<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/NCT03275402</url>
  </required_header>
  <id_info>
    <org_study_id>101</org_study_id>
    <nct_id>NCT03275402</nct_id>
  </id_info>
  <brief_title>131I-omburtamab Radioimmunotherapy for Neuroblastoma Central Nervous System/Leptomeningeal Metastases</brief_title>
  <official_title>A Multicenter Phase 2/3 Trial of the Efficacy and Safety of Intracerebroventricular Radioimmunotherapy Using 131I-omburtamab for Neuroblastoma Central Nervous System/Leptomeningeal Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Y-mAbs Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Y-mAbs Therapeutics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Children with a neuroblastoma diagnose and central nervous system (CNS)/leptomeningeal&#xD;
      metastases will be given up to 2 rounds of intracerebroventricular treatment with a&#xD;
      radiolabelled monoclonal antibody, 131I-omburtamab to evaluate efficacy and safety&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      One 131I-omburtamab treatment cycle takes 4 weeks and includes a treatment dose, and an&#xD;
      observation period and post-treatment evaluations.&#xD;
&#xD;
      One 131I-omburtamab treatment cycle for Japan only takes 5 weeks and includes a dosimetry&#xD;
      dose (2mCi) of 131I-omburtamab is administered during week 1 followed by blood/cerebral&#xD;
      spinal fluid (CSF) samples and whole-body scintigraphy at predefined intervals during the&#xD;
      following 48 hours after treatment.&#xD;
&#xD;
        -  A therapeutic dose (50mCi) of 131I-omburtamab is administered during week 1 (week 2 for&#xD;
           Japan) followed by a 3-week observation period that includes a repeated MRI, CSF&#xD;
           cytology, and safety monitoring.&#xD;
&#xD;
        -  A second treatment cycle of 131I-omburtamab is administered during week 5 (week 6 for&#xD;
           Japan) if there is no objective disease progression week 5 after the first injection,&#xD;
           and the participant is presenting without unexpected and clinical significant Grade 4&#xD;
           toxicity. For participants with ongoing Grade 3 toxicity a second doing cycle will take&#xD;
           place according to the discretion of the investigator.&#xD;
&#xD;
      Participants can be treated in an outpatient setting or may be admitted as inpatients for&#xD;
      both the dosimetry and the therapeutic injections.&#xD;
&#xD;
      Participants completing at least one treatment period will first enter a follow-up period&#xD;
      through week 26 and thereafter the long-term follow-up where patients will be evaluated for&#xD;
      up to 3 years post-131I-omburtamab treatment where after the trial is ended&#xD;
&#xD;
      Participants will be monitored for adverse events during and after 131I-omburtamab injection&#xD;
      and will have pre- and post-treatment clinical assessments including neurologic examination,&#xD;
      hematology and serum chemistry, blood and CSF cultures, endocrinology assessments, CSF&#xD;
      analysis, and, pre- and post 131I-omburtamab performance testing. Performance testing will be&#xD;
      performed at trial baseline, at week 26 and every 6 months during trial period.&#xD;
&#xD;
      In case the patient has a subsequent relapse in the CNS/LM after 131I-omburtamab therapy&#xD;
      during the follow-up period, re-treatment to target minimal residual disease can be&#xD;
      considered and allowed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 11, 2018</start_date>
  <completion_date type="Anticipated">December 2026</completion_date>
  <primary_completion_date type="Anticipated">May 2026</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Patients will receive up to two cycles of intracerebroventricular 131I-omburtamab. Safety and efficacy will be investigated with short-term follow-up at 26 weeks after treatment and with long-term follow-up for up to 3 years following treatment.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival rate</measure>
    <time_frame>3 years</time_frame>
    <description>Overall survival rate at 3 years after the first treatment dose of 131I-omburtamab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>3 years</time_frame>
    <description>Overall survival at 3 years after the first treatment dose of 131I-omburtamab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>3 years</time_frame>
    <description>ORR is defined and assessed as a combination of partial response and complete response as defined by the RANO criteria and CSF cytology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>3 years</time_frame>
    <description>ORR according to CSF cytology. ORR is defined and assessed as a combination of partial response and complete response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CNS progression free survival (PFS)</measure>
    <time_frame>6 month</time_frame>
    <description>CNS PFS will be assessed at 6 months after the first treatment dose of 131I-omburtamab by comparing baseline radiological scans by MRI to radiological scans conducted 26 weeks after 131I-omburtamab treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dosimetry of 131I-omburtamab</measure>
    <time_frame>2 weeks</time_frame>
    <description>Whole-body, organ, blood, and CSF radiation dosimetry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of peak plasma concentration (Cmax) of 131I-omburtamab</measure>
    <time_frame>Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days</time_frame>
    <description>Cmax will be calculated and summarized with descriptive statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of residence time of 131I-omburtamab</measure>
