<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/NCT02204020</url>
  </required_header>
  <id_info>
    <org_study_id>UPCI 13-165</org_study_id>
    <nct_id>NCT02204020</nct_id>
  </id_info>
  <brief_title>Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS</brief_title>
  <acronym>UPCI 13-165</acronym>
  <official_title>Phase II Study of 5-azacytidine Maintenance After Allogeneic Hematopoietic Cell Transplantation for High-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute&#xD;
      Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high&#xD;
      and is the most common cause of mortality after HCT. Moreover, treatment options for relapse&#xD;
      after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who&#xD;
      are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has&#xD;
      shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect,&#xD;
      including upregulation of tumor-associated antigen and costimulatory molecule expression.&#xD;
      Moreover, 5-aza has properties that suggest protection against graft-versus-host disease&#xD;
      (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical&#xD;
      use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy.&#xD;
      This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or&#xD;
      MDS with risk factors that are associated with a high risk for relapse.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT)&#xD;
      for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies&#xD;
      indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that&#xD;
      may enhance the graft-versus-leukemia (GVL) effect, including upregulation of&#xD;
      tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties&#xD;
      that suggest protection against graft-versus-host disease (GVHD). The primary objective is to&#xD;
      evaluate relapse rate at one year. Secondary objectives will include the incidence of both&#xD;
      acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity.&#xD;
      Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune&#xD;
      system.&#xD;
&#xD;
      Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects&#xD;
      are consented, screened, then transplanted. Those showing complete response and no active&#xD;
      GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are&#xD;
      performed for response assessment after transplant as well as every three cycles (1 cycle=28&#xD;
      days) while on treatment. Dosing starts at 32mg/m2 and can be increased every 2 cycles&#xD;
      without a serious adverse event (SAE), or reduced per toxicity for up to 12 cycles.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Lack of interest with investigators - no subjects enrolled&#xD;
  </why_stopped>
  <start_date type="Actual">April 2015</start_date>
  <completion_date type="Actual">May 4, 2016</completion_date>
  <primary_completion_date type="Actual">April 2015</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 rate at 1 year</measure>
    <time_frame>3 years</time_frame>
    <description>Study will evaluate the relapse rate associated with 5-azacytidine (5-aza) as maintenance therapy after HCT in patients with high-risk AML or MDS.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of Toxicity Requiring Treatment Discontinuation (TRTD)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute GVHD</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Toxicity Requiring Treatment Discontinuation (TRTD)</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>relapse-free survival</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of chronic GVHD</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Effect on the immune system</measure>
    <time_frame>3 years</time_frame>
    <description>Study will evaluate the effect of 5-aza maintenance on the immune system using T-cell phenotype subsets and receptor expression, cytokine levels including tumor necrosis factor alpha (TNFα) and Interferon-y (IFNγ) (proinflammatory), and interleukin 7 (IL-7) and interleukin 15 (IL-15) (homeostatic) and association of correlative measures with relapse and incidence of GVHD.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Acute Myeloid Leukemia (AML)</condition>
  <condition>Myelodysplastic Syndrome (MDS)</condition>
  <arm_group>
    <arm_group_label>5-azacytidine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5-aza SC or IV 32mg/m2 - 75mg/m2 (based on dose escalation)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-azacytidine (5-aza) maintenance therapy after transplant</intervention_name>
    <description>The planned initial dose of 5-aza is 32mg/m2 (Level 0) administered either subcutaneously or intravenously for days 1 through 5 of a 28-day cycle, which will be initiated between day+30 and day+100 after HCT. Patients who tolerate this dose based on hematologic parameters and with no SAEs for two consecutive cycles will be eligible for a dose escalation to 50mg/m2 (Level +1). Patients who tolerate this dose based on the same criteria as above for two consecutive cycles will be eligible for a dose escalation to 75mg/m² (Level +2). Patients will continue at dose Level +2 for the remainder of the study provided there are no toxicities that require dose reduction. Patients requiring a dose reduction are not eligible for re-escalation.</description>
    <arm_group_label>5-azacytidine</arm_group_label>
    <other_name>5-aza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age≥18 with MDS or high-risk AML, morphologically confirmed and based on World Health&#xD;
             Organization criteria (see below for definition of high-risk AML)*, who are transplant&#xD;
             candidates with an available human leukocyte antigen (HLA) -matched sibling or&#xD;
             unrelated donor with at least 8/8 match&#xD;
&#xD;
             *Definition of high-risk AML:&#xD;
&#xD;
          -  Age≥60 years&#xD;
&#xD;
          -  Age&lt;60 years with any of the following:&#xD;
&#xD;
               -  Secondary AML&#xD;
&#xD;
               -  Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7,&#xD;
