<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/NCT03286634</url>
  </required_header>
  <id_info>
    <org_study_id>ASIA-DS-ALL-2016</org_study_id>
    <nct_id>NCT03286634</nct_id>
  </id_info>
  <brief_title>ASIA Down Syndrome Acute Lymphoblastic Leukemia 2016</brief_title>
  <official_title>Asia-wide, Multicenter Open-label, Phase II Non-randomised Study Involving Children With Down Syndrome Under 21 Year-old With Newly Diagnosed, Treatment naïve Acute Lymphoblastic Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Hospital Organization Nagoya Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Hospital Organization Nagoya Medical Center</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>
      To evaluate the outcome of a prednisolone and low dose methotrexate based protocol in Down&#xD;
      syndrome children with ALL (DS-ALL) in an Asia-wide study. The treatment protocol was&#xD;
      modified based upon backbone of Taiwan Pediatric Oncology Group (TPOG)-ALL protocol in which&#xD;
      risk classification will be guided by level of flow minimal residual disease (MRD) instead.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 18, 2017</start_date>
  <completion_date type="Anticipated">March 31, 2033</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2028</primary_completion_date>
  <phase>Phase 2</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>risk stratification-directed chemotherapy</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Event Free Survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Percentage of patients who are event free at 5 years.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Percentage of patients who survive at 5 years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Percentage of patients who are leukemia free at 5 years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Induction failure</measure>
    <time_frame>5 weeks</time_frame>
    <description>Percentage of patients who had failed induction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete remission rate</measure>
    <time_frame>5 weeks</time_frame>
    <description>Percentage of patients who had achieved complete remission at the end of induction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of relapse</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of treatment-related adverse events</measure>
    <time_frame>Up to 10 years</time_frame>
    <description>Incidence of treatment-related infectious and metabolic complications (throughout various phases of study therapy) and secondary neoplasms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Flow MRD at day 15</measure>
    <time_frame>At day 15 of induction therapy</time_frame>
    <description>To assess the prognostic value flow MRD level during induction for DS-ALL.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Down Syndrome</condition>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Childhood Cancer</condition>
  <arm_group>
    <arm_group_label>SR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard Risk (SR) :&#xD;
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD &lt;0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%&#xD;
SR strategy:&#xD;
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.&#xD;
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low Risk (LR):&#xD;
Time-point #1 (Day 15 induction) Flow MRD &lt;1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) &lt;0.01% AND CNS 1 only&#xD;
LR strategy:&#xD;
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.&#xD;
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Daunorubicin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>DNR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone</intervention_name>
    <description>Given PO or IV</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>Pred</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>VCR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epirubicin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>EPI</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>E-coli L-asparaginase</intervention_name>
    <description>Given IM or IV</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>E-coli L-Asp</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6-Mercaptopurine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>6-MP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Given IV, PO or IT</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
    <other_name>MTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydrocortisone</intervention_name>
    <description>Given IT</description>
    <arm_group_label>LR</arm_group_label>
    <arm_group_label>SR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Given IV, IT or SC</description>
    <arm_group_label>SR</arm_group_label>
    <other_name>Ara-C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>SR</arm_group_label>
    <other_name>Cy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Down syndrome diagnosed clinically or cytogenetically (including Mosaic Down)&#xD;
&#xD;
          -  Newly diagnosed ALL according to WHO 2016 classification.&#xD;
&#xD;
          -  Age &lt; 21 years old at time of enrollment.&#xD;
&#xD;
          -  ECOG performance status (PS) score of 0-2.&#xD;
&#xD;
          -  Written informed consent obtained from legally acceptable representatives.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Second malignancy.&#xD;
&#xD;
          -  Philadelphia positive ALL.&#xD;
&#xD;
          -  Mature B-ALL.&#xD;
&#xD;
          -  Mixed phenotype acute leukemia.&#xD;
&#xD;
          -  Any previous treatment with cytotoxic chemotherapy excluding treatment for TAM or&#xD;
             radiation therapy. Patient pre-treated with short term steroid (&lt; 7 days of duration&#xD;
             within last 1 month prior to treatment start) can be enrolled into this study.&#xD;
&#xD;
          -  Renal dysfunction with creatinine &gt;2x upper limit of normal (ULN). Patients whose&#xD;
             creatinine has improved to &lt;2x ULN before treatment commencement can enrol subject to&#xD;
             discretion of site PI.&#xD;
&#xD;
