<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/NCT03813186</url>
  </required_header>
  <id_info>
    <org_study_id>ASTX727-04</org_study_id>
    <nct_id>NCT03813186</nct_id>
  </id_info>
  <brief_title>Effect of Food on Blood Levels of ASTX727</brief_title>
  <official_title>A Phase 1b Study to Evaluate the Effect of Food on Pharmacokinetics of ASTX727 (Cedazuridine and Decitabine) in Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Astex Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Astex Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed to examine blood levels of ASTX727, a fixed-dose combination tablet&#xD;
      containing the combination of cedazuridine (100 mg) and decitabine (35 mg), when given under&#xD;
      fed versus fasted conditions to participants with myelodysplastic syndromes (MDS), including&#xD;
      refractory anemia with excess blasts in transformation or chronic myelomonocytic leukemia&#xD;
      (CMML), or acute myeloid leukemia (AML). This study will also assess the safety of ASTX727.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 1b, multicenter, open-label, randomized, two-sequence, crossover study of&#xD;
      ASTX727 in participants with MDS, including refractory anemia with excess blasts in&#xD;
      transformation or CMML, and AML. Participants will continue to be enrolled until evaluable&#xD;
      data is collected from 12 participants. It is expected that approximately 18 participants&#xD;
      will be enrolled in total.&#xD;
&#xD;
      This study will be conducted in 28-day cycles. All participants will take part in Cycle 1 and&#xD;
      may continue into Cycles ≥2 at the investigator's discretion. Participants will receive one&#xD;
      tablet of ASTX727 containing 100 mg cedazuridine and 35 mg decitabine once daily for 5 days&#xD;
      in 28-day cycles starting from Cycle 1 Day 1.&#xD;
&#xD;
      Participants will be randomized in a 1:1 ratio to receive high-calorie, high-fat breakfast&#xD;
      meal pre-dose on either Day 2 or Day 4 of Cycle 1. Blood will be drawn at specified time&#xD;
      points in Cycle 1 on Days 2 through 5 to assess the effect of food on the PK of cedazuridine&#xD;
      and decitabine.&#xD;
&#xD;
      After completion of the first treatment cycle, participants may continue to receive treatment&#xD;
      with ASTX727 at the investigator's discretion for subsequent cycles (Days 1 through 5 of&#xD;
      28-day cycles), until disease progression, unacceptable toxicity, investigator decision to&#xD;
      discontinue treatment, or the participant decides to discontinue treatment or withdraw from&#xD;
      the study. In Cycles ≥2, participants will fast for 2 hours before and 2 hours after taking&#xD;
      the ASTX727 tablet on all dosing days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 8, 2018</start_date>
  <completion_date type="Actual">December 16, 2019</completion_date>
  <primary_completion_date type="Actual">June 14, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC0-t (area under the concentration-time curve from time 0 to t hours).</measure>
    <time_frame>6 months</time_frame>
    <description>Area under the concentration-time curve from time 0 to t hours.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-8 (area under the concentration-time curve from time 0 to 8 hours).</measure>
    <time_frame>6 months</time_frame>
    <description>Area under the concentration-time curve from time 0 to 8 hours.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-24 (area under the concentration-time curve from time 0 to 24 hours).</measure>
    <time_frame>6 months</time_frame>
    <description>Area under the concentration-time curve from time 0 to 24 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-inf (area under the concentration-time curve from time 0 to infinity).</measure>
    <time_frame>6 months</time_frame>
    <description>Area under the concentration-time curve from time 0 to infinity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax (maximum plasma concentration).</measure>
    <time_frame>6 months</time_frame>
    <description>Maximum plasma concentration.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>hemoglobin level</measure>
    <time_frame>6 months</time_frame>
    <description>Assessed in g/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>platelet count</measure>
    <time_frame>6 months</time_frame>
    <description>Assessed as 10^9/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>white blood cell count</measure>
    <time_frame>6 months</time_frame>
    <description>Assessed as fraction of 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>neutrophils</measure>
    <time_frame>6 months</time_frame>
    <description>Assessed as percent</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subject-reported and investigator-observed incidence and severity of adverse events.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Chronic Myelomonocytic Leukemia</condition>
  <condition>Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>ASTX727 + Day 2 Food</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive ASTX727 on Days 1-5 of Cycle 1 and a high-calorie, high-fat breakfast meal of 800-1000 calories pre-dose on Day 2 of Cycle 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ASTX727 + Day 4 Food</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive ASTX727 on Days 1-5 of Cycle 1 and a high-calorie, high-fat breakfast meal of 800-1000 calories pre-dose on Day 4 of Cycle 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ASTX727 + Day 2 Food</intervention_name>
    <description>ASTX727 is an oral drug product composed of a fixed-dose combination of cedazuridine (E7727), a CDA inhibitor, and decitabine. Food is a high-calorie, high-fat breakfast meal of 800-1000 calories given on Day 2.</description>
    <arm_group_label>ASTX727 + Day 2 Food</arm_group_label>
    <other_name>cedazuridine + decitabine + food on Day 2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ASTX727 + Day 4 Food</intervention_name>