                  trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype&#xD;
&#xD;
               -  Fms-like tyrosine kinase 3 (FLT3) mutation&#xD;
&#xD;
               -  Disease status ≥ second complete remission (CR2) at time of HCT&#xD;
&#xD;
               -  Detectable disease at time of HCT&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Adequate major organ function, as defined by AST and ALT &lt; 2 x upper limit of normal,&#xD;
             total serum bilirubin &lt; 2 x upper limit of normal (unless due to hemolysis or&#xD;
             Gilbert's syndrome, then no upper limit), creatinine &lt; 2 x upper limit of normal,&#xD;
             unless there is known chronic kidney disease (creatinine must be at baseline for&#xD;
             subjects with chronic kidney disease)&#xD;
&#xD;
          -  In agreement to use an effective barrier method of birth control to avoid pregnancy&#xD;
             during the study and for a minimum of 30 days after study treatment, for all male and&#xD;
             female patients who are fertile&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled, life-threatening infection that is not responding to antimicrobial&#xD;
             therapy&#xD;
&#xD;
          -  Serum creatinine &gt; 2 x upper limit of normal, unless there is known chronic kidney&#xD;
             disease (creatinine must be at baseline for subjects with chronic kidney disease),&#xD;
             aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin &gt;&#xD;
             2x upper limit of normal&#xD;
&#xD;
          -  History of psychiatric disorder which may compromise compliance with the protocol or&#xD;
             which does not allow for appropriate informed consent&#xD;
&#xD;
          -  Patient may not be receiving any other antineoplastic agents&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Concurrent use of any other investigational agents on a clinical trial&#xD;
&#xD;
          -  Prior allogeneic stem cell transplant&#xD;
&#xD;
          -  Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is&#xD;
             allowed&#xD;
&#xD;
        Post-transplant eligibility and exclusion criteria&#xD;
&#xD;
        Patients will have to meet the following post-transplant eligibility criteria to initiate&#xD;
        treatment:&#xD;
&#xD;
          -  In complete response (including complete remission with incomplete blood count&#xD;
             recovery and marrow complete response) on bone marrow biopsy for response assessment&#xD;
             after HCT (typically day +30)&#xD;
&#xD;
          -  Patient is within 30-100 days after HCT&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 20,000/µL&#xD;
&#xD;
          -  ECOG performance status 0-2&#xD;
&#xD;
          -  Adequate major organ function, as defined by AST and ALT &lt; 2 x upper limit of normal,&#xD;
             total serum bilirubin &lt; 2 x upper limit of normal (unless due to hemolysis or&#xD;
             Gilbert's syndrome, then no upper limit), creatinine &lt; 2 x upper limit of normal&#xD;
             unless there is known chronic kidney disease (creatinine must be at baseline for&#xD;
             subjects with chronic kidney disease)&#xD;
&#xD;
          -  In agreement to use an effective barrier method of birth control to avoid pregnancy&#xD;
             during the study and for a minimum of 30 days after study treatment, for all male and&#xD;
             female patients who are fertile&#xD;
&#xD;
        Patients may not have any of the following post-transplant exclusion criteria:&#xD;
&#xD;
          -  Active grade II-IV acute GVHD, for example requiring treatment with steroids at a dose&#xD;
             equivalent to prednisone 1mg/kg daily or higher&#xD;
&#xD;
          -  Uncontrolled, life-threatening infection that is not responding to antimicrobial&#xD;
             therapy&#xD;
&#xD;
          -  Serum creatinine &gt; 2 x upper limit of normal unless there is known chronic kidney&#xD;
             disease (creatinine must be at baseline for subjects with chronic kidney disease),&#xD;
             aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin &gt;&#xD;
             2x upper limit of normal&#xD;
&#xD;
          -  History of psychiatric disorder which may compromise compliance with the protocol or&#xD;
             which does not allow for appropriate informed consent&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Concurrent use of any other investigational agents on a clinical trial&#xD;
&#xD;
          -  Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is&#xD;
             allowed&#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>Annie Im, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>July 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>March 29, 2018</last_update_submitted>
  <last_update_submitted_qc>March 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Annie Im, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Acute Myeloid Leukemia (AML)</keyword>
  <keyword>Myelodysplastic Syndrome (MDS)</keyword>
  <keyword>allogeneic</keyword>
  <keyword>5-azacytidine (5-aza)</keyword>
  <keyword>hematopoietic</keyword>
  <keyword>transplantation</keyword>
  <keyword>transplant</keyword>
  <keyword>graft-versus-tumor</keyword>
  <keyword>graft-versus-host disease (GVHD)</keyword>
  <keyword>epigenetic</keyword>
  <keyword>maintenance</keyword>
  <keyword>hypomethylation</keyword>
  <keyword>relapse</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azacitidine</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/NCT02204020
org study id: UPCI 13-165
nct id: NCT02204020
lead sponsor: 
has dmc: Yes
Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute
      Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high
      and is the most common cause of mortality after HCT. Moreover, treatment options for relapse
      after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who
      are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has
      shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect,
      including upregulation of tumor-associated antigen and costimulatory molecule expression.
