<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/NCT01719341</url>
  </required_header>
  <id_info>
    <org_study_id>2012/00465</org_study_id>
    <nct_id>NCT01719341</nct_id>
  </id_info>
  <brief_title>Study of Non-Myeloablative Haplo-identical Haematopoietic Stem Cell Transplantation in Patients With Haematological Malignancies or Acquired Aplastic Anaemia</brief_title>
  <sponsors>
    <lead_sponsor>
      <agency>National University Hospital, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National University Hospital, Singapore</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative therapy&#xD;
      for patients with both haematological and some non-haematological disorders. However, one of&#xD;
      the major limiting factors for transplantation is the inability to identify a suitable&#xD;
      HLA-matched donor. Development of an cost-effective and clinically efficacious alternative to&#xD;
      HLA-identical sibling or unrelated donor transplantation would significantly expand the&#xD;
      availability of allogeneic HSCT to patients in Singapore. Preliminary results indicate that&#xD;
      the use of high dose post-transplant cyclophosphamide (Cy) for graft versus host disease&#xD;
      (GVHD) prophylaxis in haplo-identical allogeneic HSCT is associated a low incidence of GVHD&#xD;
      and low treatment related toxicity. We propose a phase II clinical trial to assess the&#xD;
      efficacy of a haplo-identical allogeneic transplantation protocol using high dose&#xD;
      post-transplant Cy for the treatment of patients with haematological disorders. A&#xD;
      non-myeloablative protocol (Fludarabine-low dose cyclophosphamide-TBI) will be used for&#xD;
      patients with bone marrow failure syndromes and indolent lymphoid disease. In view of the&#xD;
      higher relapse risk of patients with myeloid malignancies, these patients will be treated&#xD;
      with a reduced intensity conditioning regimen (Fludarabine-Busulphan). The primary end-point&#xD;
      of the study will be overall survival at one year. Economic cost of the haplo-identical&#xD;
      transplantation, as well as treatment timelines will be recorded and compared will other&#xD;
      forms of unrelated donor allogeneic transplantation (umbilical cord blood transplantation and&#xD;
      unrelated HLA-matched adult donor). Immunological reconstitution of patients following&#xD;
      haplo-transplantation will be analysed and data will be utilized to guide future&#xD;
      immunotherapy strategies post-transplantation.&#xD;
&#xD;
      One year survival after non-myeloablative haploidentical stem cell transplantation is not&#xD;
      inferior to that observed after non-myeloablative volunteer unrelated donor or unrelated cord&#xD;
      blood haematopoietic stem cell transplantation.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2012</start_date>
  <primary_completion_date type="Anticipated">June 2014</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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>1 year overall survival after HLA-Haploidentical transplantation</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival one and 2 years post-transplantation</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of relapse/progression at one and 2 years post-transplant</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <enrollment type="Anticipated">21</enrollment>
  <condition>Haematological Malignancies</condition>
  <condition>Acquired Aplastic Anaemia</condition>
  <eligibility>
    <study_pop>
      <textblock>
        Sample size estimation based on Case and Morgan Two Stage Phase II Design with an expected&#xD;
        duration of accrual of 2 years, assuming a power of 80% and a level of significance of 10%.&#xD;
        With an S0 of 0.25 and SA of 0.50, an interim analysis will be performed after 14 patients&#xD;
        are recruited with an anticipated final recruitment total of 21 patients for each arm of&#xD;
        the study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patient Selection Inclusion criteria&#xD;
&#xD;
          1. Age under 70 years and older than 18 years&#xD;
&#xD;
          2. Absence of HLA fully compatible related donor&#xD;
&#xD;
          3. Need for an urgent transplantation, defined as within 8 weeks of referral to the&#xD;
             transplant centre or absence of HLA-compatible VUD after searching the international&#xD;
             registries. Patients with a HLA-compatible VUD but whose donor is considered by the&#xD;
             transplantation centre as unsuitable will also be eligible. 4. Informed consent.&#xD;
&#xD;
        Disease inclusion criteria:&#xD;
&#xD;
        In general this encompasses all haematological disorders where a volunteer unrelated donor&#xD;
        (UD) transplant is clinically indicated.&#xD;
&#xD;
        1. Acute, chronic leukaemia or myelodysplastic syndrome for which allogeneic&#xD;
