
intervention type: Drug
intervention name: Aldesleukin
arm group label: Experimental arm
other name: Proleukin
other name: Interleukin-2
other name: IL-2
intervention type: Drug
intervention name: Isotretinoin
arm group label: Comparator arm
arm group label: Experimental arm
other name: 13-cis-Retinoic acid
other name: 13-cis-RA
criteria: 
gender: All
minimum age: 1 Year
maximum age: 21 Years
healthy volunteers: No
last name: Holger Lode, MD, PhD
role: Principal Investigator
affiliation: University Medicine Greifswald
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country: Austria
country: France
country: Germany
country: Israel
country: Italy
country: Spain
country: United Kingdom
url: http://www.kinderkrebsforschung.at/
description: Related Info
url: https://www.siopen-r-net.org/
description: Related Info
responsible party type: Sponsor
mesh term: Neuroblastoma
mesh term: Aldesleukin
mesh term: Interleukin-2
mesh term: Dinutuximab
mesh term: Isotretinoin