    <description>ASTX727 is an oral drug product composed of a fixed-dose combination of cedazuridine (E7727), a CDA inhibitor, and decitabine. Food is a high-calorie, high-fat breakfast meal of 800-1000 calories given on Day 4.</description>
    <arm_group_label>ASTX727 + Day 4 Food</arm_group_label>
    <other_name>cedazuridine + decitabine + food on Day 4</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to understand and comply with the study procedures, including the ability to&#xD;
             completely consume the breakfast meal in 20 minutes, understand the risks involved in&#xD;
             the study, and provide written informed consent before the first study-specific&#xD;
             procedure.&#xD;
&#xD;
          2. Men or women ≥18 years with either:&#xD;
&#xD;
               1. MDS, including all French-American-British subtypes (refractory anemia,&#xD;
                  refractory anemia with ringed sideroblasts, refractory anemia with excess blasts,&#xD;
                  refractory anemia with excess blasts in transformation, CMML), and subjects with&#xD;
                  MDS IPSS int-1, -2, or high-risk MDS.&#xD;
&#xD;
               2. AML, as diagnosed according to the 2016 WHO guidelines on acute leukemia, of any&#xD;
                  subtype except M3 (Acute Promyelocytic Leukemia), who are not candidates for&#xD;
                  intensive chemotherapy&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.&#xD;
&#xD;
          4. Adequate organ function defined as follows:&#xD;
&#xD;
               1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate&#xD;
                  aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine&#xD;
                  aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤5 × ULN.&#xD;
&#xD;
               2. Renal: serum creatinine ≤1.5 × ULN or if serum creatinine is elevated; calculated&#xD;
                  creatinine clearance or glomerular filtration rate ≥50 mL/min.&#xD;
&#xD;
          5. Women of child-bearing potential (according to recommendations of the Clinical Trial&#xD;
             Facilitation Group) must not be pregnant or breastfeeding and must have a negative&#xD;
             pregnancy test at screening.&#xD;
&#xD;
          6. Subjects and their partners with reproductive potential must agree to use 2 highly&#xD;
             effective contraceptive measures during the study and must agree not to become&#xD;
             pregnant or father a child for 3 months after the last dose of study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known or suspected hypersensitivity to decitabine, azacitidine, or cedazuridine.&#xD;
&#xD;
          2. Treated with any investigational drug or therapy within 2 weeks of study treatment, or&#xD;
             5 half-lives, whichever is longer, before the protocol-defined first dose of study&#xD;
             treatment, or ongoing clinically significant adverse events (AEs) from previous&#xD;
             treatment with investigational drug or therapy.&#xD;
&#xD;
          3. Poor medical risk because of other conditions such as uncontrolled systemic diseases&#xD;
             or active uncontrolled infections.&#xD;
&#xD;
          4. Life-threatening illness, medical condition or organ system dysfunction, or other&#xD;
             reasons including laboratory abnormalities, which, in the investigator's opinion,&#xD;
             could compromise the subject's safety, interfere with the absorption or metabolism of&#xD;
             decitabine + cedazuridine or compromise the integrity of the study outcomes.&#xD;
&#xD;
          5. Prior gastric surgery for ulcer disease, weight loss, etc., that would impair normal&#xD;
             motility or absorption.&#xD;
&#xD;
          6. Second malignancy currently requiring active chemotherapy. To clarify, patients with&#xD;
             breast or prostate cancer stable on or responding to endocrine therapy, are eligible.&#xD;
&#xD;
          7. Known history of human immunodeficiency virus or if known seropositive for hepatitis C&#xD;
             virus or hepatitis B virus.&#xD;
&#xD;
          8. Active uncontrolled gastric or duodenal ulcer.&#xD;
&#xD;
          9. Subjects with Acute Promyelocytic Leukemia.&#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>Kartik Krishnan, MD</last_name>
    <role>Study Director</role>
    <affiliation>Astex Pharmaceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Roswell Park</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gabrail Cancer Center</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44718</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mays Cancer Center UT Health San Antonio MD Anderson Cancer Center</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.</citation>
    <PMID>16609072</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>February 16, 2020</last_update_submitted>
  <last_update_submitted_qc>February 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MDS</keyword>
  <keyword>CMML</keyword>
  <keyword>ASTX727</keyword>
  <keyword>decitabine</keyword>
  <keyword>AML</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>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Juvenile</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Decitabine</mesh_term>
    <mesh_term>Decitabine and cedazuridine drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03813186
org study id: ASTX727-04
nct id: NCT03813186
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This study is designed to examine blood levels of ASTX727, a fixed-dose combination tablet
      containing the combination of cedazuridine (100 mg) and decitabine (35 mg), when given under
      fed versus fasted conditions to participants with myelodysplastic syndromes (MDS), including
      refractory anemia with excess blasts in transformation or chronic myelomonocytic leukemia
      (CMML), or acute myeloid leukemia (AML). This study will also assess the safety of ASTX727.
