<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/NCT01684150</url>
  </required_header>
  <id_info>
    <org_study_id>EPZ-5676-12-001</org_study_id>
    <nct_id>NCT01684150</nct_id>
  </id_info>
  <brief_title>A Phase 1, Open-Label, Dose-Escalation &amp; Expanded Cohort, Continuous IV Infusion, Multi-center Study of the Safety, Tolerability,PK &amp; PD of EPZ-5676 in Treatment Relapsed/Refractory Patients With Leukemias Involving</brief_title>
  <official_title>A Phase 1, Open-Label, Dose-Escalation &amp; Expanded Cohort, Continuous IV Infusion, Multi-center Study of the Safety, Tolerability,PK &amp; PD of EPZ-5676 in Treatment Relapsed/Refractory Patients With Leukemias Involving Translocation of the MLL Gene at 11q23 or Advanced Hematologic Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Epizyme, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Celgene</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ipsen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the safe dose of EPZ-5676, to evaluate the safety&#xD;
      of EPZ-5676 in patients with advanced hematologic malignancies, and to conduct a preliminary&#xD;
      assessment of the anti-leukemia activity of EPZ-5676 in patients with acute leukemias bearing&#xD;
      rearrangements of the MLL gene.&#xD;
&#xD;
      Currently this study is in the MLL-r restricted/expansion phase and is only enrolling&#xD;
      patients with rearrangements involving the MLL gene, including 11q23 or partial tandem&#xD;
      duplications (PTD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A subset of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)&#xD;
      harbor rearrangements of the MLL gene, which are detected either by cytogenetic or&#xD;
      fluorescent in situ hybridization evaluation at the time of diagnosis. A protein called DOT1L&#xD;
      plays an important role in the malignant process in these leukemias. EPZ-5676 is a molecule&#xD;
      that blocks the activity of DOT1L, and is therefore being evaluated in the treatment of&#xD;
      patients with MLL-rearranged leukemias.&#xD;
&#xD;
      The dose escalation portion has been completed. Currently this study is in the expansion&#xD;
      phase and patients with MLL-r and MLL-PTD will receive EPZ-5676 as a 28-day continuous&#xD;
      intravenous infusion (CIV).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">November 2015</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 maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events.</measure>
    <time_frame>up to 12 months</time_frame>
    <description>The MTD is defined as the dose level below in which &gt;1 patient out of 3 or &gt;2 patients out of 6 experience dose-limiting adverse events (as defined by the protocol).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile of EPZ-5676</measure>
    <time_frame>up to 24 months</time_frame>
    <description>analysis of Cmax, AUC and steady state concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of adverse events in patients treated with EPZ-5676</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Evaluation of response by standard criteria for AML or ALL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).</measure>
    <time_frame>up to 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells</measure>
    <time_frame>up to 24 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">51</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Myelodysplastic Syndrome</condition>
  <condition>Myeloproliferative Disorders</condition>
  <arm_group>
    <arm_group_label>EPZ-5676 Extension cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EPZ-5676</intervention_name>
    <description>MLL-r and MLL-PTD 28-day continuous IV infusion of each 28-day cycle. Number of cycles: until disease progression or unacceptable toxicity develops.</description>
    <arm_group_label>EPZ-5676 Extension cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male and female patients aged ≥ 18 years.&#xD;
&#xD;
          2. Patients with relapsed /refractory AML, ALL, or MLL with rearrangement of the MLL&#xD;
             gene, including 11q23 or PTD, are eligible for the expanded cohort:&#xD;
&#xD;
               -  At least one prior therapy;&#xD;
&#xD;
               -  Refractory disease on most recent therapy, or disease recurrence following&#xD;
                  remission on most recent therapy;&#xD;
&#xD;
               -  Received and failed all known effective therapies for their disease;&#xD;
&#xD;
               -  Not a candidate for allogeneic stem cell transplantation&#xD;
&#xD;
               -  &gt; 10% blasts or biopsy-documented leukemia cutis or myeloid sarcoma.&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.&#xD;
&#xD;
          4. Patients must have the following clinical laboratory values:&#xD;
&#xD;
               -  Serum creatinine ≤2 mg/dL or creatinine clearance &gt; 60 mL/minute;&#xD;
&#xD;
               -  Total bilirubin ≤2.0 times the ULN for the institution, unless considered due to&#xD;
                  Gilbert's syndrome;&#xD;
&#xD;
               -  ALT or AST ≤ twice the upper limit of normal (ULN), unless considered due to&#xD;
                  organ leukemic involvement;&#xD;
&#xD;
               -  Absolute neutrophil count ≥1,000/µL (unless due to documented leukemic&#xD;
                  involvement of the bone marrow at the time of study entry)&#xD;
&#xD;
               -  Platelets ≥100,000/µL (unless due to documented leukemic involvement of the bone&#xD;
                  marrow at the time of study entry).&#xD;
&#xD;
               -  PT or aPTT &lt; 1.5 times the ULN&#xD;
&#xD;
          5. Able and willing to give written informed consent.&#xD;
&#xD;
          6. Life expectancy of at least 3 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Uncontrolled intercurrent illness or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements.&#xD;
&#xD;
          2. Active heart disease&#xD;
&#xD;
          3. Receiving any other standard treatment for their hematologic malignancy.&#xD;
&#xD;
          4. Receiving strong CYP3A4 inhibitors/ inducers.&#xD;
&#xD;
