<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/NCT04474964</url>
  </required_header>
  <id_info>
    <org_study_id>3468</org_study_id>
    <nct_id>NCT04474964</nct_id>
  </id_info>
  <brief_title>Focal Radiotherapy Plus Low Dose Craniospinal Irradiation Followed by Adjuvant Chemotherapy in WNT Medulloblastoma.</brief_title>
  <acronym>FOR-WNT2</acronym>
  <official_title>Focal Radiotherapy Plus Low Dose Craniospinal Irradiation Followed by Adjuvant Chemotherapy in WNT Subgroup Medulloblastoma.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tata Memorial Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tata Memorial Centre</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical study is going to be done on a type of brain tumor in children called&#xD;
      Medulloblastoma. The WNT pathway type of medulloblastoma is considered to be low risk and&#xD;
      have the best outcomes in terms of survival. With the current standard of care for this type&#xD;
      of medulloblastoma it is believed by the investigators that we are over treating the disease&#xD;
      and increasing the long term side effects of these children. Several groups in the world are&#xD;
      testing de-intensification of treatment in this favourable subset of children who experience&#xD;
      long term late side effects of therapy. By reducing the dose to the craniospinal axis and&#xD;
      keeping the total tumor bed dose the same in this study the investigators are expecting to&#xD;
      reduce some of the late side effects of craniospinal irradiation without compromising disease&#xD;
      control and survival.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      WNT pathway medulloblastomas have the best prognosis amongst all four subgroups with 5-year&#xD;
      overall survival exceeding 90%. Overall medulloblastoma is more common in males. They can&#xD;
      occur at all ages, but, are uncommon in infants. They are mostly uniform in their genetic&#xD;
      aberrations, histological pattern, and clinical presentation. The WNT pathway is involved in&#xD;
      regulating embryonal development in the brain. They are frequently described as having CTNNB1&#xD;
      mutations, nuclear immunohistochemical staining for β-catenin, and monosomy six (deletion of&#xD;
      one copy of chromosome 6 in the tumor). Thus monosomy 6 in conjunction with nuclear β-catenin&#xD;
      accumulation is considered a sensitive and specific marker for WNT pathway medulloblastoma&#xD;
      they are typically located in the midline vermian region filling up the fourth ventricle and&#xD;
      infiltrating the brain stem consistent with their proposed cell of origin from the dorsal&#xD;
      brainstem nuclei. The immediate impact of enhanced understanding of molecular biology has led&#xD;
      to biologically driven next-generation clinical trials in newly diagnosed medulloblastoma.&#xD;
      Given the excellent long-term survival outcomes in WNT-pathway medulloblastoma and potential&#xD;
      for significant late toxicities with currently prevalent doses of CSI (23.4-36Gy), it has&#xD;
      been hypothesized that further reduction of dose or in certain cases avoidance of CSI would&#xD;
      translate into reduction in late morbidity of treatment.&#xD;
&#xD;
      In our first generation FOR-WNT study, the investigators had avoided upfront CSI and treated&#xD;
      the tumor-bed alone with focal conformal radiotherapy in low-risk WNT-pathway medulloblastoma&#xD;
      followed by 6-cycles of adjuvant systemic chemotherapy. However, early experience from our&#xD;
      own study and similar results from another study (primary chemotherapy approach completely&#xD;
      avoiding radiotherapy) suggests an unduly increased risk of relapse - spinal leptomeningeal&#xD;
      or supratentorial if CSI is avoided and local recurrence at primary site too if radiation is&#xD;
      completely avoided. Given the excellent long-term survival outcomes in WNT-pathway&#xD;
      medulloblastoma treated with currently prevalent doses of CSI (23.4-36Gy), presence of&#xD;
      significant late toxicities with such doses, but the increased risk of relapse with avoidance&#xD;
      of CSI and/or local irradiation, the investigators hypothesize that further moderate&#xD;
      reduction of CSI dose to 18Gy/10fx keeping the primary-site dose to 54Gy/30fx would translate&#xD;
      into a meaningful reduction in late morbidity of treatment without compromising disease&#xD;
      control or survival. Thus, the investigators herewith propose the second-generation study&#xD;