This is a Phase 1b, multicenter, open-label, randomized, two-sequence, crossover study of
      ASTX727 in participants with MDS, including refractory anemia with excess blasts in
      transformation or CMML, and AML. Participants will continue to be enrolled until evaluable
      data is collected from 12 participants. It is expected that approximately 18 participants
      will be enrolled in total.

      This study will be conducted in 28-day cycles. All participants will take part in Cycle 1 and
      may continue into Cycles ≥2 at the investigator's discretion. Participants will receive one
      tablet of ASTX727 containing 100 mg cedazuridine and 35 mg decitabine once daily for 5 days
      in 28-day cycles starting from Cycle 1 Day 1.

      Participants will be randomized in a 1:1 ratio to receive high-calorie, high-fat breakfast
      meal pre-dose on either Day 2 or Day 4 of Cycle 1. Blood will be drawn at specified time
      points in Cycle 1 on Days 2 through 5 to assess the effect of food on the PK of cedazuridine
      and decitabine.

      After completion of the first treatment cycle, participants may continue to receive treatment
      with ASTX727 at the investigator's discretion for subsequent cycles (Days 1 through 5 of
      28-day cycles), until disease progression, unacceptable toxicity, investigator decision to
      discontinue treatment, or the participant decides to discontinue treatment or withdraw from
      the study. In Cycles ≥2, participants will fast for 2 hours before and 2 hours after taking
      the ASTX727 tablet on all dosing days.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: AUC0-t (area under the concentration-time curve from time 0 to t hours).
time frame: 6 months
description: Area under the concentration-time curve from time 0 to t hours.
measure: AUC0-8 (area under the concentration-time curve from time 0 to 8 hours).
time frame: 6 months
description: Area under the concentration-time curve from time 0 to 8 hours.
measure: AUC0-24 (area under the concentration-time curve from time 0 to 24 hours).
time frame: 6 months
description: Area under the concentration-time curve from time 0 to 24 hours
measure: AUC0-inf (area under the concentration-time curve from time 0 to infinity).
time frame: 6 months
description: Area under the concentration-time curve from time 0 to infinity.
measure: Cmax (maximum plasma concentration).
time frame: 6 months
description: Maximum plasma concentration.
measure: hemoglobin level
time frame: 6 months
description: Assessed in g/dL
measure: platelet count
time frame: 6 months
description: Assessed as 10^9/L
measure: white blood cell count
time frame: 6 months
description: Assessed as fraction of 1
measure: neutrophils
time frame: 6 months
description: Assessed as percent
measure: Subject-reported and investigator-observed incidence and severity of adverse events.
time frame: 6 months
arm group label: ASTX727 + Day 2 Food
arm group type: Experimental
description: Subjects will receive ASTX727 on Days 1-5 of Cycle 1 and a high-calorie, high-fat breakfast meal of 800-1000 calories pre-dose on Day 2 of Cycle 1.
arm group label: ASTX727 + Day 4 Food
arm group type: Experimental
description: Subjects will receive ASTX727 on Days 1-5 of Cycle 1 and a high-calorie, high-fat breakfast meal of 800-1000 calories pre-dose on Day 4 of Cycle 1.
intervention type: Drug
intervention name: ASTX727 + Day 2 Food
description: ASTX727 is an oral drug product composed of a fixed-dose combination of cedazuridine (E7727), a CDA inhibitor, and decitabine. Food is a high-calorie, high-fat breakfast meal of 800-1000 calories given on Day 2.
arm group label: ASTX727 + Day 2 Food
other name: cedazuridine + decitabine + food on Day 2
intervention type: Drug
intervention name: ASTX727 + Day 4 Food
description: ASTX727 is an oral drug product composed of a fixed-dose combination of cedazuridine (E7727), a CDA inhibitor, and decitabine. Food is a high-calorie, high-fat breakfast meal of 800-1000 calories given on Day 4.
arm group label: ASTX727 + Day 4 Food
other name: cedazuridine + decitabine + food on Day 4
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kartik Krishnan, MD
role: Study Director
affiliation: Astex Pharmaceuticals, Inc.
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
PMID: 16609072
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
mesh term: Myelodysplastic Syndromes
mesh term: Decitabine
mesh term: Decitabine and cedazuridine drug combination
sharing ipd: No