xml: <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/NCT06000787</url>
    </required_header>
    <id_info>
      <org_study_id>2023P002087</org_study_id>
      <nct_id>NCT06000787</nct_id>
    </id_info>
    <brief_title>MCT for the Harvard/UCSF ROBIN Center</brief_title>
    <official_title>Molecular Characterization Trial for the Harvard/UCSF ROBIN Center: Radiation Oncology at the Interface of Pediatric Cancer Biology and Data Science</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Brigham and Women's Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Dana-Farber Cancer Institute</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>National Cancer Institute (NCI)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
      <collaborator>
        <agency>University of California, San Francisco</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Brigham and Women's Hospital</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>Yes</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of the Molecular Characterization Trial (MCT) is to obtain biological specimens and&#xD;
        data resources from patients enrolled on prospective trials, to ensure that the Harvard/UCSF&#xD;
        ROBIN Center accomplishes its key objective of advancing our understanding of the biological&#xD;
        mechanisms that underlie how radiation treats tumors but also can cause unwanted side&#xD;
        effects. The MCT focuses on collection of research biospecimens before, during, and after&#xD;
        radiation. Also critical to the MCT is the deep annotation of these research biospecimens&#xD;
        with elements that complement each other to provide a holistic, detailed view of each&#xD;
        patient. Annotated elements include those used in the past such as clinical and biological&#xD;
        features but extend to factors we have so far neglected but must incorporate in the future&#xD;
        such as dosimetry (precise anatomical measurement of radiation dose), artificial&#xD;
        intelligence, computational biology, and natural language processing.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The MCT is critical to testing the central hypothesis of the Harvard/UCSF ROBIN and achieving&#xD;
        the central goals of the Center. This hypothesis centers on recent observations that cells&#xD;
        within a single tumor show tremendous variability from a developmental and biological&#xD;
        perspective. This contrasts with how radiation oncologists usually approach individual tumors&#xD;
        as they plan the radiotherapy course: generally, the entire tumor is targeted with a uniform&#xD;
        dose of radiation albeit with efforts to keep doses to adjacent normal tissues as low as&#xD;
        possible. The Harvard/UCSF ROBIN Center proposes to test the hypothesis that this marked&#xD;
        variability within a given tumor-both in the actual tumor cells and in the normal cells and&#xD;
        microenvironment elements-is also reflected at the level of biological responses to&#xD;
        radiation. New technologies that allow deep, molecular analyses of single cells within&#xD;
        individual tumors, will for the first time be applied specifically to molecular underpinnings&#xD;
        of cellular responses to radiation.&#xD;
  &#xD;
        The investigators chose to focus on pediatric cancers precisely because the iterative,&#xD;
        deep-dive approach of the ROBIN positions the children-focused ROBIN to transform radiation&#xD;
        biology for the benefit of adult and pediatric patients alike. In particular, childhood&#xD;
        cancers have simpler genetic landscapes that minimize potentially confounding passenger&#xD;
        mutations occurring with age. Accordingly, biospecimens and multiscale analyses of pediatric&#xD;
        cancers are more likely to yield deeper insights into causal biological mechanisms of&#xD;
        radiation response. Historical validation of this approach rests in the many oncogenic&#xD;
        drivers and tumor suppressors that were first identified in childhood cancers, only to then&#xD;
        prove widely relevant to adult cancers.&#xD;
  &#xD;
        The pediatric cancers being studied by the Harvard/UCSF ROBIN are the two most common solid&#xD;
        tumors in children-glioma (specifically, diffuse midline glioma, a type of primary brain&#xD;
        tumor) and neuroblastoma (a tumor of the peripheral nervous system). The MCT will centralize&#xD;
        all of the biospecimen and data resources for the Harvard/UCSF ROBIN Center by leveraging two&#xD;
        international consortia studies of these pediatric tumors. In addition to its focus on&#xD;
        pediatric malignancies that are responsible for disproportionate person-years lost, the&#xD;
        Harvard/UCSF ROBIN underscores inclusion of two key radiation modalities (i.e., external beam&#xD;
        radiation and radiopharmaceuticals). The MCT will manage the regulatory aspects of all&#xD;
        biospecimen and data collection, including site protocols for collection of protected health&#xD;
        information (PHI) and biospecimens in institutional biorepositories.&#xD;
  &#xD;
