<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/NCT04411030</url>
  </required_header>
  <id_info>
    <org_study_id>ASTX660-12</org_study_id>
    <nct_id>NCT04411030</nct_id>
  </id_info>
  <brief_title>A Study to Investigate the Effect of CYP3A4 Inhibition on the Single Dose Pharmacokinetics of ASTX660 and the Effect of a Single Dose of ASTX660 on the Pharmacokinetics of the CYP3A4 Substrate Midazolam</brief_title>
  <official_title>A Two Cohort, Open-Label, Fixed Sequence Study to Investigate the Effect of CYP3A4 Inhibition on the Single Dose Pharmacokinetics of ASTX660 and the Effect of a Single Dose of ASTX660 on the Pharmacokinetics of the CYP3A4 Substrate Midazolam</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>
      In Part 1, the primary objective is to investigate the effect of multiple doses of&#xD;
      itraconazole, an inhibitor of CYP3A4, on the pharmacokinetic (PK) profile of a single dose of&#xD;
      ASTX660.&#xD;
&#xD;
      In Part 2, the primary objective is to investigate the effect of a single dose of ASTX660 on&#xD;
      the pharmacokinetics of the CYP3A4 substrate midazolam and its metabolite, 1-hydroxy&#xD;
      midazolam.&#xD;
&#xD;
      Safety and tolerability of a single dose of ASTX660 in the absence and presence of multiple&#xD;
      doses of the CYP3A4 inhibitor itraconazole and in the presence of a single dose of the CYP3A4&#xD;
      substrate midazolam will also be evaluated.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 20, 2020</start_date>
  <completion_date type="Actual">August 29, 2020</completion_date>
  <primary_completion_date type="Actual">August 23, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of ASTX660: Cmax</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of ASTX660: AUC0-t</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero to the last measurable concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of ASTX660: AUC0-24</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero to 24 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of ASTX660: AUC0-inf</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero extrapolated to infinity</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: Cmax</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-t</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero to the last measurable concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-24</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero to 24 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-inf</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Area under the plasma concentration versus time curve from time zero extrapolated to infinity</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter for ASTX660: CL/F</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Total apparent clearance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter for ASTX660: t1/2</measure>
    <time_frame>From predose up to Day 14</time_frame>
    <description>Observed terminal half-life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter for midazolam: CL/F</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Total apparent clearance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter for midazolam: t1/2</measure>
    <time_frame>From predose up to Day 9</time_frame>
    <description>Observed terminal half-life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety: Number of participants with adverse events</measure>
    <time_frame>Up to Day 35</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Healthy Volunteer</condition>
  <arm_group>
    <arm_group_label>Part 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral administration of ASTX660 and itraconazole at specific time points.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral administration of ASTX660 and midazolam at specific time points.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ASTX660</intervention_name>
    <description>Form: capsule; Route of administration: oral</description>
    <arm_group_label>Part 1</arm_group_label>
    <arm_group_label>Part 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Form: syrup; Route of administration: oral</description>
    <arm_group_label>Part 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Itraconazole</intervention_name>
    <description>Form: capsule; Route of administration: oral</description>
    <arm_group_label>Part 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participant understands the study procedures and agrees to participate by providing&#xD;
             written informed consent.&#xD;
&#xD;
          2. Participant is willing and able to comply with all study procedures and restrictions.&#xD;
&#xD;
          3. Participant is male aged 18 to 45 years, inclusive at Screening.&#xD;
&#xD;
          4. Participant has a body mass index (BMI) ≥ 18.5 kg/m2 and ≤ 30.0 kg/m2 at Screening.&#xD;
&#xD;
          5. Participant is considered medically healthy as determined by the investigator, based&#xD;
             on clinical evaluations including medical history, physical examination, clinical&#xD;
             laboratory tests, 12-lead electrocardiogram (ECG) in triplicate, and vital sign&#xD;
             measurements performed at Screening.&#xD;
&#xD;
          6. Participants must be willing to use adequate contraception (double-barrier) from&#xD;
             screening until 3 months after study completion. Male vasectomy is accepted as&#xD;
             contraception if the vasectomy took place ≥ 6 months prior to first dose.&#xD;
&#xD;
          7. Participants must refrain from sperm donation, from screening until 3 months after&#xD;
