<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/NCT03291288</url>
  </required_header>
  <id_info>
    <org_study_id>PL3397-A-U126</org_study_id>
    <nct_id>NCT03291288</nct_id>
  </id_info>
  <brief_title>Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)</brief_title>
  <official_title>An Open-label, Single Sequence, Crossover Drug-drug Interaction Study Assessing the Effect of Pexidartinib on the Pharmacokinetics of CYP3A4 and CYP2C9 Substrates in Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Daiichi Sankyo, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Daiichi Sankyo, 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 has two parts.&#xD;
&#xD;
      Part 1 will evaluate how pexidartinib affects the way the body processes CYP3A4 and CYP2C9&#xD;
      substrates using midazolam and tolbutamide, respectively, as probe agents.&#xD;
&#xD;
      Part 2 will test the efficacy and safety of pexidartinib treatment in various tumor types.&#xD;
&#xD;
      In Part 2, the same participants will continue to receive pexidartinib twice daily.&#xD;
&#xD;
      Participants will be allowed to continue using pexidartinib as long as the participant&#xD;
      derives benefit.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 26, 2018</start_date>
  <completion_date type="Actual">April 16, 2021</completion_date>
  <primary_completion_date type="Actual">September 26, 2018</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>Sequential Assignment</intervention_model>
    <intervention_model_description>Open-label, single sequence study with 2 parts</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide</measure>
    <time_frame>Baseline to 15 days post treatment</time_frame>
    <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Summary of Treatment-emergent Adverse Events</measure>
    <time_frame>Baseline to 1 year post treatment</time_frame>
    <description>Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam</measure>
    <time_frame>Baseline to 13 days post treatment</time_frame>
    <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).&#xD;
Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Drug Interaction Potential</condition>
  <arm_group>
    <arm_group_label>Pexidartinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 1 (Drug-drug Interaction Phase):&#xD;
On Day 1, all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/d) in twice daily (400 mg BID) dosing will be initiated and continue throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning dose of pexidartinib (400 mg).&#xD;
Part 2 (Efficacy and Safety Phase):&#xD;
All participants will continue to receive pexidartinib 400 mg BID.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolbutamide</intervention_name>
    <description>Commercially available tolbutamide</description>
    <arm_group_label>Pexidartinib</arm_group_label>
    <other_name>Orinase</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Commercially available midazolam</description>
    <arm_group_label>Pexidartinib</arm_group_label>
    <other_name>Dormicum</other_name>
    <other_name>Hypnovel</other_name>
    <other_name>Versed</other_name>
    <other_name>Others</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pexidartinib</intervention_name>
    <description>Pexidartinib is formulated as opaque, white, 200-mg capsules</description>
    <arm_group_label>Pexidartinib</arm_group_label>
    <other_name>PLX-3397</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Is the age of majority in country of residence&#xD;
&#xD;
          -  Has a diagnosis of:&#xD;
&#xD;
               1. tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity&#xD;
                  or functional limitations and for whom surgery is not an option (prior&#xD;
                  pexidartinib is permitted for TGCT patients unless ineffective or not tolerated&#xD;
                  and there has been a washout period of at least 4 weeks)&#xD;
&#xD;
               2. KIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST),&#xD;
                  for which there is no standard systemic therapy, or&#xD;
&#xD;
               3. other solid tumors (all comers) for which there is no standard systemic therapy&#xD;
                  and there is a rationale for use of pexidartinib at the Investigator's discretion&#xD;
&#xD;
          -  If a female of childbearing potential, had a negative serum pregnancy test within 14&#xD;
             days before enrollment, or within 72 hours before enrollment where required&#xD;
&#xD;
          -  Is a non-sterile male or female willing to use of one of the protocol-defined highly&#xD;
             effective contraception methods:&#xD;
&#xD;
               1. intra-uterine device (nonhormonal or hormonal)&#xD;
&#xD;
               2. sexual abstinence (only if this is in line with the patient's current lifestyle)&#xD;
&#xD;
               3. barrier methods (eg, condom, diaphragm) used in combination with hormonal methods&#xD;
                  associated with inhibition of ovulation&#xD;
&#xD;
          -  Is a surgically sterile male or female, or is postmenopausal for at least 1 year, at&#xD;
             least 50 years of age, with a follicle-stimulating hormone level &gt; 40&#xD;
             milli-International units per mL (mIU/mL)&#xD;
&#xD;
          -  Has adequate hematologic, hepatic, and renal function as defined by the protocol&#xD;
&#xD;
          -  Is able and willing to follow all study procedures&#xD;
&#xD;
          -  Has provided a signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Is pregnant or breastfeeding&#xD;
&#xD;
          -  Is unable to swallow oral medication&#xD;
&#xD;
          -  Is unable to follow study procedures&#xD;
&#xD;
          -  Is taking or has taken any medications or therapies outside of protocol-defined&#xD;
             parameters&#xD;
&#xD;
          -  Has any disease or condition that, per protocol or in the opinion of the investigator,&#xD;
             might affect:&#xD;
&#xD;
               1. safety and well-being of the participant or offspring&#xD;
&#xD;
               2. safety of study staff&#xD;
&#xD;
               3. analysis of results&#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>Global Clinical Leader</last_name>
    <role>Study Chair</role>