        One cohort consists of 18-23 subjects from the Pacific Pediatric Neuro-Oncology Consortium&#xD;
        PNOC023: Open label Phase 1 and Target Validation study of ONC206 in Children and Young&#xD;
        Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent&#xD;
        Primary Malignant Brain Tumors (NCT04732065). Blood samples will be obtained from all&#xD;
        subjects before, during and after RT. Cerebrospinal fluid (CSF) samples will be obtained from&#xD;
        all subjects before and after RT. Tumor samples will be obtained from all subjects before RT&#xD;
        and then at the time of autopsy, which occurs disconcertingly soon in this uniformly deadly&#xD;
        disease. This trial is highly innovative in that it collects tumor tissue and molecular data&#xD;
        on each enrolled patient as well as longitudinally collected CSF, blood, MRI imaging, and a&#xD;
        battery of validated quality of life outcome measures that are so critical to the well-being&#xD;
        of patients and their families. This is one of the first clinical trials for DMG integrating&#xD;
        the collection of such a myriad of sample types and molecular data making this an ideal&#xD;
        parent trial for the MCT in order to support the investigators' research in the response of&#xD;
        tumors and normal tissues to radiation. Collection of tumor samples after RT will be&#xD;
        essential for studies of pre- and post-treatment paired samples. Unfortunately given the&#xD;
        severity of the disease, most patients die within a short interval due to disease&#xD;
        progression. Uniform mortality, together with the short time from diagnosis to death, enables&#xD;
        postmortem tumor samples to serve as a surrogate for post-therapy tissue. Postmortem tumor&#xD;
        samples can be paired with diagnostic biopsy tissues to create paired sample sets--an&#xD;
        unprecedented research tool for DMGs that are never resected, and historically not even&#xD;
        biopsied. Postmortem tumor samples will be collected under an established protocol, with&#xD;
        support from the Gift of a Child Foundation.&#xD;
  &#xD;
        The second cohort within the MCT similarly supports achievement of the ROBIN overarching goal&#xD;
        of defining biological underpinnings of the effects of radiation on tumors and normal&#xD;
        tissues. For neuroblastoma, the team identified Children's Oncology Group (COG) ANBL1531&#xD;
        (NCT03126916), a phase 3 study of 131I-MIBG or crizotinib added to intensive therapy for&#xD;
        children with newly diagnosed high-risk neuroblastoma. ANBL1531 features unique aspects that&#xD;
        are particularly suitable for fulfilling the aims of research on neuroblastoma and&#xD;
        radiopharmaceuticals, which are drugs that are preferentially taken up by tumor cells and&#xD;
        expose them to radiation. ANBL1531 is the current North American randomized phase 3 trial for&#xD;
        children with newly diagnosed high-risk neuroblastoma. It is the largest clinical trial of&#xD;
        131I-MIBG ever conducted. This trial will accrue 774 patients with high-risk neuroblastoma&#xD;
        over 5.1 years, followed by 3 years of follow-up for clinical outcomes. Patients are eligible&#xD;
        for ANBL1531 if they are 1-30 years of age; and have newly diagnosed high-risk neuroblastoma&#xD;
        without prior treatment. If the patient's tumor takes up MIBG, the patient is randomized to&#xD;
        either COG standard therapy (Arm A) or to COG standard therapy with the addition of the&#xD;
        radiopharmaceutical 131I-MIBG (Arm B); the randomized portion of the study is comprised of&#xD;
        500 of the subjects in the study. As the only difference between Arm A and Arm B is receipt&#xD;
        of 131I-MIBG, the investigators will be able to isolate the effects of 131I-MIBG therapy on&#xD;
        clinical endpoints and on key biomarkers. The endpoints documented and collected by the study&#xD;
        are not only relevant to tumor control and patient survival but also relevant to key quality&#xD;
        of life and late toxicities features, such as thyroid toxicity, impaired growth, impaired&#xD;
        pubertal development, and second malignancies. In addition, this study is particularly&#xD;
        poignant for the ROBIN Center's goals because it has embedded within it a rich array of&#xD;
        biospecimens and imaging studies to learn as much as possible about how radiopharmaceuticals&#xD;
        cure tumors but also cause unwanted side-effects. It includes collection of tumor specimens&#xD;
        at diagnosis prior to any therapy, and after 131I-MIBG therapy at the time of surgery. Blood&#xD;
        is collected at multiple timepoints for a host of studies, including paired samples obtained&#xD;
        just prior to 131I-MIBG therapy and again 72 hours after, in formats suitable for measuring&#xD;
        the expression levels of genes and various RNA molecules.&#xD;
  &#xD;
        In summary, the MCT focuses on a small number of subjects (e.g., 18-23 subjects for DMG and&#xD;
        24 subjects for neuroblastoma), treated with standard-of-care radiation therapy (external&#xD;