        transplantation is considered as the best treatment option.&#xD;
&#xD;
        a. Acute myeloid leukaemia (AML) i. In first complete remission (CR1) with one of the&#xD;
        following characteristics:&#xD;
&#xD;
          1. High risk cytogenetic or molecular alterations (e.g. t(9;22), deletion 7/7q-, monosomy&#xD;
             5 or del(5q), 3q26 alterations, complex karyotype [3 or more anomalies], p53&#xD;
             alterations, 11q23 especially t(6;11) abnormalities, FLT-3 ITD, monosomal karyotype.&#xD;
&#xD;
          2. Leukocytes at diagnosis &gt; 50 x109/l (except in cases with good prognosis molecular&#xD;
             rearrangements for which leukocytes should be &gt; 100 x 109/l) b. Myelodysplastic&#xD;
             syndromes1. International Prognosis Index (IPSS) above 1 (intermediate group 2 or high&#xD;
             risk)&#xD;
&#xD;
        2. IPSS 0 or 0.5 in the presence of cytopenias requiring treatment. c. Therapy related AML&#xD;
        or MDS in first CRd. AML or MDS in second (CR2) or subsequent CRe. Ph'-positive chronic&#xD;
        myeloid leukaemia i. In first chronic phase if refractory and/or intolerance to tyrosine&#xD;
        kinase inhibitors is clearly demonstrated ii. In second chronic phase 2. Acute&#xD;
        lymphoblastic leukaemia (ALL)a. In CR1 with one of the following characteristics: i. Very&#xD;
        high risk chromosome or molecular alterations (e.g. t(9;22), t(4;11), complex karyotype in&#xD;
        adults, bcr/abl rearrangements, MLL rearrangements) ii. Slow response to induction&#xD;
        treatment defined as the presence of &gt;10% blasts in bone marrow at day 14 of induction&#xD;
        treatmentiii. Adults aged &gt; 30 yearsiv. Adults with B ALL cell line with a number of&#xD;
        leukocytes at diagnosis &gt;25 x 109/L or T ALL cell line with a number of leukocytes at&#xD;
        diagnosis &gt;100X109/Lb. In CR2 or subsequent CR 3. Non-Hodgkin's lymphomaa. Follicular NHL:&#xD;
        in second or subsequent complete or partial remissionb. Mantle cell NHL: in second or&#xD;
        subsequent complete or partial remissionc. High grade NHL: in second complete or very good&#xD;
        partial remission 4. Hodgkin's diseasea. in second or subsequent complete or partial&#xD;
        remission 5. Chronic lymphocytic leukaemia. a. in second or subsequent remissionb. with&#xD;
        adverse risk prognostic features in first remission 6. Acquired Aplastic Anaemia 7.&#xD;
        Myelofibrosis- Lille score -high, Cervantes score-high 8. Other haematological malignancies&#xD;
        for which UD HSCT is indicated&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with an available 7-8/8 HLA-A, -B, -C, -DRB1 matched sibling donor or 7-8/8&#xD;
             unrelated bone marrow donor&#xD;
&#xD;
          2. Availability of suitable UCB unit/s and eligible for an UCB transplant&#xD;
&#xD;
          3. ECOG performance status worse than 2&#xD;
&#xD;
          4. Cardiac insufficiency requiring treatment, symptomatic coronary artery disease or LVEF&#xD;
             less than 35%.&#xD;
&#xD;
          5. Hepatic disease, with total bilirubin greater than 2 times upper limit of normal or&#xD;
             AST &gt; 5 times upper limit of normal.&#xD;
&#xD;
          6. Severe hypoxaemia, pO2 &lt; 70 mm Hg, with decreased DLCO &lt; 50% of predicted; or mild&#xD;
             hypoxemia, pO2 &lt; 80 mm Hg with severely decreased DLCO &lt; 50% of predicted.&#xD;
&#xD;
          7. Impaired renal function (creatinine &gt; 2 times upper limit of normal or creatinine&#xD;
             clearance &lt; 50% for age, gender, weight).&#xD;
&#xD;
          8. Previous irradiation that precludes the safe administration of an additional dose of&#xD;
             200 cGy of total body irradiation (TBI).&#xD;
&#xD;
          9. HIV positive patients.&#xD;
&#xD;
         10. Female patients who are pregnant or breast feeding due to risks to foetus from&#xD;
             conditioning regimen and potential risks to nursing infants.&#xD;
&#xD;
         11. Life expectancy severely limited by diseases other than the disease indication for&#xD;
             transplant&#xD;
&#xD;
         12. Serious concurrent uncontrolled infection e.g. active tuberculosis, mycoses or viral&#xD;
             infection&#xD;
&#xD;
         13. Serious psychiatric/ psychological disorders&#xD;
&#xD;
         14. Absence of /inability to provide informed consent&#xD;
&#xD;
         15. Patients with acute leukaemia with &gt;5% bone marrow blasts&#xD;
&#xD;
         16. Intermediate or high grade NHL, mantle cell NHL and Hodgkin's disease that is&#xD;
             refractory to salvage therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zi Yi Lim, MB ChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zi Yi Lim, MB ChB</last_name>
    <phone>65 6779 5555</phone>
    <email>Zi_Yi_Lim@nuhs.edu.sg</email>
  </overall_contact>
  <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>Zi Yi Lim, MB ChB</last_name>
      <phone>65 6779 5555</phone>
      <email>Zi_Yi_Lim@nuhs.edu.sg</email>
    </contact>
    <investigator>
      <last_name>Zi Yi Lim, MB ChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <reference>
    <citation>Aversa F. Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States. Bone Marrow Transplant. 2008 Mar;41(5):473-81. doi: 10.1038/sj.bmt.1705966. Epub 2008 Jan 7.</citation>
    <PMID>18176612</PMID>
  </reference>
  <reference>
    <citation>Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, Huff CA, Borrello I, Matsui W, Powell JD, Kasamon Y, Goodman SN, Hess A, Levitsky HI, Ambinder RF, Jones RJ, Fuchs EJ. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010 Apr 22;115(16):3224-30. doi: 10.1182/blood-2009-11-251595. Epub 2010 Feb 2.</citation>
    <PMID>20124511</PMID>
  </reference>
  <verification_date>December 2013</verification_date>
  <study_first_submitted>October 30, 2012</study_first_submitted>
  <study_first_submitted_qc>October 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 1, 2012</study_first_posted>
  <last_update_submitted>December 10, 2013</last_update_submitted>
  <last_update_submitted_qc>December 10, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 11, 2013</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>Neoplasms</mesh_term>
    <mesh_term>Hematologic Neoplasms</mesh_term>
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Anemia, Aplastic</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/NCT01719341
org study id: 2012/00465
nct id: NCT01719341
lead sponsor: 
has dmc: Yes
Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative therapy
      for patients with both haematological and some non-haematological disorders. However, one of
      the major limiting factors for transplantation is the inability to identify a suitable
      HLA-matched donor. Development of an cost-effective and clinically efficacious alternative to
      HLA-identical sibling or unrelated donor transplantation would significantly expand the
      availability of allogeneic HSCT to patients in Singapore. Preliminary results indicate that
      the use of high dose post-transplant cyclophosphamide (Cy) for graft versus host disease
      (GVHD) prophylaxis in haplo-identical allogeneic HSCT is associated a low incidence of GVHD
      and low treatment related toxicity. We propose a phase II clinical trial to assess the
      efficacy of a haplo-identical allogeneic transplantation protocol using high dose
      post-transplant Cy for the treatment of patients with haematological disorders. A
      non-myeloablative protocol (Fludarabine-low dose cyclophosphamide-TBI) will be used for
      patients with bone marrow failure syndromes and indolent lymphoid disease. In view of the
      higher relapse risk of patients with myeloid malignancies, these patients will be treated
      with a reduced intensity conditioning regimen (Fludarabine-Busulphan). The primary end-point
      of the study will be overall survival at one year. Economic cost of the haplo-identical
      transplantation, as well as treatment timelines will be recorded and compared will other
      forms of unrelated donor allogeneic transplantation (umbilical cord blood transplantation and
      unrelated HLA-matched adult donor). Immunological reconstitution of patients following
      haplo-transplantation will be analysed and data will be utilized to guide future
      immunotherapy strategies post-transplantation.

      One year survival after non-myeloablative haploidentical stem cell transplantation is not
      inferior to that observed after non-myeloablative volunteer unrelated donor or unrelated cord
      blood haematopoietic stem cell transplantation.
observational model: Cohort
time perspective: Prospective
measure: 1 year overall survival after HLA-Haploidentical transplantation
time frame: 1 year
measure: Progression free survival one and 2 years post-transplantation
time frame: 2 years
measure: Cumulative incidence of relapse/progression at one and 2 years post-transplant
time frame: 2 years
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Zi Yi Lim, MB ChB
role: Principal Investigator
affiliation: National University Hospital, Singapore
last name: Zi Yi Lim, MB ChB
phone: 65 6779 5555
email: Zi_Yi_Lim@nuhs.edu.sg
facility: 
status: Recruiting
contact: 
investigator: 
country: Singapore
citation: Aversa F. Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States. Bone Marrow Transplant. 2008 Mar;41(5):473-81. doi: 10.1038/sj.bmt.1705966. Epub 2008 Jan 7.
PMID: 18176612
citation: Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, Huff CA, Borrello I, Matsui W, Powell JD, Kasamon Y, Goodman SN, Hess A, Levitsky HI, Ambinder RF, Jones RJ, Fuchs EJ. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010 Apr 22;115(16):3224-30. doi: 10.1182/blood-2009-11-251595. Epub 2010 Feb 2.
PMID: 20124511
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Hematologic Neoplasms
mesh term: Anemia
mesh term: Anemia, Aplastic