<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/NCT03263936</url>
  </required_header>
  <id_info>
    <org_study_id>T2016-003</org_study_id>
    <nct_id>NCT03263936</nct_id>
  </id_info>
  <brief_title>Epigenetic Reprogramming in Relapse/Refractory AML</brief_title>
  <official_title>Epigenetic Reprogramming in Relapse AML: A Phase 1 Study of Decitabine and Vorinostat Followed by Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults With Relapsed/Refractory AML</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Therapeutic Advances in Childhood Leukemia Consortium</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Therapeutic Advances in Childhood Leukemia Consortium</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot study using decitabine and vorinostat before and during chemotherapy with&#xD;
      fludarabine, cytarabine and G-CSF (FLAG).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of&#xD;
      demethylating agents and HDAC inhibitors in combination have been previously shown to have&#xD;
      synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in&#xD;
      human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal&#xD;
      cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the&#xD;
      leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This&#xD;
      study will ask the question as to whether or not the combination of decitabine and vorinostat&#xD;
      followed by chemotherapy is feasible and whether it can positively impact outcome in patients&#xD;
      with relapsed or refractory acute myelogenous leukemia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 11, 2017</start_date>
  <completion_date type="Actual">February 10, 2022</completion_date>
  <primary_completion_date type="Actual">July 9, 2020</primary_completion_date>
  <phase>Phase 1</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>The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG)</measure>
    <time_frame>during course 1, approx 5 weeks</time_frame>
    <description>The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To examine peripheral blood mononuclear cells for immunophenotypic changes.</measure>
    <time_frame>approx 8 weeks</time_frame>
    <description>To examine peripheral blood mononuclear cells for immunophenotypic changes using peripheral blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To analyze plasma for cytokine content.</measure>
    <time_frame>approx 8 weeks</time_frame>
    <description>To analyze plasma for cytokine content using plasma samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To analyze the correlation between biological changes and clinical response.</measure>
    <time_frame>approx 8 weeks</time_frame>
    <description>To analyze the correlation between biological changes and clinical response using standard statistical methods</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment:</measure>
    <time_frame>approx 8 weeks</time_frame>
    <description>Reduced representation bisulfite sequencing (RRBS) will be used to analyze the genome-wide methylation profiles on a single nucleotide level; To quantitatively assess global changes in DNA methylation, a LINE-methylation assay will be utilized and specific genes monitored through advanced Infinium MethylationEPIC BeadChip from Illumina. Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications associated with transcriptional activation (H3K4me3 and H3K27ac) and repression (H3K9me3 and H3K27me3) and isotype controls, followed by DNA sequencing (ChIP-seq); RNA sequencing analysis will be used to measure global transcriptome changes. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, or Peripheral Blood Stem Cells (PBSCs) will be used as normal controls for each sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat.</measure>
    <time_frame>approx 8 weeks</time_frame>
    <description>Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by comparing the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic blasts: Reversal of DNA promoter hypermethylation of &quot;repressed&quot; genes of interest using RRBS, validated with Pyrosequencing-based methylation assay; Increase in H3K9/14 acetylation in association with &quot;repressed&quot; genes of interest using H3K9/14 ChIP-seq, validated with ChIP-qPCR; Reversal of transcriptional silencing of &quot;repressed&quot; genes of interest using RNA seq, validated by qRT-PCR. Since significant acute cell kill is unlikely during the 5-day &quot;window&quot; of DNMTi/HDACi, we will have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 sample. The Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients whose leukemic blasts persist at these time points.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">37</enrollment>
  <condition>Acute Myelogenous Leukemia</condition>
  <arm_group>
    <arm_group_label>Other</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Decitabine</intervention_name>
    <description>Dose Level #0: 5 mg/m2 Dose Level #1: 7.5 mg/m2 Dose Level #2: 10 mg/m2 Dose Level #3: 15 mg/m2 Dose Level #4: 20 mg/m2 given IV over __ hour on days 1 through 5</description>
    <arm_group_label>Other</arm_group_label>