      (FOR-WNT 2) to include low-dose CSI (18Gy/10fx) plus tumor-bed boost (36Gy/20fx) for a total&#xD;
      primary site dose of 54Gy/30fx without concurrent chemotherapy followed by standard 6-cycles&#xD;
      of adjuvant systemic chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 13, 2020</start_date>
  <completion_date type="Anticipated">July 2030</completion_date>
  <primary_completion_date type="Anticipated">July 2030</primary_completion_date>
  <phase>N/A</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relapse-free survival will be analysed using using the product-limit method of Kaplan-Meier and compared using the log-rank test.</measure>
    <time_frame>5 years</time_frame>
    <description>Measure Relapse-free survival in WNT medulloblastoma treated with low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy. Relapse free survival will be calculated from the date of surgery till the first documented clinico-radiological evidence of relapse (recurrence/progression).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Survival of Participants will be analysed using the product-limit method of Kaplan-Meier and compared using the log-rank test.</measure>
    <time_frame>5 years</time_frame>
    <description>Measure Overall survival in WNT medulloblastoma treated with low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy.Overall survival will be measured from the date of diagnosis till death from any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Neuro-cognitive function of Participants will be analysed longitudinally over time using linear regression model with time-test for trend</measure>
    <time_frame>5 years</time_frame>
    <description>Neurocognitive Outcome will be assessed using Wechsler scale for children by comparing pre-radiotherapy result with assessment done 3-6 months after radiotherapy, at 1-year post-treatment, and annually thereafter till 5-years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Growth Hormone levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.</measure>
    <time_frame>5 years</time_frame>
    <description>Serial Serum growth hormone(ng/ml) levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thyroid function levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.</measure>
    <time_frame>5 years</time_frame>
    <description>Serial Thyroid function levels : TSH , T3, T4 levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortisol levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.</measure>
    <time_frame>5 years</time_frame>
    <description>Serial Cortisol levels (mcg/dl) will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sex Hormone levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.</measure>
    <time_frame>5 years</time_frame>
    <description>Sex Hormone levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pure tone Audiometry of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.</measure>
    <time_frame>5 years</time_frame>
    <description>Hearing assessment will be done by comparing baseline results with hearing assessment 3-6 months after radiotherapy, at 1-year post-treatment, and annually thereafter for 5-years.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Medulloblastoma, WNT-activated</condition>
  <arm_group>
    <arm_group_label>Low Dose Craniospinal Irradiation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>WNT subgroup medulloblastoma patients accrued in the study will be treated with Low-dose Craniospinal Irradiation (18Gy/10fx) plus focal conformal tumor-bed boost (36Gy/20fx) for total primary-site dose of 54Gy/30fx over 6-weeks. Followed by adjuvant multi-agent systemic chemotherapy which will be initiated 4-6 weeks after completion of radiotherapy provided the ANC &gt;1500 and platelet count &gt;1,00,000. A total of 6 cycles of alternating chemotherapy every 4-weekly will be planned as per our standard practice using CET protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Low dose Craniospinal Irradiation plus Focal Radiotherapy</intervention_name>
    <description>The intervention arm of the study is to prospectively evaluate disease-related outcomes of low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy in WNT-pathway medulloblastoma.</description>
    <arm_group_label>Low Dose Craniospinal Irradiation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age more than 3 years and less than 16 years.&#xD;
&#xD;
          -  Newly diagnosed WNT pathway medulloblastoma.&#xD;
&#xD;