    <affiliation>Daiichi Sankyo, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>HonorHealth</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85258</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85719</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</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>Karmanos Cancer Center</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwell Health</name>
      <address>
        <city>Lake Success</city>
        <state>New York</state>
        <zip>10042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mary Crowley Cancer Research</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leids Universitair Medisch Centrum</name>
      <address>
        <city>Leiden</city>
        <zip>2333 ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Christchurch Hospital NZ</name>
      <address>
        <city>Christchurch</city>
        <zip>8011</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>10002</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
    <country>New Zealand</country>
    <country>Taiwan</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Korea, Republic of</country>
  </removed_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <results_first_submitted>February 12, 2020</results_first_submitted>
  <results_first_submitted_qc>March 5, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">March 19, 2020</results_first_posted>
  <last_update_submitted>April 19, 2021</last_update_submitted>
  <last_update_submitted_qc>April 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tenosynovial Giant Cell Tumors (TGCT)</keyword>
  <keyword>Kit-mutant melanoma</keyword>
  <keyword>Kit-mutant gastrointestinal stromal tumor (GIST)</keyword>
  <keyword>Cocktail drug-drug interaction (DDI)</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tolbutamide</mesh_term>
    <mesh_term>Midazolam</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.</ipd_time_frame>
    <ipd_access_criteria>Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.</ipd_access_criteria>
    <ipd_url>https://vivli.org/ourmember/daiichi-sankyo/</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 28, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/88/NCT03291288/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 32 participants who met all inclusion and no exclusion criteria were enrolled in the study; 2 participants did not receive pexidartinib treatment.</recruitment_details>
      <pre_assignment_details>This open-label, single sequence crossover study comprised of 2 parts. Part 1 was the initial single sequence crossover part to evaluate the effect of pexidartinib on the pharmacokinetics of midazolam and tolbutamide, the drug-drug interaction (DDI) phase. Part 2 was an evaluation of efficacy and safety of pexidartinib treatment in various tumors.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Part 1: Drug-drug Interaction Phase</title>
          <description>On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg).&#xD;
On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning pexidartinib dose (400 mg).&#xD;
On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).</description>
        </group>
        <group group_id="P2">
          <title>Part 2: Pexidartinib Only</title>
          <description>All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Drug-drug Interaction Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Disease progression</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Pexidartinib Only</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0">This is a crossover trial; participants who completed Part 1 continued to Part 2.</participants>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Ongoing</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Participants</title>
          <description>All participants who received pexidartinib in Part 1 and Part 2 of the study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50.8" spread="19.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam</title>
        <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam</title>
          <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.6" spread="6.8"/>
                    <measurement group_id="O2" value="12.0" spread="4.9"/>
                    <measurement group_id="O3" value="9.7" spread="4.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide</title>
        <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Tolbutamide Only</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide</title>
          <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44400" spread="13100"/>
                    <measurement group_id="O2" value="46700" spread="16300"/>
                    <measurement group_id="O3" value="44400" spread="12200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam</title>
        <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam</title>
          <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.525" lower_limit="0.333" upper_limit="1.37"/>
                    <measurement group_id="O2" value="0.5" lower_limit="0.417" upper_limit="1.42"/>
                    <measurement group_id="O3" value="0.5" lower_limit="0.333" upper_limit="0.917"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide</title>
        <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Tolbutamide Only</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide</title>
          <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.90" lower_limit="1" upper_limit="8.2"/>
                    <measurement group_id="O2" value="2.94" lower_limit="1.52" upper_limit="8.08"/>
                    <measurement group_id="O3" value="3.17" lower_limit="2.45" upper_limit="6.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam</title>
        <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam</title>
          <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng*hour/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.7" spread="34.1"/>
                    <measurement group_id="O2" value="31.6" spread="19.6"/>
                    <measurement group_id="O3" value="18.5" spread="8.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide</title>
        <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