    <other_name>Dacogen</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vorinostat</intervention_name>
    <description>Age &lt;18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.</description>
    <arm_group_label>Other</arm_group_label>
    <other_name>Zolinza, SAHA, suberoylanilide acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Filgrastim (G-CSF)</intervention_name>
    <description>Given on days 5 until evidence of ANC recovery (&gt;500/µL)5µg/kg/dose IV or SQ (starting at hour 0)</description>
    <arm_group_label>Other</arm_group_label>
    <other_name>G-CSF, neupogen</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)</description>
    <arm_group_label>Other</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10</description>
    <arm_group_label>Other</arm_group_label>
    <other_name>Cytosine arabinoside, Ara-C, Cytosar</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - Patients must be ≥ 1 and ≤25 years of age.&#xD;
&#xD;
        Diagnosis: Patients with relapse or refractory AML must have measurable disease ( &gt;M1&#xD;
        marrow)&#xD;
&#xD;
          -  1st or greater relapse, OR&#xD;
&#xD;
          -  Failed to go into remission after 1st or greater relapse, OR&#xD;
&#xD;
          -  Failed to go into remission from original diagnosis after 2 or more induction attempts&#xD;
&#xD;
        Eligibility for patients with an M1 marrow; defined as &gt;0.1% by flow or molecular testing&#xD;
        (e.g. PCR).&#xD;
&#xD;
          -  must include two serial marrows (at least 1-week apart) demonstrating stable or rising&#xD;
             minimal residual disease (MRD) (i.e. not declining).&#xD;
&#xD;
          -  Patients may have CNS or other sites of extramedullary disease. No cranial irradiation&#xD;
             is allowed during the protocol therapy.&#xD;
&#xD;
          -  Patients with secondary AML are eligible.&#xD;
&#xD;
          -  Patients with Down syndrome are eligible.&#xD;
&#xD;
          -  Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are&#xD;
             excluded.&#xD;
&#xD;
        Performance Level:&#xD;
&#xD;
        - Karnofsky &gt;50% for patients &gt;16 years of age and Lansky &gt; 50% for patients ≤ 16 years of&#xD;
        age (See Appendix II for Performance Scales)&#xD;
&#xD;
        Prior therapy - Patients must have fully recovered from the acute toxic effects of all&#xD;
        prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.&#xD;
&#xD;
          1. Cytoreduction with hydroxyurea: hydroxyurea can be initiated and continued for up to&#xD;
             24 hours prior to the start of decitabine/vorinostat. It is recommended to use&#xD;
             hydroxyurea in patients with significant leukocytosis (WBC &gt;50,000/L) to control blast&#xD;
             count before initiation of systemic protocol therapy.&#xD;
&#xD;
          2. Patients who relapsed while they are receiving cytotoxic therapy: at least 14 days&#xD;
             must have elapsed since the completion of the cytotoxic therapy, except Intrathecal&#xD;
             chemotherapy.&#xD;
&#xD;
        Hematopoietic stem cell transplant (HSCT):&#xD;
&#xD;
        - Patients who have experienced their relapse after a HSCT are eligible, provided they have&#xD;
        no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant&#xD;
        immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus).&#xD;
        Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable.&#xD;
&#xD;
        Hematopoietic growth factors:&#xD;
&#xD;
        - It must have been at least 7 days since the completion of therapy with GCSF or other&#xD;
        growth factors at the time of enrollment. It must have been at least 14 days since the&#xD;
        completion of therapy with pegfilgrastim (Neulasta ®)&#xD;
&#xD;
        Biologic (anti-neoplastic agent):&#xD;
&#xD;
        -At least 7 days after the last dose of a biologic agent. For agents that have known&#xD;
        adverse events occurring beyond 7 days after administration, this period must be extended&#xD;
        beyond the time during which adverse events are known to occur. The duration of this&#xD;
        interval must be discussed with the study chair.&#xD;
&#xD;
        Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the&#xD;
        last dose of monoclonal antibody (i.e. Gemtuzumab = 36 days)&#xD;
&#xD;
        Immunotherapy: At least 42 days after the completion of any time of immunotherapy, e.g.&#xD;
        tumor vaccines or CAR T-cell therapy.&#xD;
&#xD;
        XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. No washout period is&#xD;
        necessary for radiation given to non-CNS chloromas; &gt;90 days must have elapsed if prior&#xD;
        TBI, cranio or craniospinal XRT.&#xD;
&#xD;
        Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior DNMTi&#xD;
        (e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to participate in&#xD;
        this Phase 1 study. At least 7 days must have passed from prior DNMTi or HDACi as a washout&#xD;
        period.&#xD;
&#xD;
        Renal and hepatic function: Patients must have adequate renal and hepatic functions as&#xD;
        indicated by the following laboratory values:&#xD;
&#xD;
        A. Adequate renal function defined as: Patient must have a calculated creatinine clearance&#xD;