          5. Known history of cerebrovascular accident in the past 6 months.&#xD;
&#xD;
          6. Known bleeding diathesis.&#xD;
&#xD;
          7. Known, active (symptomatic) involvement of the central nervous system by leukemia.&#xD;
&#xD;
          8. On immunosuppressive therapy.&#xD;
&#xD;
          9. Known active infection.&#xD;
&#xD;
         10. Pregnant or nursing females.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Martin S. Tallman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jesus Berdeja, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>SCRI Development Innovations, LLC</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David A Rizzieri, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Guillermo Garcia-Manero, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jessica Altman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwestern University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Raoul Tibes, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic Scottsdale-Phoenix</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mojca Jongen-Lavrencic, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hartmut Döhner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsklinikum Ulm</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic Scottsdale-Phoenix</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Health System</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon Research Institute</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT MD Anderson Cancer</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Ulm</name>
      <address>
        <city>Ulm</city>
        <zip>89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus University Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>September 6, 2012</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2012</study_first_posted>
  <last_update_submitted>June 15, 2023</last_update_submitted>
  <last_update_submitted_qc>June 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Leukemia</keyword>
  <keyword>Advanced hematologic malignancies</keyword>
  <keyword>Epizyme</keyword>
  <keyword>Phase 1</keyword>
  <keyword>Mixed Lineage Leukemia (MLL)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Myeloproliferative Disorders</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/NCT01684150
org study id: EPZ-5676-12-001
nct id: NCT01684150
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to determine the safe dose of EPZ-5676, to evaluate the safety
      of EPZ-5676 in patients with advanced hematologic malignancies, and to conduct a preliminary
      assessment of the anti-leukemia activity of EPZ-5676 in patients with acute leukemias bearing
      rearrangements of the MLL gene.

      Currently this study is in the MLL-r restricted/expansion phase and is only enrolling
      patients with rearrangements involving the MLL gene, including 11q23 or partial tandem
      duplications (PTD).
A subset of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
      harbor rearrangements of the MLL gene, which are detected either by cytogenetic or
      fluorescent in situ hybridization evaluation at the time of diagnosis. A protein called DOT1L
      plays an important role in the malignant process in these leukemias. EPZ-5676 is a molecule
      that blocks the activity of DOT1L, and is therefore being evaluated in the treatment of
      patients with MLL-rearranged leukemias.

      The dose escalation portion has been completed. Currently this study is in the expansion
      phase and patients with MLL-r and MLL-PTD will receive EPZ-5676 as a 28-day continuous
      intravenous infusion (CIV).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of EPZ-5676 as determined by incidence of protocol-specified dose-limiting adverse events.
time frame: up to 12 months
description: The MTD is defined as the dose level below in which >1 patient out of 3 or >2 patients out of 6 experience dose-limiting adverse events (as defined by the protocol).
measure: Pharmacokinetic profile of EPZ-5676
time frame: up to 24 months
description: analysis of Cmax, AUC and steady state concentration
measure: The incidence of adverse events in patients treated with EPZ-5676
time frame: up to 24 months
description: Evaluation of adverse events, vital signs, physical examination, 12-lead ECG, and laboratory assessments
measure: Anti-leukemic activity of EPZ-5676 in patients with acute leukemia harboring a MLL-rearrangement
time frame: up to 24 months
description: Evaluation of response by standard criteria for AML or ALL
measure: Effects of EPZ-5676 on histone H3K79 methylation in peripheral blood mononuclear cells (PBMC).
time frame: up to 24 months
measure: Effects of EPZ-5676 on histone H3K79 methylation in leukemia cells
time frame: up to 24 months
arm group label: EPZ-5676 Extension cohort
arm group type: Experimental
intervention type: Drug
intervention name: EPZ-5676
description: MLL-r and MLL-PTD 28-day continuous IV infusion of each 28-day cycle. Number of cycles: until disease progression or unacceptable toxicity develops.
arm group label: EPZ-5676 Extension cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Martin S. Tallman, MD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
last name: Jesus Berdeja, MD
role: Principal Investigator
affiliation: SCRI Development Innovations, LLC
last name: David A Rizzieri, MD
role: Principal Investigator
affiliation: Duke University
last name: Guillermo Garcia-Manero, MD
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
last name: Jessica Altman, MD
role: Principal Investigator
affiliation: Northwestern University
last name: Raoul Tibes, MD
role: Principal Investigator
affiliation: Mayo Clinic Scottsdale-Phoenix
last name: Mojca Jongen-Lavrencic, MD
role: Principal Investigator
affiliation: Erasmus Medical Center
last name: Hartmut Döhner, MD
role: Principal Investigator
affiliation: Universitätsklinikum Ulm
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
country: Netherlands
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Myelodysplastic Syndromes
mesh term: Myeloproliferative Disorders