    <time_frame>Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days.</time_frame>
    <description>Residence time will be calculated and summarized with descriptive statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of elimination half-life of 131I-omburtamab</measure>
    <time_frame>Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days.</time_frame>
    <description>Elimination half-life will be calculated and summarized with descriptive statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of 131I-omburtamab</measure>
    <time_frame>3 years</time_frame>
    <description>The frequency, type, and duration of treatment-emergent severe adverse events and serious adverse events, including clinically significant laboratory abnormalities. All adverse events will be graded according to CTCAE, version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Performance assessment</measure>
    <time_frame>3 years</time_frame>
    <description>Performance assessment to monitor gross changes in neurological function is performed at week 26 and subsequently every 6 months during trial period using Lansky (&lt; 16 years) and Karnofsky (≥ 16 years).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Neuroblastoma</condition>
  <condition>CNS Metastases</condition>
  <condition>Leptomeningeal Metastases</condition>
  <arm_group>
    <arm_group_label>131I-omburtamab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One treatment cycle of 131I-omburtamab consists of 1 dose at 50mCi at week 1. For Japan only one treatment cycle of 131I-omburtamab consists of 2 doses: 2mCi at week 1 and 50mCi at week 2. First cycle is initiated right after confirmation of eligibility at week 1. At week 5 (week 6 for Japan) the participant will be evaluated for safety and if eligible, receive a second cycle of 131I-omburtamab.&#xD;
Secondary efficacy endpoints will be evaluated at week 26 and primary efficacy endpoint will be evaluated at week 156.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>131I-omburtamab</intervention_name>
    <description>Murine IgG1 monoclonal antibody radiolabeled with iodine-131</description>
    <arm_group_label>131I-omburtamab</arm_group_label>
    <other_name>131I-8H9</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a histologically confirmed diagnosis of neuroblastoma with relapse&#xD;
             in the central nervous system or in the meninges (leptomeningeal).&#xD;
&#xD;
          -  Patients must be between the ages of birth and 18 years at the time of screening.&#xD;
&#xD;
          -  Patients must have a life expectancy of at least 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with primary neuroblastoma in central nervous system.&#xD;
&#xD;
          -  Patients must not have an uncontrolled life-threatening infection.&#xD;
&#xD;
          -  Patients must not have received cranial or spinal irradiation less than 3 weeks prior&#xD;
             to first dose of 131I-omburtamab in this trial.&#xD;
&#xD;
          -  Patients must not have received systemic chemotherapy (corticosteroids not included)&#xD;
             less than 3 weeks prior to enrollment in this trial.&#xD;
&#xD;
          -  Patients must not have severe major non-hematologic organ toxicity; specifically, any&#xD;
             renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity must fall&#xD;
             below Grade 3 prior to enrollment in this trial. Patients with stable neurological&#xD;
             deficits (due to brain tumor) are not excluded. Patients with Grade 3 or lower hearing&#xD;
             loss are not excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Roemer, MD</last_name>
    <role>Study Director</role>
    <affiliation>Y-mAbs Therapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Childrens Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Riley Hospital for Children</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>M.D. Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet</name>
      <address>
        <city>København</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Pediatric Oncology Fukushima Medical University Hospita</name>
      <address>
        <city>Fukushima City</city>
        <zip>960-1295</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Joan de Déu</name>
      <address>
        <city>Barcelona</city>
        <zip>08010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>Japan</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Canada</country>
    <country>Germany</country>
    <country>United Kingdom</country>
  </removed_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <last_update_submitted>March 8, 2023</last_update_submitted>
  <last_update_submitted_qc>March 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Radioimmunotherapy</keyword>
  <keyword>Neuroblastoma</keyword>
  <keyword>CNS Metastases</keyword>
  <keyword>Leptomeningeal Metastases</keyword>
  <keyword>Pediatric</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Neoplasms, Second Primary</mesh_term>
    <mesh_term>Neuroblastoma</mesh_term>
    <mesh_term>Meningeal Carcinomatosis</mesh_term>
  </condition_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/NCT03275402
org study id: 101
nct id: NCT03275402
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Children with a neuroblastoma diagnose and central nervous system (CNS)/leptomeningeal
      metastases will be given up to 2 rounds of intracerebroventricular treatment with a
      radiolabelled monoclonal antibody, 131I-omburtamab to evaluate efficacy and safety
One 131I-omburtamab treatment cycle takes 4 weeks and includes a treatment dose, and an
      observation period and post-treatment evaluations.