        or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender.&#xD;
&#xD;
        B. Adequate Liver Function Defined as: Direct bilirubin &lt; 1.5 x upper limit of normal (ULN)&#xD;
        for age or normal, AND alanine transaminase (ALT) &lt; 5 x ULN for age. The hepatic&#xD;
        requirements are waived for patients with known or suspected liver involvement by leukemia.&#xD;
        This must be reviewed by and approved by the study chair or vice chair.&#xD;
&#xD;
        Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% by echocardiogram, OR&#xD;
        ejection fraction of ≥ 50% by radionuclide angiogram (MUGA).&#xD;
&#xD;
        Reproductive Function A. Female patients of childbearing potential must have a negative&#xD;
        urine or serum pregnancy test confirmed within 1 week prior to enrollment.&#xD;
&#xD;
        B. Female patients with infants must agree not to breastfeed their infants while on this&#xD;
        study.&#xD;
&#xD;
        C. Male and female patients of child-bearing potential must agree to use an effective&#xD;
        method of contraception approved by the investigator during the study and for a minimum of&#xD;
        6 months after study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No NG or G-Tube administration of Vorinostat is allowed. Capsule must be swallowed&#xD;
             whole or given as oral suspension.&#xD;
&#xD;
          -  They are currently receiving other investigational drugs.&#xD;
&#xD;
          -  There is a plan to administer non-protocol chemotherapy, radiation therapy, or&#xD;
             immunotherapy during the study period.&#xD;
&#xD;
          -  They have significant concurrent disease, illness, psychiatric disorder or social&#xD;
             issue that would compromise patient safety or compliance, interfere with consent,&#xD;
             study participation, follow up, or interpretation of study results.&#xD;
&#xD;
          -  They have a known allergy to any of the drugs used in the study.&#xD;
&#xD;
          -  Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom&#xD;
             Syndrome)&#xD;
&#xD;
          -  They are receiving valproic acid (VPA) therapy.&#xD;
&#xD;
          -  Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded&#xD;
&#xD;
          -  Patients with documented active and uncontrolled infection at the time of study entry&#xD;
             are not eligible&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Children's Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF School of Medicine</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Children's Hospital, University of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>All Children's Hospital</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta, Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lurie Children's Hospital of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center at Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cancer Institute, Pediatric Oncology Branch</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C.S. Mott Children's Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109-0914</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CS Mott Children's Hospital, Ann Arbor</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospitals and Clinics of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital New York-Presbyterian</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Levine Children's Hospital</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cook Children's Medical Center</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Children's Cancer Center, Baylor</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Hospital</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sydney Children's Hospital</name>
      <address>
        <city>Randwick</city>
        <state>New South Wales</state>
        <zip>2031</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital at Westmead</name>
      <address>
        <city>Westmead</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>British Columbia Children's Hospital</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V6H 3V4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital for Sick Children</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sainte Justine University Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 28, 2017</study_first_posted>
  <last_update_submitted>June 22, 2022</last_update_submitted>
  <last_update_submitted_qc>June 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 24, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Relapse</keyword>
  <keyword>Myelogenous</keyword>
  <keyword>Leukemia</keyword>
  <keyword>Refractory</keyword>
  <keyword>Acute</keyword>
  <keyword>Pediatric</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Decitabine</mesh_term>
    <mesh_term>Vorinostat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 26, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03263936
org study id: T2016-003
nct id: NCT03263936
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a pilot study using decitabine and vorinostat before and during chemotherapy with
      fludarabine, cytarabine and G-CSF (FLAG).
Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of
      demethylating agents and HDAC inhibitors in combination have been previously shown to have
      synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in
      human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal
      cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the
      leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This
      study will ask the question as to whether or not the combination of decitabine and vorinostat
      followed by chemotherapy is feasible and whether it can positively impact outcome in patients
      with relapsed or refractory acute myelogenous leukemia.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG)
time frame: during course 1, approx 5 weeks
description: The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy
measure: To examine peripheral blood mononuclear cells for immunophenotypic changes.
time frame: approx 8 weeks
description: To examine peripheral blood mononuclear cells for immunophenotypic changes using peripheral blood samples
measure: To analyze plasma for cytokine content.
time frame: approx 8 weeks
description: To analyze plasma for cytokine content using plasma samples.
measure: To analyze the correlation between biological changes and clinical response.
time frame: approx 8 weeks
description: To analyze the correlation between biological changes and clinical response using standard statistical methods
measure: To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment:
time frame: approx 8 weeks
description: Reduced representation bisulfite sequencing (RRBS) will be used to analyze the genome-wide methylation profiles on a single nucleotide level; To quantitatively assess global changes in DNA methylation, a LINE-methylation assay will be utilized and specific genes monitored through advanced Infinium MethylationEPIC BeadChip from Illumina. Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications associated with transcriptional activation (H3K4me3 and H3K27ac) and repression (H3K9me3 and H3K27me3) and isotype controls, followed by DNA sequencing (ChIP-seq); RNA sequencing analysis will be used to measure global transcriptome changes. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, or Peripheral Blood Stem Cells (PBSCs) will be used as normal controls for each sample.
measure: To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat.
time frame: approx 8 weeks
description: Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by comparing the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic blasts: Reversal of DNA promoter hypermethylation of "repressed" genes of interest using RRBS, validated with Pyrosequencing-based methylation assay; Increase in H3K9/14 acetylation in association with "repressed" genes of interest using H3K9/14 ChIP-seq, validated with ChIP-qPCR; Reversal of transcriptional silencing of "repressed" genes of interest using RNA seq, validated by qRT-PCR. Since significant acute cell kill is unlikely during the 5-day "window" of DNMTi/HDACi, we will have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 sample. The Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients whose leukemic blasts persist at these time points.
arm group label: Other
arm group type: Other
description: decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)
intervention type: Drug
intervention name: Decitabine
description: Dose Level #0: 5 mg/m2 Dose Level #1: 7.5 mg/m2 Dose Level #2: 10 mg/m2 Dose Level #3: 15 mg/m2 Dose Level #4: 20 mg/m2 given IV over __ hour on days 1 through 5
arm group label: Other
other name: Dacogen
intervention type: Drug
intervention name: Vorinostat
description: Age <18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.
arm group label: Other
other name: Zolinza, SAHA, suberoylanilide acid
intervention type: Drug
intervention name: Filgrastim (G-CSF)
description: Given on days 5 until evidence of ANC recovery (>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)
arm group label: Other
other name: G-CSF, neupogen
intervention type: Drug
intervention name: Fludarabine
description: 30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)
arm group label: Other
other name: Fludara
intervention type: Drug
intervention name: Cytarabine
description: 2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10
arm group label: Other
other name: Cytosine arabinoside, Ara-C, Cytosar
criteria: 
gender: All
minimum age: 1 Year
maximum age: 25 Years
healthy volunteers: No
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country: Australia
country: Canada
country: United States
responsible party type: Sponsor
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Recurrence
mesh term: Cytarabine
mesh term: Fludarabine
mesh term: Decitabine
mesh term: Vorinostat
sharing ipd: Undecided
submitted: May 26, 2023