<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/NCT02225093</url>
  </required_header>
  <id_info>
    <org_study_id>9785-CL-0406</org_study_id>
    <nct_id>NCT02225093</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate How Daily Dosing With Enzalutamide Affects the Metabolism of Caffeine and Dextromethorphan in Men With Prostate Cancer</brief_title>
  <official_title>A Phase 1 Open-label Study to Evaluate the Effect of Multiple Doses of Enzalutamide on the Pharmacokinetics of Substrates for CYP1A2 and CYP2D6 in Male Subjects With Prostate Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Astellas Pharma Europe B.V.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medivation, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Astellas Pharma Inc</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates how once daily enzalutamide affects the metabolism of caffeine and&#xD;
      dextromethorphan in men with prostate cancer by measuring concentrations of these drugs and&#xD;
      their metabolites in plasma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, fixed-sequence, crossover drug-drug interaction study in subjects with&#xD;
      prostate cancer.&#xD;
&#xD;
      Screening takes place between Day -28 and Day -7, and subjects are admitted to the clinic on&#xD;
      Day -1 where they remain until Day 4.&#xD;
&#xD;
      On Day 1, they receive a single oral cocktail containing caffeine and dextromethorphan plus a&#xD;
      dose of enzalutamide placebo in order to assess possible effects of excipients of the&#xD;
      enzalutamide formulation. On Days 1 to 3 blood samples for pharmacokinetic (PK) assessment&#xD;
      are collected. From Days 4 to 54, (or Day 55 if the subject rolls over into the extension&#xD;
      study) the subjects take a daily oral dose of enzalutamide. On Day 28, the subjects return to&#xD;
      the clinic where a plasma sample is taken to determine enzalutamide PK exposure. From Days 52&#xD;
      to 55 they are re-admitted to the clinic where a plasma sample is collected on Day 52 for&#xD;
      enzalutamide PK exposure.On Day 53, subjects receive a single oral cocktail of caffeine and&#xD;
      dextromethorphan concomitantly with enzalutamide. PK samples are collected from Days 53 to&#xD;
      55.&#xD;
&#xD;
      From Day 55 onwards, subjects experiencing clinical benefit may roll over into an extension&#xD;
      study. Only subjects who enroll into the extension study continue to receive enzalutamide&#xD;
      otherwise daily dosing with enzalutamide is discontinued on Day 54.&#xD;
&#xD;
      An End of Study Visit (ESV) takes place approximately 30 days (±7 days) after the last dose&#xD;
      of enzalutamide.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2, 2013</start_date>
  <completion_date type="Actual">February 3, 2014</completion_date>
  <primary_completion_date type="Actual">February 3, 2014</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PK measured by Pharmacokinetic parameter Maximum concentration (Cmax)</measure>
    <time_frame>Day 1 and Day 53 (28 times)</time_frame>
    <description>For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>PK measured by Pharmacokinetic parameter Area under the curve (AUC) from the time of dosing to the last measurable concentration (AUC0-t)</measure>
    <time_frame>Day 1 and Day 53 (28 times)</time_frame>
    <description>For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>PK measured by PK parameter area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf)</measure>
    <time_frame>Day 1 and Day 53 (28 times)</time_frame>
    <description>For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PK measured by PK parameters tmax, terminal elimination half-life (t1/2), apparent total systemic clearance after oral dosing (CL/F), apparent volume of distribution during terminal elimination phase (Vz/F) and extrapolated AUC (%AUC)</measure>
    <time_frame>Day 1 and Day 53 (28 times)</time_frame>
    <description>Tmax is time to maximum concentration. These PK parameters will be measured for the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK measured by PK parameters Cmax, AUC0-t, AUC0-inf, %AUC, tmax and t1/2</measure>
    <time_frame>Day 1 and Day 53 (28 times)</time_frame>
    <description>For 1,7-dimethylxanthine (metabolite caffeine), dextrorphan (metabolite dextromethorphan).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK measured by PK parameters Cmax, trough concentrations (Ctrough) at Days 28, 52, 53, 54 and 55, tmax, AUC during the time interval between consecutive dosing (AUCtau), CL/F (parent only) and peak-to-trough ratio (PTR)</measure>
    <time_frame>Day 28 (± 1 day), and Days 52 to 55 (15 times)</time_frame>
    <description>For Enzalutamide, N-desmethyl enzalutamide (M2) and sum of enzalutamide + M2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability measured by vital signs, adverse events, laboratory assessments and electrocardiogram</measure>
    <time_frame>Screening (Day -28 to Day -7) to ESV (&gt;153 times)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Pharmacokinetics of Dextromethorphan</condition>