        beam radiation therapy for DMG and the 131IMIBG radiopharmaceutical for neuroblastoma). The&#xD;
        MCT is configured to isolate the effects of radiation, incorporates longitudinal sampling&#xD;
        (baseline, on-treatment, post-treatment), and incorporates both invasive and non-invasive&#xD;
        approaches such as tumor biopsies, imaging, blood and CSF sampling, dosimetry (precise&#xD;
        anatomical measurement of radiation dose). Patient-reported outcomes, and other&#xD;
        quality-of-life measures are also monitored. As a key feature, because the subjects are being&#xD;
        selected from trials with substantially higher numbers of participants (e.g., N = 60-216 for&#xD;
        PNOC023 and N = 500 for ANBL1531), findings from the proposed ROBIN studies can be readily&#xD;
        validated using data and biospecimens from additional subjects participating in these trials.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 21, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">July 31, 2028</primary_completion_date>
    <phase>N/A</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>
      <intervention_model_description>Two non-randomized cohorts with assignment based on tumor type</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Event-free survival by tumor heterogeneity</measure>
      <time_frame>up to 3 years</time_frame>
      <description>EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing high versus low tumor heterogeneity assessed quantitatively based on single-cell RNA sequencing.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Event-free survival by DNA damage response</measure>
      <time_frame>up to 3 years</time_frame>
      <description>EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing intact versus defective responses to treatment-induced DNA damage determined by immunohistochemistry and microRNA profiling.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Event-free survival by tumor DNA alterations</measure>
      <time_frame>up to 3 years</time_frame>
      <description>EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing presence or absence of point mutations and copy number alterations detected in tumor tissue or circulating cell-free DNA.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Proportion of patients with serious adverse events by DNA damage response</measure>
      <time_frame>up to 18 months</time_frame>
      <description>Serious adverse events will be defined as one or more Grade 3 or higher toxicities during protocol therapy graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, or meeting protocol-specified criteria for dose-limiting toxicities. This will be compared in participants with blood samples showing intact versus defective responses to treatment-induced DNA damage determined by immunohistochemistry and microRNA profiling.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">47</enrollment>
    <condition>Glioma, Childhood Brainstem</condition>
    <condition>Neuroblastoma</condition>
    <arm_group>
      <arm_group_label>Diffuse Midline Glioma</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>Subjects with diffuse midline glioma on PNOC023 (NCT04732065) Arm A or B</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Neuroblastoma</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>Subjects with high-risk neuroblastoma on COG ANBL1531 (NCT03126916) Arm B</description>
    </arm_group>
    <intervention>
      <intervention_type>Radiation</intervention_type>
      <intervention_name>External beam radiotherapy</intervention_name>
      <description>Subjects with diffuse midline glioma on PNOC023 (NCT04732065) Arm A or B receive standard-of-care external beam radiotherapy to the brain tumor.</description>
      <arm_group_label>Diffuse Midline Glioma</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Radiation</intervention_type>
      <intervention_name>131I-Metaiodobenzylguanidine (MIBG)</intervention_name>
      <description>Subjects with high-risk neuroblastoma on COG ANBL1531 (NCT03126916) Arm B receive the radiopharmaceutical 131I-Metaiodobenzylguanidine (MIBG) 15 mCi/kg via either a central or a peripheral IV catheter over 1.5 to 2 hours at a maximum rate of 500 mCi/hour.</description>
      <arm_group_label>Neuroblastoma</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Enrollment on one of the following clinical trials:&#xD;
  &#xD;
                 -  Pacific Pediatric Neuro-Oncology Consortium PNOC023: Open label Phase 1 and&#xD;
                    Target Validation study of ONC206 in Children and Young Adults with Newly&#xD;
                    Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary&#xD;
                    Malignant Brain Tumors (NCT04732065) - Arm A or B (Key Eligibility Criteria:&#xD;
                    Newly diagnosed DMG, Age ≥ 2 years, If on corticosteroids, on a stable or&#xD;
                    decreasing dose for ≥ 3 days prior to baseline MRI scan, Karnofsky ≥ 50 for age&#xD;
                    &gt;16 or Lansky ≥ 50 for age ≤ 16, No known disorder that affects the immune system&#xD;
                    or uncontrolled infection)&#xD;
  &#xD;
                 -  Children's Oncology Group ANBL1531: A Phase 3 Study of&#xD;