          -  Liver dysfunction with direct bilirubin &gt; 5x ULN.&#xD;
&#xD;
          -  Any serious uncontrolled medical condition or impending end organ dysfunction that&#xD;
             would impair the ability of the subject to receive protocol therapy, including:&#xD;
&#xD;
               1. History of coronary arterial disease, cardiomyopathy, heart failure, arrhythmia&#xD;
                  (other than sinus arrhythmia) or severe cardiac malformation which with residual&#xD;
                  abnormalities or requires further major corrective surgery within 2 years.&#xD;
&#xD;
               2. Ongoing uncontrolled hypertension.&#xD;
&#xD;
               3. Ongoing uncontrolled diabetes mellitus.&#xD;
&#xD;
               4. Ongoing uncontrolled infection.&#xD;
&#xD;
               5. History of congenital or acquired immunodeficiency including HIV infection.&#xD;
&#xD;
               6. History of interstitial pneumonia, pulmonary fibrosis, bronchiectasis or severe&#xD;
                  pulmonary emphysema.&#xD;
&#xD;
               7. CNS hemorrhage.&#xD;
&#xD;
               8. Psychiatric disorder.&#xD;
&#xD;
               9. Other concurrent active neoplasms.&#xD;
&#xD;
          -  Pregnant or lactating women.&#xD;
&#xD;
          -  Doubtful compliance or ability to complete study therapy due to financial, social,&#xD;
             familial or geographic reason, or in the judgement of site investigator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Years</minimum_age>
    <maximum_age>20 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Allen Yeoh, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Allen Yeoh, MBBS</last_name>
    <phone>(65) 67724406</phone>
    <email>paeyej@nus.edu.sg</email>
  </overall_contact>
  <location>
    <facility>
      <name>Prince of Wales Hospital</name>
      <address>
        <city>Shatin</city>
        <state>New Territories</state>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chi Kong Li, MBBS</last_name>
      <email>ckli@cuhk.edu.hk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kagoshima University Hospital</name>
      <address>
        <city>Kagoshima</city>
        <zip>890-8544</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yasuhiro Okamoto</last_name>
      <email>okamoto@m2.kufm.kagoshima-u.ac.jp</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Malaya Medical Centre</name>
      <address>
        <city>Kuala Lumpur</city>
        <zip>59100</zip>
        <country>Malaysia</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Hany Arrifin, MBBS</last_name>
      <email>hany@ummc.edu.my</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Subang Jaya Medical Centre</name>
      <address>
        <city>Subang Jaya</city>
        <zip>47500</zip>
        <country>Malaysia</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Hai Peng Lin, MBBS</last_name>
      <email>flslhp@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Lee Lee Chan, MBBS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>National University Hospital</name>
      <address>
        <city>Singapore</city>
        <zip>119074</zip>
        <country>Singapore</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Allen Yeoh, MBBS</last_name>
      <email>allen_yeoh@nuhs.edu.sg</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>KK Women's and Children's Hospital</name>
      <address>
        <city>Singapore</city>
        <zip>229899</zip>
        <country>Singapore</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ah Moy Tan, MBBS</last_name>
      <email>tan.ah.moy01@singhealth.com.sg</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Children's Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Tsamn Lin Dong, MD</last_name>
      <email>dtlin@ntuh.gov.tw</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Mackay Memorial Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>10449</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hsi-Che Liu, MD</last_name>
      <email>hsiche@mmh.org.tw</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Chang Gung Memorial Hopsital, Linkou</name>
      <address>
        <city>Taoyuan</city>
        <zip>333</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Shih-Hsiang Chen, MD</last_name>
      <email>samechen@cgmh.org.tw</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Siriraj Hospital Mahidol University</name>
      <address>
        <city>Bangkok</city>
        <zip>10700</zip>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jassada Buaboonnam, MD</last_name>
      <email>onco008@yahoo.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Hong Kong</country>
    <country>Japan</country>
    <country>Malaysia</country>
    <country>Singapore</country>
    <country>Taiwan</country>
    <country>Thailand</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 18, 2017</study_first_posted>
  <last_update_submitted>September 26, 2022</last_update_submitted>
  <last_update_submitted_qc>September 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </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>
    <mesh_term>Down Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Hydrocortisone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Daunorubicin</mesh_term>
    <mesh_term>Asparaginase</mesh_term>
    <mesh_term>Epirubicin</mesh_term>
    <mesh_term>Mercaptopurine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03286634
org study id: ASIA-DS-ALL-2016
nct id: NCT03286634
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To evaluate the outcome of a prednisolone and low dose methotrexate based protocol in Down
      syndrome children with ALL (DS-ALL) in an Asia-wide study. The treatment protocol was
      modified based upon backbone of Taiwan Pediatric Oncology Group (TPOG)-ALL protocol in which
      risk classification will be guided by level of flow minimal residual disease (MRD) instead.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: risk stratification-directed chemotherapy
primary purpose: Treatment
masking: None (Open Label)
measure: Event Free Survival
time frame: Up to 5 years
description: Percentage of patients who are event free at 5 years.