          -  Post-surgery residual disease less than 1.5 cm2 on post-operative MRI brain.&#xD;
&#xD;
          -  No evidence of metastatic disease in the brain, spine or cerebral spinal fluid (CSF)&#xD;
             assessed by MRI of the brain/spine and lumbar puncture for CSF cytology.&#xD;
&#xD;
          -  Fit for initiation of adjuvant treatment within 6-weeks of surgery&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age Less than 3 and more than 16 years.&#xD;
&#xD;
          -  Molecular subgroup other than WNT pathway.&#xD;
&#xD;
          -  Post-surgery residual disease more than 1.5cm2 on post-operative imaging.&#xD;
&#xD;
          -  Evidence of any metastatic disease in the brain, spine or CSF.&#xD;
&#xD;
          -  Previous history of radiotherapy or chemotherapy prior to study enrollment.&#xD;
&#xD;
          -  Not fit for initiation of adjuvant treatment within 6 weeks of surgery.&#xD;
&#xD;
          -  Not willing for consent/assent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>16 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Tejpal Dr Gupta, MD</last_name>
    <phone>(022) 2417 6015</phone>
    <email>tejpalgupta@rediffmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Tata Memorial Hospital</name>
      <address>
        <city>Mumbai</city>
        <state>Maharashtra</state>
        <zip>400012</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dr Tejpal Gupta, MD</last_name>
      <phone>022-24177000</phone>
      <phone_ext>6015</phone_ext>
      <email>tejpalgupta@rediffmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>October 20, 2022</last_update_submitted>
  <last_update_submitted_qc>October 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 24, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>WNT medulloblastoma</keyword>
  <keyword>low dose craniospinal irradiation</keyword>
  <keyword>overall survival</keyword>
  <keyword>long term toxicities</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Medulloblastoma</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/NCT04474964
org study id: 3468
nct id: NCT04474964
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This clinical study is going to be done on a type of brain tumor in children called
      Medulloblastoma. The WNT pathway type of medulloblastoma is considered to be low risk and
      have the best outcomes in terms of survival. With the current standard of care for this type
      of medulloblastoma it is believed by the investigators that we are over treating the disease
      and increasing the long term side effects of these children. Several groups in the world are
      testing de-intensification of treatment in this favourable subset of children who experience
      long term late side effects of therapy. By reducing the dose to the craniospinal axis and
      keeping the total tumor bed dose the same in this study the investigators are expecting to
      reduce some of the late side effects of craniospinal irradiation without compromising disease
      control and survival.
WNT pathway medulloblastomas have the best prognosis amongst all four subgroups with 5-year
      overall survival exceeding 90%. Overall medulloblastoma is more common in males. They can
      occur at all ages, but, are uncommon in infants. They are mostly uniform in their genetic
      aberrations, histological pattern, and clinical presentation. The WNT pathway is involved in
      regulating embryonal development in the brain. They are frequently described as having CTNNB1
      mutations, nuclear immunohistochemical staining for β-catenin, and monosomy six (deletion of
      one copy of chromosome 6 in the tumor). Thus monosomy 6 in conjunction with nuclear β-catenin
      accumulation is considered a sensitive and specific marker for WNT pathway medulloblastoma
      they are typically located in the midline vermian region filling up the fourth ventricle and
      infiltrating the brain stem consistent with their proposed cell of origin from the dorsal
      brainstem nuclei. The immediate impact of enhanced understanding of molecular biology has led
      to biologically driven next-generation clinical trials in newly diagnosed medulloblastoma.
      Given the excellent long-term survival outcomes in WNT-pathway medulloblastoma and potential
      for significant late toxicities with currently prevalent doses of CSI (23.4-36Gy), it has
      been hypothesized that further reduction of dose or in certain cases avoidance of CSI would
      translate into reduction in late morbidity of treatment.