                    131I-Metaiodobenzylguanidine (131I-MIBG) or Crizotinib Added to Intensive Therapy&#xD;
                    for Children with Newly Diagnosed High-Risk Neuroblastoma (NCT03126916) - Arm B&#xD;
                    (Key Eligibility Criteria: Diagnosis of high-risk neuroblastoma (INRG Stage M&#xD;
                    with MYCN amplification or age &gt; 547 days, INRG Stage MS with MYCN amplification,&#xD;
                    INRG Stage L2 with MYCN amplification, or progression to Stage M in certain&#xD;
                    groups), Age ≥ 1 and ≤ 30 years at diagnosis, No prior systemic or radiation&#xD;
                    therapy, with certain exceptions, No contraindication to targeted&#xD;
                    radiopharmaceutical therapy)&#xD;
  &#xD;
            -  Tumor tissue confirmation of malignancy&#xD;
  &#xD;
            -  Adequate bone marrow, renal, liver and neurologic function&#xD;
  &#xD;
            -  Availability of tumor tissue, blood and/or CSF biospecimens&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Pregnancy or breastfeeding&#xD;
  &#xD;
            -  Inability to follow the procedures of the study&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>N/A</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>David Kozono, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Brigham and Women's Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>David Kozono, MD, PhD</last_name>
      <phone>617-582-8237</phone>
      <email>dkozono@bwh.harvard.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>University of California, San Francisco</name>
        <address>
          <city>San Francisco</city>
          <state>California</state>
          <zip>94143</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Sabine Mueller, MD, PhD</last_name>
      </contact>
    </location>
    <location>
      <facility>
        <name>Brigham and Women's Hospital</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02115</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>David Kozono, MD, PhD</last_name>
      </contact>
      <investigator>
        <last_name>David Kozono, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 3, 2023</study_first_submitted>
    <study_first_submitted_qc>August 17, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 17, 2023</last_update_submitted>
    <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
      <investigator_full_name>David E. Kozono</investigator_full_name>
      <investigator_title>Assistant Professor of Radiation Oncology</investigator_title>
    </responsible_party>
    <keyword>Diffuse midline glioma</keyword>
    <keyword>Iodine-131 meta-iodobenzylguanidine</keyword>
    <keyword>Radiation oncology</keyword>
    <keyword>Radiobiology</keyword>
    <keyword>Radiopharmaceutical</keyword>
    <keyword>Radiotherapy</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>3-Iodobenzylguanidine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06000787
  org study id: 2023P002087
  nct id: NCT06000787
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: Yes
  The goal of the Molecular Characterization Trial (MCT) is to obtain biological specimens and
        data resources from patients enrolled on prospective trials, to ensure that the Harvard/UCSF
        ROBIN Center accomplishes its key objective of advancing our understanding of the biological
        mechanisms that underlie how radiation treats tumors but also can cause unwanted side
        effects. The MCT focuses on collection of research biospecimens before, during, and after
        radiation. Also critical to the MCT is the deep annotation of these research biospecimens
        with elements that complement each other to provide a holistic, detailed view of each
        patient. Annotated elements include those used in the past such as clinical and biological
        features but extend to factors we have so far neglected but must incorporate in the future
        such as dosimetry (precise anatomical measurement of radiation dose), artificial
        intelligence, computational biology, and natural language processing.
  The MCT is critical to testing the central hypothesis of the Harvard/UCSF ROBIN and achieving
        the central goals of the Center. This hypothesis centers on recent observations that cells
        within a single tumor show tremendous variability from a developmental and biological
        perspective. This contrasts with how radiation oncologists usually approach individual tumors
        as they plan the radiotherapy course: generally, the entire tumor is targeted with a uniform
        dose of radiation albeit with efforts to keep doses to adjacent normal tissues as low as
        possible. The Harvard/UCSF ROBIN Center proposes to test the hypothesis that this marked
        variability within a given tumor-both in the actual tumor cells and in the normal cells and
        microenvironment elements-is also reflected at the level of biological responses to
        radiation. New technologies that allow deep, molecular analyses of single cells within
        individual tumors, will for the first time be applied specifically to molecular underpinnings
        of cellular responses to radiation.