        <time_frame>Baseline to 15 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Tolbutamide Only</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide</title>
          <description>Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng*hour/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="500000" spread="196000"/>
                    <measurement group_id="O2" value="585000" spread="234000"/>
                    <measurement group_id="O3" value="700000" spread="207000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Overall Summary of Treatment-emergent Adverse Events</title>
        <description>Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.</description>
        <time_frame>Baseline to 1 year post treatment</time_frame>
        <population>Treatment-emergent adverse events (TEAEs) were assessed in the Safety Analysis population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Drug-drug Interaction Phase</title>
            <description>On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg).&#xD;
On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning pexidartinib dose (400 mg).&#xD;
On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).</description>
          </group>
          <group group_id="O2">
            <title>Part 2: Pexidartinib Only</title>
            <description>All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Summary of Treatment-emergent Adverse Events</title>
          <description>Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.</description>
          <population>Treatment-emergent adverse events (TEAEs) were assessed in the Safety Analysis population.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pexidartinib-related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Treatment-emergent serious adverse events (SAEs)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pexidartinib-related SAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite</title>
        <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Pexidartinib (Cycle 1, Day 1)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib (Cycle 1, Day 11)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite</title>
          <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pexidartinib</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3140" spread="1250"/>
                    <measurement group_id="O2" value="8320" spread="2530"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ZAAD-1006a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3330" spread="1520"/>
                    <measurement group_id="O2" value="13500" spread="5980"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite</title>
        <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Pexidartinib (Cycle 1, Day 1)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib (Cycle 1, Day 11)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite</title>
          <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pexidartinib</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.03" lower_limit="1.08" upper_limit="7.83"/>
                    <measurement group_id="O2" value="1.93" lower_limit="0.92" upper_limit="8.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ZAAD-1006a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.04" lower_limit="2.37" upper_limit="9.07"/>
                    <measurement group_id="O2" value="2.53" lower_limit="0" upper_limit="8.25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite</title>
        <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Pexidartinib (Cycle 1, Day 1)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib (Cycle 1, Day 11)</title>
            <description>Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite</title>
          <description>Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng*hour/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pexidartinib</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14400" spread="5870"/>
                    <measurement group_id="O2" value="53200" spread="17800"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ZAAD-1006a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18300" spread="7240"/>
                    <measurement group_id="O2" value="102000" spread="44100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
        <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
          <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.7" spread="17.9"/>
                    <measurement group_id="O2" value="52.1" spread="17.4"/>
                    <measurement group_id="O3" value="55.7" spread="17.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
        <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
          <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" lower_limit="0.333" upper_limit="1.45"/>
                    <measurement group_id="O2" value="0.933" lower_limit="0.417" upper_limit="1.37"/>
                    <measurement group_id="O3" value="0.833" lower_limit="0.383" upper_limit="1.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
        <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam</title>
          <description>Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>ng*hour/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="200" spread="93"/>
                    <measurement group_id="O2" value="206" spread="95.5"/>
                    <measurement group_id="O3" value="212" spread="99.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam</title>
        <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).&#xD;
Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value.</description>
        <time_frame>Baseline to 13 days post treatment</time_frame>
        <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Midazolam Only</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
          <group group_id="O3">
            <title>Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)</title>
            <description>All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam</title>
          <description>Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).&#xD;
Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value.</description>
          <population>Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.</population>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="587" spread="359"/>