  <condition>Pharmacokinetics of Caffeine</condition>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>1:Caffeine, Dextromethorphan and Enzalutamide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1-sequence crossover here</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Caffeine</intervention_name>
    <description>Oral</description>
    <arm_group_label>1:Caffeine, Dextromethorphan and Enzalutamide</arm_group_label>
    <other_name>CYP1A2 substrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dextromethorphan</intervention_name>
    <description>Oral /.L</description>
    <arm_group_label>1:Caffeine, Dextromethorphan and Enzalutamide</arm_group_label>
    <other_name>CYP2D6 substrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzalutamide</intervention_name>
    <description>Oral</description>
    <arm_group_label>1:Caffeine, Dextromethorphan and Enzalutamide</arm_group_label>
    <other_name>Xtandi</other_name>
    <other_name>MDV3100</other_name>
    <other_name>ASP9785</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzalutamide Placebo to Match (PTM)</intervention_name>
    <description>Oral</description>
    <arm_group_label>1:Caffeine, Dextromethorphan and Enzalutamide</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject is a male aged 18 years old or older (at screening) with histologically&#xD;
             confirmed prostate cancer (all stages) for whom androgen deprivation therapy is&#xD;
             indicated (except when indicated in a neoadjuvant/adjuvant setting). Subjects may be&#xD;
             on ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH)&#xD;
             analogue or have undergone prior bilateral orchiectomy at screening.&#xD;
&#xD;
          -  Subject has progressive disease by prostate-specific antigen (PSA) or imaging.&#xD;
&#xD;
          -  Subject has received no more than 2 prior chemotherapy regimens.&#xD;
&#xD;
          -  Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.&#xD;
&#xD;
          -  Male subject must use a condom if having sex with a pregnant woman.&#xD;
&#xD;
          -  Male subject and their female spouse/partners who are of childbearing potential must&#xD;
             use 2 acceptable methods of birth control starting at screening and continuing&#xD;
             throughout the study period and for 3 months after final study drug administration.&#xD;
&#xD;
          -  Subject has an estimated life expectancy of at least 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has confirmed CYP2D6 poor metabolizer, or CYP2D6 ultrarapid metabolizer status&#xD;
             based on genotyping analysis.&#xD;
&#xD;
          -  Subject has known metastases in the liver or any hepatic disorder that could affect&#xD;
             drug metabolism deemed clinically significant by the investigator after discussion&#xD;
             with the sponsor.&#xD;
&#xD;
          -  Subject has undergone major surgery within 4 weeks prior to day 1.&#xD;
&#xD;
          -  Subject received treatment with chemotherapy within 4 weeks prior to enrollment (day 1&#xD;
             visit) or plans to initiate treatment with chemotherapy during the study.&#xD;
&#xD;
          -  Subject uses concomitant medications that are potent inducers and/or inhibitors of&#xD;
             CYP1A2, CYP2C8, CYP2D6, or CYP3A4.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Astellas Pharma Europe B.V.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Arensia</name>
      <address>
        <city>Chisinau</city>
        <zip>2025</zip>
        <country>Moldova, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Moldova, Republic of</country>
  </location_countries>
  <link>
    <url>https://www.astellasclinicalstudyresults.com/study.aspx?ID=43</url>
    <description>Link to results on Astellas Clinical Study Results website</description>
  </link>
  <verification_date>June 2017</verification_date>
  <study_first_submitted>August 22, 2014</study_first_submitted>
  <study_first_submitted_qc>August 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 26, 2014</study_first_posted>
  <last_update_submitted>June 26, 2017</last_update_submitted>
  <last_update_submitted_qc>June 26, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Safety</keyword>
  <keyword>Dextromethorphan</keyword>
  <keyword>CYP2D6</keyword>
  <keyword>Phase 1</keyword>
  <keyword>Prostate cancer</keyword>
  <keyword>CYP1A2</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Drug-drug interactions</keyword>
  <keyword>Caffeine</keyword>
  <keyword>Enzalutamide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dextromethorphan</mesh_term>
    <mesh_term>Caffeine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02225093
org study id: 9785-CL-0406
nct id: NCT02225093
lead sponsor: 
collaborator: 
has dmc: No
This study evaluates how once daily enzalutamide affects the metabolism of caffeine and
      dextromethorphan in men with prostate cancer by measuring concentrations of these drugs and
      their metabolites in plasma.