  
        The investigators chose to focus on pediatric cancers precisely because the iterative,
        deep-dive approach of the ROBIN positions the children-focused ROBIN to transform radiation
        biology for the benefit of adult and pediatric patients alike. In particular, childhood
        cancers have simpler genetic landscapes that minimize potentially confounding passenger
        mutations occurring with age. Accordingly, biospecimens and multiscale analyses of pediatric
        cancers are more likely to yield deeper insights into causal biological mechanisms of
        radiation response. Historical validation of this approach rests in the many oncogenic
        drivers and tumor suppressors that were first identified in childhood cancers, only to then
        prove widely relevant to adult cancers.
  
        The pediatric cancers being studied by the Harvard/UCSF ROBIN are the two most common solid
        tumors in children-glioma (specifically, diffuse midline glioma, a type of primary brain
        tumor) and neuroblastoma (a tumor of the peripheral nervous system). The MCT will centralize
        all of the biospecimen and data resources for the Harvard/UCSF ROBIN Center by leveraging two
        international consortia studies of these pediatric tumors. In addition to its focus on
        pediatric malignancies that are responsible for disproportionate person-years lost, the
        Harvard/UCSF ROBIN underscores inclusion of two key radiation modalities (i.e., external beam
        radiation and radiopharmaceuticals). The MCT will manage the regulatory aspects of all
        biospecimen and data collection, including site protocols for collection of protected health
        information (PHI) and biospecimens in institutional biorepositories.
  
        One cohort consists of 18-23 subjects from the Pacific Pediatric Neuro-Oncology Consortium
        PNOC023: Open label Phase 1 and Target Validation study of ONC206 in Children and Young
        Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent
        Primary Malignant Brain Tumors (NCT04732065). Blood samples will be obtained from all
        subjects before, during and after RT. Cerebrospinal fluid (CSF) samples will be obtained from
        all subjects before and after RT. Tumor samples will be obtained from all subjects before RT
        and then at the time of autopsy, which occurs disconcertingly soon in this uniformly deadly
        disease. This trial is highly innovative in that it collects tumor tissue and molecular data
        on each enrolled patient as well as longitudinally collected CSF, blood, MRI imaging, and a
        battery of validated quality of life outcome measures that are so critical to the well-being
        of patients and their families. This is one of the first clinical trials for DMG integrating
        the collection of such a myriad of sample types and molecular data making this an ideal
        parent trial for the MCT in order to support the investigators' research in the response of
        tumors and normal tissues to radiation. Collection of tumor samples after RT will be
        essential for studies of pre- and post-treatment paired samples. Unfortunately given the
        severity of the disease, most patients die within a short interval due to disease
        progression. Uniform mortality, together with the short time from diagnosis to death, enables
        postmortem tumor samples to serve as a surrogate for post-therapy tissue. Postmortem tumor
        samples can be paired with diagnostic biopsy tissues to create paired sample sets--an
        unprecedented research tool for DMGs that are never resected, and historically not even
        biopsied. Postmortem tumor samples will be collected under an established protocol, with
        support from the Gift of a Child Foundation.
  
        The second cohort within the MCT similarly supports achievement of the ROBIN overarching goal
        of defining biological underpinnings of the effects of radiation on tumors and normal
        tissues. For neuroblastoma, the team identified Children's Oncology Group (COG) ANBL1531
        (NCT03126916), a phase 3 study of 131I-MIBG or crizotinib added to intensive therapy for
        children with newly diagnosed high-risk neuroblastoma. ANBL1531 features unique aspects that
        are particularly suitable for fulfilling the aims of research on neuroblastoma and
        radiopharmaceuticals, which are drugs that are preferentially taken up by tumor cells and
        expose them to radiation. ANBL1531 is the current North American randomized phase 3 trial for
        children with newly diagnosed high-risk neuroblastoma. It is the largest clinical trial of
        131I-MIBG ever conducted. This trial will accrue 774 patients with high-risk neuroblastoma
        over 5.1 years, followed by 3 years of follow-up for clinical outcomes. Patients are eligible
        for ANBL1531 if they are 1-30 years of age; and have newly diagnosed high-risk neuroblastoma
        without prior treatment. If the patient's tumor takes up MIBG, the patient is randomized to
        either COG standard therapy (Arm A) or to COG standard therapy with the addition of the
        radiopharmaceutical 131I-MIBG (Arm B); the randomized portion of the study is comprised of
        500 of the subjects in the study. As the only difference between Arm A and Arm B is receipt
        of 131I-MIBG, the investigators will be able to isolate the effects of 131I-MIBG therapy on
        clinical endpoints and on key biomarkers. The endpoints documented and collected by the study
        are not only relevant to tumor control and patient survival but also relevant to key quality
        of life and late toxicities features, such as thyroid toxicity, impaired growth, impaired
        pubertal development, and second malignancies. In addition, this study is particularly
        poignant for the ROBIN Center's goals because it has embedded within it a rich array of
        biospecimens and imaging studies to learn as much as possible about how radiopharmaceuticals
        cure tumors but also cause unwanted side-effects. It includes collection of tumor specimens
        at diagnosis prior to any therapy, and after 131I-MIBG therapy at the time of surgery. Blood
        is collected at multiple timepoints for a host of studies, including paired samples obtained
        just prior to 131I-MIBG therapy and again 72 hours after, in formats suitable for measuring
        the expression levels of genes and various RNA molecules.