      One 131I-omburtamab treatment cycle for Japan only takes 5 weeks and includes a dosimetry
      dose (2mCi) of 131I-omburtamab is administered during week 1 followed by blood/cerebral
      spinal fluid (CSF) samples and whole-body scintigraphy at predefined intervals during the
      following 48 hours after treatment.

        -  A therapeutic dose (50mCi) of 131I-omburtamab is administered during week 1 (week 2 for
           Japan) followed by a 3-week observation period that includes a repeated MRI, CSF
           cytology, and safety monitoring.

        -  A second treatment cycle of 131I-omburtamab is administered during week 5 (week 6 for
           Japan) if there is no objective disease progression week 5 after the first injection,
           and the participant is presenting without unexpected and clinical significant Grade 4
           toxicity. For participants with ongoing Grade 3 toxicity a second doing cycle will take
           place according to the discretion of the investigator.

      Participants can be treated in an outpatient setting or may be admitted as inpatients for
      both the dosimetry and the therapeutic injections.

      Participants completing at least one treatment period will first enter a follow-up period
      through week 26 and thereafter the long-term follow-up where patients will be evaluated for
      up to 3 years post-131I-omburtamab treatment where after the trial is ended

      Participants will be monitored for adverse events during and after 131I-omburtamab injection
      and will have pre- and post-treatment clinical assessments including neurologic examination,
      hematology and serum chemistry, blood and CSF cultures, endocrinology assessments, CSF
      analysis, and, pre- and post 131I-omburtamab performance testing. Performance testing will be
      performed at trial baseline, at week 26 and every 6 months during trial period.

      In case the patient has a subsequent relapse in the CNS/LM after 131I-omburtamab therapy
      during the follow-up period, re-treatment to target minimal residual disease can be
      considered and allowed.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Patients will receive up to two cycles of intracerebroventricular 131I-omburtamab. Safety and efficacy will be investigated with short-term follow-up at 26 weeks after treatment and with long-term follow-up for up to 3 years following treatment.
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival rate
time frame: 3 years
description: Overall survival rate at 3 years after the first treatment dose of 131I-omburtamab.
measure: Overall survival
time frame: 3 years
description: Overall survival at 3 years after the first treatment dose of 131I-omburtamab.
measure: Objective response rate (ORR)
time frame: 3 years
description: ORR is defined and assessed as a combination of partial response and complete response as defined by the RANO criteria and CSF cytology.
measure: Objective response rate (ORR)
time frame: 3 years
description: ORR according to CSF cytology. ORR is defined and assessed as a combination of partial response and complete response.
measure: CNS progression free survival (PFS)
time frame: 6 month
description: CNS PFS will be assessed at 6 months after the first treatment dose of 131I-omburtamab by comparing baseline radiological scans by MRI to radiological scans conducted 26 weeks after 131I-omburtamab treatment.
measure: Dosimetry of 131I-omburtamab
time frame: 2 weeks
description: Whole-body, organ, blood, and CSF radiation dosimetry.
measure: Assessment of peak plasma concentration (Cmax) of 131I-omburtamab
time frame: Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days
description: Cmax will be calculated and summarized with descriptive statistics.
measure: Assessment of residence time of 131I-omburtamab
time frame: Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days.
description: Residence time will be calculated and summarized with descriptive statistics.
measure: Assessment of elimination half-life of 131I-omburtamab
time frame: Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days.
description: Elimination half-life will be calculated and summarized with descriptive statistics.
measure: Safety of 131I-omburtamab
time frame: 3 years
description: The frequency, type, and duration of treatment-emergent severe adverse events and serious adverse events, including clinically significant laboratory abnormalities. All adverse events will be graded according to CTCAE, version 4.0.
measure: Performance assessment
time frame: 3 years
description: Performance assessment to monitor gross changes in neurological function is performed at week 26 and subsequently every 6 months during trial period using Lansky (< 16 years) and Karnofsky (≥ 16 years).
arm group label: 131I-omburtamab
arm group type: Experimental
description: One treatment cycle of 131I-omburtamab consists of 1 dose at 50mCi at week 1. For Japan only one treatment cycle of 131I-omburtamab consists of 2 doses: 2mCi at week 1 and 50mCi at week 2. First cycle is initiated right after confirmation of eligibility at week 1. At week 5 (week 6 for Japan) the participant will be evaluated for safety and if eligible, receive a second cycle of 131I-omburtamab.
Secondary efficacy endpoints will be evaluated at week 26 and primary efficacy endpoint will be evaluated at week 156.
intervention type: Biological
intervention name: 131I-omburtamab
description: Murine IgG1 monoclonal antibody radiolabeled with iodine-131
arm group label: 131I-omburtamab
other name: 131I-8H9
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: John Roemer, MD
role: Study Director
affiliation: Y-mAbs Therapeutics
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Denmark
country: Japan
country: Spain
country: United States
country: Canada
country: Germany
country: United Kingdom
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Neoplasms, Second Primary
mesh term: Neuroblastoma
mesh term: Meningeal Carcinomatosis
sharing ipd: No