                    <measurement group_id="O2" value="750" spread="391"/>
                    <measurement group_id="O3" value="1220" spread="657"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected after first dose up to 28 days after the last dose of study drug, up to 1 year.</time_frame>
      <desc>A treatment emergent adverse event (TEAE) was defined as an adverse event that emerges during treatment of Pexidartinib, having been absent pretreatment (Pexidartinib), or worsens relative to the pre-treatment (Pexidartinib) state.</desc>
      <group_list>
        <group group_id="E1">
          <title>Part 1: Drug-drug Interaction Phase</title>
          <description>On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg).&#xD;
On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning pexidartinib dose (400 mg).&#xD;
On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).</description>
        </group>
        <group group_id="E2">
          <title>Part 2: Pexidartinib Only</title>
          <description>All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 21.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cardiac tamponade</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Malignant bowel obstruction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Oesophagitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Large intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholestasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Subdural haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Chest wall haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Malignant pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 21.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood cholesterol increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hair colour changes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Contact for Clinical Trial Information</name_or_title>
      <organization>Daiichi Sankyo, Inc.</organization>
      <phone>908-992-6400</phone>
      <email>CTRinfo@dsi.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03291288
org study id: PL3397-A-U126
nct id: NCT03291288
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This study has two parts.

      Part 1 will evaluate how pexidartinib affects the way the body processes CYP3A4 and CYP2C9
      substrates using midazolam and tolbutamide, respectively, as probe agents.

      Part 2 will test the efficacy and safety of pexidartinib treatment in various tumor types.

      In Part 2, the same participants will continue to receive pexidartinib twice daily.

      Participants will be allowed to continue using pexidartinib as long as the participant
      derives benefit.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: Open-label, single sequence study with 2 parts
primary purpose: Treatment
masking: None (Open Label)
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
time frame: Baseline to 15 days post treatment
description: Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide
time frame: Baseline to 15 days post treatment
description: Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
time frame: Baseline to 15 days post treatment
description: Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
time frame: Baseline to 15 days post treatment
description: Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
time frame: Baseline to 15 days post treatment
description: Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide
time frame: Baseline to 15 days post treatment
description: Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
measure: Overall Summary of Treatment-emergent Adverse Events
time frame: Baseline to 1 year post treatment
description: Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite
time frame: Baseline to 13 days post treatment
description: Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite
time frame: Baseline to 13 days post treatment
description: Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite
time frame: Baseline to 13 days post treatment
description: Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
time frame: Baseline to 13 days post treatment
description: Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
time frame: Baseline to 13 days post treatment
description: Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam
time frame: Baseline to 13 days post treatment
description: Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
measure: Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam
time frame: Baseline to 13 days post treatment
description: Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value.
arm group label: Pexidartinib
arm group type: Experimental
description: Part 1 (Drug-drug Interaction Phase):
On Day 1, all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/d) in twice daily (400 mg BID) dosing will be initiated and continue throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning dose of pexidartinib (400 mg).
Part 2 (Efficacy and Safety Phase):
All participants will continue to receive pexidartinib 400 mg BID.
intervention type: Drug
intervention name: Tolbutamide
description: Commercially available tolbutamide
arm group label: Pexidartinib
other name: Orinase
intervention type: Drug
intervention name: Midazolam
description: Commercially available midazolam
arm group label: Pexidartinib
other name: Dormicum
other name: Hypnovel
other name: Versed
other name: Others
intervention type: Drug
intervention name: Pexidartinib
description: Pexidartinib is formulated as opaque, white, 200-mg capsules
arm group label: Pexidartinib
other name: PLX-3397
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Global Clinical Leader
role: Study Chair
affiliation: Daiichi Sankyo, Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Netherlands
country: New Zealand
country: Taiwan
country: United States
country: Korea, Republic of
responsible party type: Sponsor
mesh term: Tolbutamide
mesh term: Midazolam
sharing ipd: Yes
ipd description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
ipd access criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
ipd url: https://vivli.org/ourmember/daiichi-sankyo/
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 