measure: Overall survival
time frame: Up to 5 years
description: Percentage of patients who survive at 5 years.
measure: Disease free survival
time frame: Up to 5 years
description: Percentage of patients who are leukemia free at 5 years.
measure: Induction failure
time frame: 5 weeks
description: Percentage of patients who had failed induction.
measure: Complete remission rate
time frame: 5 weeks
description: Percentage of patients who had achieved complete remission at the end of induction.
measure: Cumulative incidence of relapse
time frame: Up to 5 years
measure: Incidence of treatment-related adverse events
time frame: Up to 10 years
description: Incidence of treatment-related infectious and metabolic complications (throughout various phases of study therapy) and secondary neoplasms.
measure: Flow MRD at day 15
time frame: At day 15 of induction therapy
description: To assess the prognostic value flow MRD level during induction for DS-ALL.
arm group label: SR
arm group type: Experimental
description: Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
arm group label: LR
arm group type: Experimental
description: Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
intervention type: Drug
intervention name: Daunorubicin
description: Given IV
arm group label: LR
arm group label: SR
other name: DNR
intervention type: Drug
intervention name: Prednisolone
description: Given PO or IV
arm group label: LR
arm group label: SR
other name: Pred
intervention type: Drug
intervention name: Vincristine
description: Given IV
arm group label: LR
arm group label: SR
other name: VCR
intervention type: Drug
intervention name: Epirubicin
description: Given IV
arm group label: LR
arm group label: SR
other name: EPI
intervention type: Drug
intervention name: E-coli L-asparaginase
description: Given IM or IV
arm group label: LR
arm group label: SR
other name: E-coli L-Asp
intervention type: Drug
intervention name: 6-Mercaptopurine
description: Given PO
arm group label: LR
arm group label: SR
other name: 6-MP
intervention type: Drug
intervention name: Methotrexate
description: Given IV, PO or IT
arm group label: LR
arm group label: SR
other name: MTX
intervention type: Drug
intervention name: Hydrocortisone
description: Given IT
arm group label: LR
arm group label: SR
intervention type: Drug
intervention name: Cytarabine
description: Given IV, IT or SC
arm group label: SR
other name: Ara-C
intervention type: Drug
intervention name: Cyclophosphamide
description: Given IV
arm group label: SR
other name: Cy
criteria: 
gender: All
minimum age: 0 Years
maximum age: 20 Years
healthy volunteers: No
last name: Allen Yeoh, MBBS
role: Principal Investigator
affiliation: National University Hospital, Singapore
last name: Allen Yeoh, MBBS
phone: (65) 67724406
email: paeyej@nus.edu.sg
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Hong Kong
country: Japan
country: Malaysia
country: Singapore
country: Taiwan
country: Thailand
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Down Syndrome
mesh term: Syndrome
mesh term: Cytarabine
mesh term: Prednisolone
mesh term: Hydrocortisone
mesh term: Cyclophosphamide
mesh term: Methotrexate
mesh term: Vincristine
mesh term: Daunorubicin
mesh term: Asparaginase
mesh term: Epirubicin
mesh term: Mercaptopurine