             study completion.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participant is mentally or legally incapacitated or has significant emotional problems&#xD;
             at the time of Screening or is expected to have such problems during the conduct of&#xD;
             the study.&#xD;
&#xD;
          2. Participant has a clinically significant medical or psychiatric condition or disease&#xD;
             (acute or chronic) that, as judged by the investigator, would make the participant&#xD;
             ineligible for participation in the study (eg, compromises the study data, limits the&#xD;
             participant's ability to complete and/or participate in the study).&#xD;
&#xD;
          3. Participant has a current condition or history of significant endocrine, hepatic,&#xD;
             renal, hematological, pulmonary, cardiovascular, gastrointestinal, urological,&#xD;
             immunological, or neurological disorders with clinical manifestations that, as judged&#xD;
             by the investigator, would make the participant ineligible for participation in the&#xD;
             study.&#xD;
&#xD;
          4. Participant has a chronic disease requiring medication, dietary restriction, physical&#xD;
             therapy, and/or other routine treatment that, as judged by the investigator, would&#xD;
             make the participant ineligible for participation in the study.&#xD;
&#xD;
          5. Participant has a history of gastrointestinal (GI) surgery including but not limited&#xD;
             to gastric resection and/or intestinal resection that resulted in a clinically&#xD;
             significant abnormality in GI function.&#xD;
&#xD;
          6. Participant has a history or presence of cancer (with the exception of a history of&#xD;
             basal cell carcinoma of the skin).&#xD;
&#xD;
          7. Participant has a history of drug and/or alcohol addiction or is a current regular&#xD;
             user (including recreational use) of any illicit drugs, has a history of drug or&#xD;
             alcohol abuse, or has ever undergone drug or alcohol rehabilitation.&#xD;
&#xD;
          8. Participant has a history of significant multiple and/or severe allergies (eg, food,&#xD;
             drug, latex allergy), or has had an anaphylactic reaction or significant intolerance&#xD;
             to food, prescription drugs or non-prescription (over-the-counter) drugs. Note:&#xD;
             participants with seasonal allergies may participate.&#xD;
&#xD;
          9. Participant has a known history of coronavirus disease 2019 (COVID-19) or has had&#xD;
             contact with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive&#xD;
             or COVID-19 patient within the 4 weeks prior to admission to the study center.&#xD;
&#xD;
         10. Participant has a QTcF interval of &gt; 450 msec at Screening.&#xD;
&#xD;
         11. Participant has an estimated creatinine clearance &lt; 90 mL/min based on the Cockcroft&#xD;
             Gault equation at Screening.&#xD;
&#xD;
         12. Participant regularly consumes excessive amounts of caffeine, defined as &gt; 6 servings&#xD;
             of coffee, tea, cola, or other caffeinated beverages, per day (1 serving is&#xD;
             approximately equivalent to 120 mg of caffeine).&#xD;
&#xD;
         13. Participant regularly consumes excessive amounts of alcohol, defined as &gt; 3 glasses of&#xD;
             alcoholic beverages per day and/or refuses to refrain from consuming such products&#xD;
             throughout the study.&#xD;
&#xD;
         14. Participant has used any medication (including prescription or non-prescription drugs,&#xD;
             dietary or vitamin/mineral supplements or herbal remedies that are known to induce&#xD;
             drug-metabolizing enzymes) within 14 days (or 5 half-lives, whichever is longer) prior&#xD;
             to study drug administration on Day 1.&#xD;
&#xD;
         15. Participant has used any medications known to be significant CYP inducers, including&#xD;
             St. John's wort, within 28 days prior to the study drug administration on Day 1.&#xD;
&#xD;
         16. Participant has consumed grapefruit, grapefruit juice, grapefruit juice-containing&#xD;
             products, Seville oranges, orange juice, and/or apple juice within 7 days prior to&#xD;
             study drug administration on Day 1 and/or refuses to refrain from consuming such&#xD;
             products throughout the study.&#xD;
&#xD;
         17. Participant has consumed vegetables from the mustard green family (eg, kale, broccoli,&#xD;
             watercress, collard greens, kohlrabi, Brussels sprouts, mustard) and/or charbroiled&#xD;
             meats within 7 days prior to study drug administration on Day 1 and/or refuses to&#xD;
             refrain from consuming such products throughout the study.&#xD;
&#xD;
         18. Participant has used tobacco- or nicotine-containing products (eg, cigarette, pipe,&#xD;
             cigar, chewing, nicotine patch, or nicotine gum) within 6 months prior to Day -1.&#xD;
&#xD;
         19. Participant refuses to refrain from using tobacco- or nicotine-containing products&#xD;
             throughout the study.&#xD;
&#xD;
         20. Participant has a positive urine drug and/or alcohol screening test result at&#xD;
             Screening or on Day -1.&#xD;
&#xD;
         21. Participant has a positive test result for any serological test including human&#xD;
             immunodeficiency virus (HIV) antigen/antibody, Hepatitis B surface antigen (HBsAg),&#xD;
             and Hepatitis C virus (HCV) antibody at Screening.&#xD;
&#xD;
