<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/NCT01678508</url>
  </required_header>
  <id_info>
    <org_study_id>NOPHO ALL2000 TPMT and outcome</org_study_id>
    <nct_id>NCT01678508</nct_id>
  </id_info>
  <brief_title>Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia</brief_title>
  <official_title>Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia - Influence on Cure Rates and Risk of Second Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In a population-based study to explore the impact of TPMT-status on the risk of relapse and&#xD;
      of second cancer among all patients treated according to the NOPHO ALL2000.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are widely used in the&#xD;
      treatment of childhood acute lymphoblastic leukemia (ALL). They primarily exert their&#xD;
      cytotoxicity through conversion into 6-thioguanine nucleotides (6TGN) that are incorporated&#xD;
      into DNA. Interindividual variations in response to thiopurine therapy are influenced by&#xD;
      genetically determined polymorphisms in the activity of the enzyme thiopurine&#xD;
      methyltransferase (TPMT). TPMT competes with the formation of 6TGN, as it methylates the&#xD;
      thiopurines (especially 6MP) and some of their metabolites. Approximately ten percent of all&#xD;
      individuals are TPMT heterozygous, with one wild type and one low activity allele, and one in&#xD;
      three hundred individuals are TPMT deficient with two low activity alleles. During the&#xD;
      maintenance therapy phase of the treatment of childhood ALL, which may last several years,&#xD;
      6MP is given on a daily basis at a starting dose of 75 mg/m.sq./day, which is subsequently&#xD;
      adjusted to a white blood cell count of 1.5-3.5 x109/L. We have previously demonstrated that&#xD;
      the risk of relapse is reduced by more than 50%, but the risk of second cancer was increased&#xD;
      3-fold among TPMT low activity patients. Accordingly, the Nordic ALL2000 protocol recommended&#xD;
      the dosing of 6MP to be based on the patients TPMT activity. In the present study of almost&#xD;
      1000 Nordic patients, we will explore whether this strategy of TPMT-based individualised 6MP&#xD;
      dosing have benefitted the patients by reducing their risk of second cancer while preserving&#xD;
      their low risk of relapse.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2002</start_date>
  <completion_date type="Actual">February 2012</completion_date>
  <primary_completion_date type="Actual">July 2011</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cumulative risk of relapse and risk of second cancer by Kaplan-Meier analysis with Gray's test comparisons at 10 years</measure>
    <time_frame>Up to 10 years from diagnosis</time_frame>
    <description>The risks will be reported as percentages.</description>
  </primary_outcome>
  <enrollment type="Actual">1020</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood stored for a subset of patients&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study cohort is based on patients enrolled in the NOPHO ALL2000 protocol.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  included in the NOPHO ALL2000 protocol&#xD;
&#xD;
          -  entered 6-mercaptopurine/Methotrexate maintenance therapy in first remission&#xD;
&#xD;
          -  available TPMT phenotype and/or genotype&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  children with Down Syndrome&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>15 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kjeld Schmiegelow, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>September 2012</verification_date>
  <study_first_submitted>May 22, 2012</study_first_submitted>
  <study_first_submitted_qc>September 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2012</study_first_posted>
  <last_update_submitted>September 4, 2012</last_update_submitted>
  <last_update_submitted_qc>September 4, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 5, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Kjeld Schmiegelow</investigator_full_name>
    <investigator_title>Professor MD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
  </condition_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/NCT01678508
org study id: NOPHO ALL2000 TPMT and outcome
nct id: NCT01678508
lead sponsor: 
has dmc: No
In a population-based study to explore the impact of TPMT-status on the risk of relapse and
      of second cancer among all patients treated according to the NOPHO ALL2000.
The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are widely used in the
      treatment of childhood acute lymphoblastic leukemia (ALL). They primarily exert their
      cytotoxicity through conversion into 6-thioguanine nucleotides (6TGN) that are incorporated
      into DNA. Interindividual variations in response to thiopurine therapy are influenced by
      genetically determined polymorphisms in the activity of the enzyme thiopurine
      methyltransferase (TPMT). TPMT competes with the formation of 6TGN, as it methylates the
      thiopurines (especially 6MP) and some of their metabolites. Approximately ten percent of all
      individuals are TPMT heterozygous, with one wild type and one low activity allele, and one in
      three hundred individuals are TPMT deficient with two low activity alleles. During the
      maintenance therapy phase of the treatment of childhood ALL, which may last several years,
      6MP is given on a daily basis at a starting dose of 75 mg/m.sq./day, which is subsequently
      adjusted to a white blood cell count of 1.5-3.5 x109/L. We have previously demonstrated that
      the risk of relapse is reduced by more than 50%, but the risk of second cancer was increased
      3-fold among TPMT low activity patients. Accordingly, the Nordic ALL2000 protocol recommended
      the dosing of 6MP to be based on the patients TPMT activity. In the present study of almost
      1000 Nordic patients, we will explore whether this strategy of TPMT-based individualised 6MP
      dosing have benefitted the patients by reducing their risk of second cancer while preserving
      their low risk of relapse.
observational model: Cohort
time perspective: Retrospective
measure: Cumulative risk of relapse and risk of second cancer by Kaplan-Meier analysis with Gray's test comparisons at 10 years
time frame: Up to 10 years from diagnosis
description: The risks will be reported as percentages.
whole blood stored for a subset of patients
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 1 Year
maximum age: 15 Years
healthy volunteers: No
last name: Kjeld Schmiegelow, M.D.
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Kjeld Schmiegelow
investigator title: Professor MD
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid