<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/NCT02252107</url>
  </required_header>
  <id_info>
    <org_study_id>PLMA34</org_study_id>
    <nct_id>NCT02252107</nct_id>
  </id_info>
  <brief_title>10-day Decitabine, Fludarabine and 2 Gray TBI as Conditioning Strategy for Poor and Very Poor Risk AML in CR1</brief_title>
  <official_title>10-day Decitabine, Fludarabine and 2 Gray TBI as Conditioning Strategy for Poor and Very Poor Risk AML in CR1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study examines whether the addition of decitabine to the standard Flu/TBI conditioning&#xD;
      regimen prior to allogeneic stem cell transplantation in poor and very poor risk AML&#xD;
      patients, reduces the risk of recurrence of the disease. Because decitabine has hardly any&#xD;
      side effects, it will likely have little impact on the occurrence of Graft Versus Host&#xD;
      Disease. The investigators are looking for a pre-treatment for transplantation which reduces&#xD;
      the chance of recurrence of the disease without involving severe damage to normal tissues.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute myeloid leukemia (AML) is a heterogeneous group of malignant hematological diseases&#xD;
      with different molecular genetic abnormalities. These are important in predicting response to&#xD;
      treatment. Recently, an analysis of 424 AML patients treated in various HOVON protocols&#xD;
      showed a 5 year overall survival for patients in good, intermediate, poor and very poor risk&#xD;
      groups of 65%, 51%, 25% and 7% respectively (HOVON 102 protocol). This shows that especially&#xD;
      for patients in the (very) poor risk group, the outcome is very disappointing, despite the&#xD;
      current treatment strategies. For patients with intermediate, poor and very poor risk&#xD;
      cytogenetics postconsolidation treatment with an allogeneic hematopoietic cell&#xD;
      transplantation (allo HCT) is standard practice after myeloablative (MAB HCT) or&#xD;
      non-myeloablative (NMA HCT) conditioning.&#xD;
&#xD;
      Unfortunately, mortality after MAB conditioning is still considerable, mainly due to therapy&#xD;
      related mortality, graft-versus-host disease, infections, or relapse. Currently, the NMA&#xD;
      conditioning is used more frequently, which is far less toxic. Nonmyeloablative regimens have&#xD;
      relied on the immunological anti-leukemia effect (graft-versus-leukemia), to prevent&#xD;
      relapsing disease. This anti-leukemia effect, however, needs time to develop, which makes it&#xD;
      necessary to be in control over the disease pre-transplantation as much as possible. This&#xD;
      extends the time the immune system of the donor has to develop an adequate anti-leukemia&#xD;
      effect, which is especially important in the (very) poor risk group patients since they have&#xD;
      the highest chance of relapse.&#xD;
&#xD;
      Epigenetic alterations are increasingly recognised for their roles in oncogenesis. These&#xD;
      alterations can for example 'silence'genes by hypermethylation. These alterations are&#xD;
      potentially reversible.&#xD;
&#xD;
      The hypomethylating agent decitabine is one of the therapeutic approaches which can&#xD;
      reactivate silenced genes by its interaction on the epigenetics. A phase II study (Blum, Proc&#xD;
      Natl Acad Sci 2010) with 53 AML patients who received 10 days decitabine, showed a complete&#xD;
      remission rate (CR) in 47% of patients. This percentage corresponds to the CR of intensive&#xD;
      chemotherapy in elderly AML patients. The median survival was 55 weeks. Furthermore, this&#xD;
      study showed that decitabine was well tolerated.&#xD;
&#xD;
      Earlier studies have shown that patients whose disease was controlled with hypomethylating&#xD;
      agents pre-transplantation had comparable survival compared with patients whose disease was&#xD;
      controlled with intensive chemotherapy(Damaj, Journal of Clinical Oncology, 2012).&#xD;
&#xD;
      In the current study the AML is already in remission after intensive chemotherapy. In an&#xD;
      attempt to design a conditioning strategy with very low toxicity but considerable&#xD;
      myelosuppressive activity, the investigators will combine the non-myeloablative (NMA)&#xD;
      fludarabine and low-dose TBI (2 Gray) with a 10-day schedule of decitabine (Dec-Flu-TBI).&#xD;
      Theoretically, it is very attractive to add a drug like decitabine (in a 10-day schedule)&#xD;
      that exerts a strong antileukemic effect, without additional extra-medullary toxicity, to the&#xD;
      standard Flu-TBI NMA conditioning regimen. The hypothesis is that in this way the&#xD;
      investigators can extent the time the immune system of the donor needs to create an adequate&#xD;
      graft-versus-leukemia effect, at the cost of low toxicity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Actual">May 2019</completion_date>
  <primary_completion_date type="Actual">May 2019</primary_completion_date>
  <phase>Phase 2</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 at 1-year after the transplantation procedure</measure>
    <time_frame>At 1-year after the transplantation procedure</time_frame>
    <description>All patients included in this study are in complete morphologic remission. Relapse at 1-year is defined as the % of patients who have relapsed within the first year after transplantation. For the computation of the incidence of relapse at 1-year, death in CR will be considered as a competing risk.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Relapse within the first 100 days after the transplantation procedure</measure>
    <time_frame>100 days after the transplantation procedure</time_frame>
    <description>All patients included in this study are in complete morphologic remission. Relapse within the first 100 days after the transplantation procedure is defined as the % of patients who have relapsed within the first100 days after the transplantation procedure. For the computation of the incidence of relapse within 100 days after the transplantation procedure, death in CR will be considered as a competing risk.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment related mortality (TRM) within the first 100 days after the transplantation procedure</measure>
    <time_frame>100 days after the transplantation procedure</time_frame>
    <description>Treatment related mortality (TRM) within the first 100 days after the transplantation procedure is defined as the % of patients deceased related to the treatment/whereby death is related to the treatment, within the first 100 days after the transplantation procedure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment related mortality (TRM) at 1-year after the transplantation procedure</measure>
    <time_frame>At 1-year after the transplantation procedure</time_frame>
    <description>Treatment related mortality (TRM) at 1-year after the transplantation procedure is defined as the % of patients deceased related to the treatment/whereby death is related to the treatment, within the first year after the transplantation procedure.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Acute Myeloid Leukemia (AML)</condition>
  <arm_group>
    <arm_group_label>Decitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single arm study: the addition of 10 days (20 mg/m2) decitabine to the conditioning regimen prior to allogeneic hematopoietic transplantation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>decitabine</intervention_name>
    <description>Single arm study: the addition of 10 days (20 mg/m2) decitabine to the conditioning regimen prior to allogeneic hematopoietic transplantation.</description>
    <arm_group_label>Decitabine</arm_group_label>
    <other_name>Dacogen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients eligible for allogeneic HCT, independent of age&#xD;
&#xD;
          -  Adult patients of any age with a cytopathologically confirmed diagnosis according to&#xD;
             WHO classification of newly diagnosed AML (not APL = AML-M3), de novo AML or secondary&#xD;
             AML&#xD;
&#xD;
          -  in first complete remission (CR1)&#xD;
&#xD;
          -  Poor risk or very poor risk subgroups&#xD;
&#xD;
          -  WHO performance status ≤ 2&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient not in CR1&#xD;
&#xD;
          -  Patients who have senile dementia, mental impairment of any other psychiatric disorder&#xD;
             that prohibits the patient from understanding and giving informed consent&#xD;
&#xD;
          -  Active serious infections like HIV, hepatitis B virus (HBV) and hepatitis C virus&#xD;
             (HCV)&#xD;
&#xD;
          -  Patient is unwilling to use contraceptive techniques during and for 12 months&#xD;
             following treatment&#xD;
&#xD;
          -  Female patient who is pregnant or breastfeeding&#xD;
&#xD;
          -  Active and uncontrolled infections&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gerwin Huls, MD. PhD.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Liège</name>
      <address>
        <city>Liège</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Groningen (UMCG)</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radboud university medical center</name>
      <address>
        <city>Nijmegen</city>
        <zip>6500 HB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>September 19, 2014</study_first_submitted>
  <study_first_submitted_qc>September 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 2014</study_first_posted>
  <last_update_submitted>March 18, 2020</last_update_submitted>
  <last_update_submitted_qc>March 18, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Decitabine</keyword>
  <keyword>Hematopoietic stem cell transplantation (HSCT)</keyword>
  <keyword>Conditioning</keyword>
  <keyword>AML</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Decitabine</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/NCT02252107
org study id: PLMA34
nct id: NCT02252107
lead sponsor: 
has dmc: Yes
This study examines whether the addition of decitabine to the standard Flu/TBI conditioning
      regimen prior to allogeneic stem cell transplantation in poor and very poor risk AML
      patients, reduces the risk of recurrence of the disease. Because decitabine has hardly any
      side effects, it will likely have little impact on the occurrence of Graft Versus Host
      Disease. The investigators are looking for a pre-treatment for transplantation which reduces
      the chance of recurrence of the disease without involving severe damage to normal tissues.
Acute myeloid leukemia (AML) is a heterogeneous group of malignant hematological diseases
      with different molecular genetic abnormalities. These are important in predicting response to
      treatment. Recently, an analysis of 424 AML patients treated in various HOVON protocols
      showed a 5 year overall survival for patients in good, intermediate, poor and very poor risk
      groups of 65%, 51%, 25% and 7% respectively (HOVON 102 protocol). This shows that especially
      for patients in the (very) poor risk group, the outcome is very disappointing, despite the
      current treatment strategies. For patients with intermediate, poor and very poor risk
      cytogenetics postconsolidation treatment with an allogeneic hematopoietic cell
      transplantation (allo HCT) is standard practice after myeloablative (MAB HCT) or
      non-myeloablative (NMA HCT) conditioning.