         22. Participant has a positive test result for SARS-CoV-2 antigen, either asymptomatic or&#xD;
             present with COVID-19 at study check-in.&#xD;
&#xD;
         23. Participant appears to have poor venous access.&#xD;
&#xD;
         24. Participant has donated blood or had significant blood loss within 56 days of study&#xD;
             drug administration on Day 1.&#xD;
&#xD;
         25. Participant has donated plasma within 7 days prior to study drug administration on Day&#xD;
             1.&#xD;
&#xD;
         26. Participant has participated in any other investigational trial or has received any&#xD;
             investigational drug within 28 days (or 5 half-lives of the previous investigational&#xD;
             drug). The date will be derived from the last study procedure [blood collection or&#xD;
             dosing] of previous trial prior to study drug administration on Day 1.&#xD;
&#xD;
         27. Participant has any hypersensitivity to the study drugs or any of their excipients.&#xD;
&#xD;
         28. Participant is ineligible for this study for any other reason, as judged by the&#xD;
             investigator.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Harold Keer, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Astex Pharmaceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>QPS Bio-kinetic</name>
      <address>
        <city>Springfield</city>
        <state>Missouri</state>
        <zip>65802</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>May 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>September 14, 2020</last_update_submitted>
  <last_update_submitted_qc>September 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Itraconazole</mesh_term>
    <mesh_term>Midazolam</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/NCT04411030
org study id: ASTX660-12
nct id: NCT04411030
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
In Part 1, the primary objective is to investigate the effect of multiple doses of
      itraconazole, an inhibitor of CYP3A4, on the pharmacokinetic (PK) profile of a single dose of
      ASTX660.

      In Part 2, the primary objective is to investigate the effect of a single dose of ASTX660 on
      the pharmacokinetics of the CYP3A4 substrate midazolam and its metabolite, 1-hydroxy
      midazolam.

      Safety and tolerability of a single dose of ASTX660 in the absence and presence of multiple
      doses of the CYP3A4 inhibitor itraconazole and in the presence of a single dose of the CYP3A4
      substrate midazolam will also be evaluated.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Pharmacokinetic parameter of ASTX660: Cmax
time frame: From predose up to Day 14
description: Maximum plasma concentration
measure: Pharmacokinetic parameter of ASTX660: AUC0-t
time frame: From predose up to Day 14
description: Area under the plasma concentration versus time curve from time zero to the last measurable concentration
measure: Pharmacokinetic parameter of ASTX660: AUC0-24
time frame: From predose up to Day 14
description: Area under the plasma concentration versus time curve from time zero to 24 hours
measure: Pharmacokinetic parameter of ASTX660: AUC0-inf
time frame: From predose up to Day 14
description: Area under the plasma concentration versus time curve from time zero extrapolated to infinity
measure: Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: Cmax
time frame: From predose up to Day 9
description: Maximum plasma concentration
measure: Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-t
time frame: From predose up to Day 9
description: Area under the plasma concentration versus time curve from time zero to the last measurable concentration
measure: Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-24
time frame: From predose up to Day 9
description: Area under the plasma concentration versus time curve from time zero to 24 hours
measure: Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-inf
time frame: From predose up to Day 9
description: Area under the plasma concentration versus time curve from time zero extrapolated to infinity
measure: Pharmacokinetic parameter for ASTX660: CL/F
time frame: From predose up to Day 14
description: Total apparent clearance
measure: Pharmacokinetic parameter for ASTX660: t1/2
time frame: From predose up to Day 14
description: Observed terminal half-life
measure: Pharmacokinetic parameter for midazolam: CL/F
time frame: From predose up to Day 9
description: Total apparent clearance
measure: Pharmacokinetic parameter for midazolam: t1/2
time frame: From predose up to Day 9
description: Observed terminal half-life
measure: Safety: Number of participants with adverse events
time frame: Up to Day 35
arm group label: Part 1
arm group type: Experimental
description: Oral administration of ASTX660 and itraconazole at specific time points.
arm group label: Part 2
arm group type: Experimental
description: Oral administration of ASTX660 and midazolam at specific time points.
intervention type: Drug
intervention name: ASTX660
description: Form: capsule; Route of administration: oral
arm group label: Part 1
arm group label: Part 2
intervention type: Drug
intervention name: Midazolam
description: Form: syrup; Route of administration: oral
arm group label: Part 2
intervention type: Drug
intervention name: Itraconazole
description: Form: capsule; Route of administration: oral
arm group label: Part 1
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Harold Keer, MD, PhD
role: Study Director
affiliation: Astex Pharmaceuticals, Inc.
facility: 
country: United States
responsible party type: Sponsor
mesh term: Itraconazole
mesh term: Midazolam
sharing ipd: No