This is an open-label, fixed-sequence, crossover drug-drug interaction study in subjects with
      prostate cancer.

      Screening takes place between Day -28 and Day -7, and subjects are admitted to the clinic on
      Day -1 where they remain until Day 4.

      On Day 1, they receive a single oral cocktail containing caffeine and dextromethorphan plus a
      dose of enzalutamide placebo in order to assess possible effects of excipients of the
      enzalutamide formulation. On Days 1 to 3 blood samples for pharmacokinetic (PK) assessment
      are collected. From Days 4 to 54, (or Day 55 if the subject rolls over into the extension
      study) the subjects take a daily oral dose of enzalutamide. On Day 28, the subjects return to
      the clinic where a plasma sample is taken to determine enzalutamide PK exposure. From Days 52
      to 55 they are re-admitted to the clinic where a plasma sample is collected on Day 52 for
      enzalutamide PK exposure.On Day 53, subjects receive a single oral cocktail of caffeine and
      dextromethorphan concomitantly with enzalutamide. PK samples are collected from Days 53 to
      55.

      From Day 55 onwards, subjects experiencing clinical benefit may roll over into an extension
      study. Only subjects who enroll into the extension study continue to receive enzalutamide
      otherwise daily dosing with enzalutamide is discontinued on Day 54.

      An End of Study Visit (ESV) takes place approximately 30 days (±7 days) after the last dose
      of enzalutamide.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: PK measured by Pharmacokinetic parameter Maximum concentration (Cmax)
time frame: Day 1 and Day 53 (28 times)
description: For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
measure: PK measured by Pharmacokinetic parameter Area under the curve (AUC) from the time of dosing to the last measurable concentration (AUC0-t)
time frame: Day 1 and Day 53 (28 times)
description: For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
measure: PK measured by PK parameter area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf)
time frame: Day 1 and Day 53 (28 times)
description: For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
measure: PK measured by PK parameters tmax, terminal elimination half-life (t1/2), apparent total systemic clearance after oral dosing (CL/F), apparent volume of distribution during terminal elimination phase (Vz/F) and extrapolated AUC (%AUC)
time frame: Day 1 and Day 53 (28 times)
description: Tmax is time to maximum concentration. These PK parameters will be measured for the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
measure: PK measured by PK parameters Cmax, AUC0-t, AUC0-inf, %AUC, tmax and t1/2
time frame: Day 1 and Day 53 (28 times)
description: For 1,7-dimethylxanthine (metabolite caffeine), dextrorphan (metabolite dextromethorphan).
measure: PK measured by PK parameters Cmax, trough concentrations (Ctrough) at Days 28, 52, 53, 54 and 55, tmax, AUC during the time interval between consecutive dosing (AUCtau), CL/F (parent only) and peak-to-trough ratio (PTR)
time frame: Day 28 (± 1 day), and Days 52 to 55 (15 times)
description: For Enzalutamide, N-desmethyl enzalutamide (M2) and sum of enzalutamide + M2.
measure: Safety and tolerability measured by vital signs, adverse events, laboratory assessments and electrocardiogram
time frame: Screening (Day -28 to Day -7) to ESV (>153 times)
arm group label: 1:Caffeine, Dextromethorphan and Enzalutamide
arm group type: Experimental
description: 1-sequence crossover here
intervention type: Drug
intervention name: Caffeine
description: Oral
arm group label: 1:Caffeine, Dextromethorphan and Enzalutamide
other name: CYP1A2 substrate
intervention type: Drug
intervention name: Dextromethorphan
description: Oral /.L
arm group label: 1:Caffeine, Dextromethorphan and Enzalutamide
other name: CYP2D6 substrate
intervention type: Drug
intervention name: Enzalutamide
description: Oral
arm group label: 1:Caffeine, Dextromethorphan and Enzalutamide
other name: Xtandi
other name: MDV3100
other name: ASP9785
intervention type: Drug
intervention name: Enzalutamide Placebo to Match (PTM)
description: Oral
arm group label: 1:Caffeine, Dextromethorphan and Enzalutamide
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Astellas Pharma Europe B.V.
facility: 
country: Moldova, Republic of
url: https://www.astellasclinicalstudyresults.com/study.aspx?ID=43
description: Link to results on Astellas Clinical Study Results website
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Dextromethorphan
mesh term: Caffeine