      Unfortunately, mortality after MAB conditioning is still considerable, mainly due to therapy
      related mortality, graft-versus-host disease, infections, or relapse. Currently, the NMA
      conditioning is used more frequently, which is far less toxic. Nonmyeloablative regimens have
      relied on the immunological anti-leukemia effect (graft-versus-leukemia), to prevent
      relapsing disease. This anti-leukemia effect, however, needs time to develop, which makes it
      necessary to be in control over the disease pre-transplantation as much as possible. This
      extends the time the immune system of the donor has to develop an adequate anti-leukemia
      effect, which is especially important in the (very) poor risk group patients since they have
      the highest chance of relapse.

      Epigenetic alterations are increasingly recognised for their roles in oncogenesis. These
      alterations can for example 'silence'genes by hypermethylation. These alterations are
      potentially reversible.

      The hypomethylating agent decitabine is one of the therapeutic approaches which can
      reactivate silenced genes by its interaction on the epigenetics. A phase II study (Blum, Proc
      Natl Acad Sci 2010) with 53 AML patients who received 10 days decitabine, showed a complete
      remission rate (CR) in 47% of patients. This percentage corresponds to the CR of intensive
      chemotherapy in elderly AML patients. The median survival was 55 weeks. Furthermore, this
      study showed that decitabine was well tolerated.

      Earlier studies have shown that patients whose disease was controlled with hypomethylating
      agents pre-transplantation had comparable survival compared with patients whose disease was
      controlled with intensive chemotherapy(Damaj, Journal of Clinical Oncology, 2012).

      In the current study the AML is already in remission after intensive chemotherapy. In an
      attempt to design a conditioning strategy with very low toxicity but considerable
      myelosuppressive activity, the investigators will combine the non-myeloablative (NMA)
      fludarabine and low-dose TBI (2 Gray) with a 10-day schedule of decitabine (Dec-Flu-TBI).
      Theoretically, it is very attractive to add a drug like decitabine (in a 10-day schedule)
      that exerts a strong antileukemic effect, without additional extra-medullary toxicity, to the
      standard Flu-TBI NMA conditioning regimen. The hypothesis is that in this way the
      investigators can extent the time the immune system of the donor needs to create an adequate
      graft-versus-leukemia effect, at the cost of low toxicity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Relapse at 1-year after the transplantation procedure
time frame: At 1-year after the transplantation procedure
description: All patients included in this study are in complete morphologic remission. Relapse at 1-year is defined as the % of patients who have relapsed within the first year after transplantation. For the computation of the incidence of relapse at 1-year, death in CR will be considered as a competing risk.
measure: Relapse within the first 100 days after the transplantation procedure
time frame: 100 days after the transplantation procedure
description: All patients included in this study are in complete morphologic remission. Relapse within the first 100 days after the transplantation procedure is defined as the % of patients who have relapsed within the first100 days after the transplantation procedure. For the computation of the incidence of relapse within 100 days after the transplantation procedure, death in CR will be considered as a competing risk.
measure: Treatment related mortality (TRM) within the first 100 days after the transplantation procedure
time frame: 100 days after the transplantation procedure
description: Treatment related mortality (TRM) within the first 100 days after the transplantation procedure is defined as the % of patients deceased related to the treatment/whereby death is related to the treatment, within the first 100 days after the transplantation procedure.
measure: Treatment related mortality (TRM) at 1-year after the transplantation procedure
time frame: At 1-year after the transplantation procedure
description: Treatment related mortality (TRM) at 1-year after the transplantation procedure is defined as the % of patients deceased related to the treatment/whereby death is related to the treatment, within the first year after the transplantation procedure.
arm group label: Decitabine
arm group type: Experimental
description: Single arm study: the addition of 10 days (20 mg/m2) decitabine to the conditioning regimen prior to allogeneic hematopoietic transplantation.
intervention type: Drug
intervention name: decitabine
description: Single arm study: the addition of 10 days (20 mg/m2) decitabine to the conditioning regimen prior to allogeneic hematopoietic transplantation.
arm group label: Decitabine
other name: Dacogen
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gerwin Huls, MD. PhD.
role: Principal Investigator
affiliation: Radboud University Medical Center
facility: 
facility: 
facility: 
country: Belgium
country: Netherlands
responsible party type: Sponsor
mesh term: Leukemia, Myeloid, Acute
mesh term: Decitabine