  
        In summary, the MCT focuses on a small number of subjects (e.g., 18-23 subjects for DMG and
        24 subjects for neuroblastoma), treated with standard-of-care radiation therapy (external
        beam radiation therapy for DMG and the 131IMIBG radiopharmaceutical for neuroblastoma). The
        MCT is configured to isolate the effects of radiation, incorporates longitudinal sampling
        (baseline, on-treatment, post-treatment), and incorporates both invasive and non-invasive
        approaches such as tumor biopsies, imaging, blood and CSF sampling, dosimetry (precise
        anatomical measurement of radiation dose). Patient-reported outcomes, and other
        quality-of-life measures are also monitored. As a key feature, because the subjects are being
        selected from trials with substantially higher numbers of participants (e.g., N = 60-216 for
        PNOC023 and N = 500 for ANBL1531), findings from the proposed ROBIN studies can be readily
        validated using data and biospecimens from additional subjects participating in these trials.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: Two non-randomized cohorts with assignment based on tumor type
  primary purpose: Basic Science
  masking: None (Open Label)
  measure: Event-free survival by tumor heterogeneity
  time frame: up to 3 years
  description: EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing high versus low tumor heterogeneity assessed quantitatively based on single-cell RNA sequencing.
  measure: Event-free survival by DNA damage response
  time frame: up to 3 years
  description: EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing intact versus defective responses to treatment-induced DNA damage determined by immunohistochemistry and microRNA profiling.
  measure: Event-free survival by tumor DNA alterations
  time frame: up to 3 years
  description: EFS is calculated from the date of treatment assignment to the first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. This will be compared in participants with tumors showing presence or absence of point mutations and copy number alterations detected in tumor tissue or circulating cell-free DNA.
  measure: Proportion of patients with serious adverse events by DNA damage response
  time frame: up to 18 months
  description: Serious adverse events will be defined as one or more Grade 3 or higher toxicities during protocol therapy graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, or meeting protocol-specified criteria for dose-limiting toxicities. This will be compared in participants with blood samples showing intact versus defective responses to treatment-induced DNA damage determined by immunohistochemistry and microRNA profiling.
  arm group label: Diffuse Midline Glioma
  arm group type: Other
  description: Subjects with diffuse midline glioma on PNOC023 (NCT04732065) Arm A or B
  arm group label: Neuroblastoma
  arm group type: Other
  description: Subjects with high-risk neuroblastoma on COG ANBL1531 (NCT03126916) Arm B
  intervention type: Radiation
  intervention name: External beam radiotherapy
  description: Subjects with diffuse midline glioma on PNOC023 (NCT04732065) Arm A or B receive standard-of-care external beam radiotherapy to the brain tumor.
  arm group label: Diffuse Midline Glioma
  intervention type: Radiation
  intervention name: 131I-Metaiodobenzylguanidine (MIBG)
  description: Subjects with high-risk neuroblastoma on COG ANBL1531 (NCT03126916) Arm B receive the radiopharmaceutical 131I-Metaiodobenzylguanidine (MIBG) 15 mCi/kg via either a central or a peripheral IV catheter over 1.5 to 2 hours at a maximum rate of 500 mCi/hour.
  arm group label: Neuroblastoma
  criteria: 
  gender: All
  minimum age: N/A
  maximum age: N/A
  healthy volunteers: No
  last name: David Kozono, MD, PhD
  role: Principal Investigator
  affiliation: Brigham and Women's Hospital
  last name: David Kozono, MD, PhD
  phone: 617-582-8237
  email: dkozono@bwh.harvard.edu
  facility: 
  contact: 
  facility: 
  contact: 
  investigator: 
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: Brigham and Women's Hospital
  investigator full name: David E. Kozono
  investigator title: Assistant Professor of Radiation Oncology
  mesh term: Neuroblastoma
  mesh term: 3-Iodobenzylguanidine
  sharing ipd: No