      Moreover, 5-aza has properties that suggest protection against graft-versus-host disease
      (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical
      use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy.
      This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or
      MDS with risk factors that are associated with a high risk for relapse.
Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT)
      for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies
      indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that
      may enhance the graft-versus-leukemia (GVL) effect, including upregulation of
      tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties
      that suggest protection against graft-versus-host disease (GVHD). The primary objective is to
      evaluate relapse rate at one year. Secondary objectives will include the incidence of both
      acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity.
      Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune
      system.

      Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects
      are consented, screened, then transplanted. Those showing complete response and no active
      GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are
      performed for response assessment after transplant as well as every three cycles (1 cycle=28
      days) while on treatment. Dosing starts at 32mg/m2 and can be increased every 2 cycles
      without a serious adverse event (SAE), or reduced per toxicity for up to 12 cycles.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Relapse rate at 1 year
time frame: 3 years
description: Study will evaluate the relapse rate associated with 5-azacytidine (5-aza) as maintenance therapy after HCT in patients with high-risk AML or MDS.
measure: Safety of Toxicity Requiring Treatment Discontinuation (TRTD)
time frame: 3 years
measure: Overall survival
time frame: 3 years
measure: Incidence of acute GVHD
time frame: 3 years
measure: Percentage of Toxicity Requiring Treatment Discontinuation (TRTD)
time frame: 3 years
measure: relapse-free survival
time frame: 3 years
measure: Incidence of chronic GVHD
time frame: 3 years
measure: Effect on the immune system
time frame: 3 years
description: Study will evaluate the effect of 5-aza maintenance on the immune system using T-cell phenotype subsets and receptor expression, cytokine levels including tumor necrosis factor alpha (TNFα) and Interferon-y (IFNγ) (proinflammatory), and interleukin 7 (IL-7) and interleukin 15 (IL-15) (homeostatic) and association of correlative measures with relapse and incidence of GVHD.
arm group label: 5-azacytidine
arm group type: Experimental
description: 5-aza SC or IV 32mg/m2 - 75mg/m2 (based on dose escalation)
intervention type: Drug
intervention name: 5-azacytidine (5-aza) maintenance therapy after transplant
description: The planned initial dose of 5-aza is 32mg/m2 (Level 0) administered either subcutaneously or intravenously for days 1 through 5 of a 28-day cycle, which will be initiated between day+30 and day+100 after HCT. Patients who tolerate this dose based on hematologic parameters and with no SAEs for two consecutive cycles will be eligible for a dose escalation to 50mg/m2 (Level +1). Patients who tolerate this dose based on the same criteria as above for two consecutive cycles will be eligible for a dose escalation to 75mg/m² (Level +2). Patients will continue at dose Level +2 for the remainder of the study provided there are no toxicities that require dose reduction. Patients requiring a dose reduction are not eligible for re-escalation.
arm group label: 5-azacytidine
other name: 5-aza
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Annie Im, MD
role: Principal Investigator
affiliation: University of Pittsburgh Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Annie Im, M.D.
investigator title: Principal Investigator
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Azacitidine