      In our first generation FOR-WNT study, the investigators had avoided upfront CSI and treated
      the tumor-bed alone with focal conformal radiotherapy in low-risk WNT-pathway medulloblastoma
      followed by 6-cycles of adjuvant systemic chemotherapy. However, early experience from our
      own study and similar results from another study (primary chemotherapy approach completely
      avoiding radiotherapy) suggests an unduly increased risk of relapse - spinal leptomeningeal
      or supratentorial if CSI is avoided and local recurrence at primary site too if radiation is
      completely avoided. Given the excellent long-term survival outcomes in WNT-pathway
      medulloblastoma treated with currently prevalent doses of CSI (23.4-36Gy), presence of
      significant late toxicities with such doses, but the increased risk of relapse with avoidance
      of CSI and/or local irradiation, the investigators hypothesize that further moderate
      reduction of CSI dose to 18Gy/10fx keeping the primary-site dose to 54Gy/30fx would translate
      into a meaningful reduction in late morbidity of treatment without compromising disease
      control or survival. Thus, the investigators herewith propose the second-generation study
      (FOR-WNT 2) to include low-dose CSI (18Gy/10fx) plus tumor-bed boost (36Gy/20fx) for a total
      primary site dose of 54Gy/30fx without concurrent chemotherapy followed by standard 6-cycles
      of adjuvant systemic chemotherapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Relapse-free survival will be analysed using using the product-limit method of Kaplan-Meier and compared using the log-rank test.
time frame: 5 years
description: Measure Relapse-free survival in WNT medulloblastoma treated with low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy. Relapse free survival will be calculated from the date of surgery till the first documented clinico-radiological evidence of relapse (recurrence/progression).
measure: Overall Survival of Participants will be analysed using the product-limit method of Kaplan-Meier and compared using the log-rank test.
time frame: 5 years
description: Measure Overall survival in WNT medulloblastoma treated with low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy.Overall survival will be measured from the date of diagnosis till death from any cause.
measure: Neuro-cognitive function of Participants will be analysed longitudinally over time using linear regression model with time-test for trend
time frame: 5 years
description: Neurocognitive Outcome will be assessed using Wechsler scale for children by comparing pre-radiotherapy result with assessment done 3-6 months after radiotherapy, at 1-year post-treatment, and annually thereafter till 5-years.
measure: Growth Hormone levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.
time frame: 5 years
description: Serial Serum growth hormone(ng/ml) levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.
measure: Thyroid function levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.
time frame: 5 years
description: Serial Thyroid function levels : TSH , T3, T4 levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.
measure: Cortisol levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.
time frame: 5 years
description: Serial Cortisol levels (mcg/dl) will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.
measure: Sex Hormone levels of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.
time frame: 5 years
description: Sex Hormone levels will be done by comparing pre-radiotherapy levels with biochemical assessment done 3-6 months after radiotherapy, at 1-year post-treatment and annually thereafter for 5-years.
measure: Pure tone Audiometry of Participants will be analysed longitudinally over time using linear regression model with time-test for trend.
time frame: 5 years
description: Hearing assessment will be done by comparing baseline results with hearing assessment 3-6 months after radiotherapy, at 1-year post-treatment, and annually thereafter for 5-years.
arm group label: Low Dose Craniospinal Irradiation
arm group type: Experimental
description: WNT subgroup medulloblastoma patients accrued in the study will be treated with Low-dose Craniospinal Irradiation (18Gy/10fx) plus focal conformal tumor-bed boost (36Gy/20fx) for total primary-site dose of 54Gy/30fx over 6-weeks. Followed by adjuvant multi-agent systemic chemotherapy which will be initiated 4-6 weeks after completion of radiotherapy provided the ANC >1500 and platelet count >1,00,000. A total of 6 cycles of alternating chemotherapy every 4-weekly will be planned as per our standard practice using CET protocol.
intervention type: Radiation
intervention name: Low dose Craniospinal Irradiation plus Focal Radiotherapy
description: The intervention arm of the study is to prospectively evaluate disease-related outcomes of low-dose CSI plus focal radiotherapy without concurrent chemotherapy followed by standard 6-cycles of adjuvant systemic chemotherapy in WNT-pathway medulloblastoma.
arm group label: Low Dose Craniospinal Irradiation
criteria: 
gender: All
minimum age: 3 Years
maximum age: 16 Years
healthy volunteers: No
last name: Tejpal Dr Gupta, MD
phone: (022) 2417 6015
email: tejpalgupta@rediffmail.com
facility: 
status: Recruiting
contact: 
country: India
responsible party type: Sponsor
mesh term: Medulloblastoma
sharing ipd: No