<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/NCT03297385</url>
  </required_header>
  <id_info>
    <org_study_id>N14DAR</org_study_id>
    <nct_id>NCT03297385</nct_id>
  </id_info>
  <brief_title>Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation</brief_title>
  <acronym>DARANA</acronym>
  <official_title>Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Astellas Pharma Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Netherlands Cancer Institute</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in&#xD;
      early prostate cancer could lead to improved patient selection for treatment.&#xD;
&#xD;
      Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA&#xD;
      interaction and gene expression.&#xD;
&#xD;
      Intervention : Men with localized prostate cancer will undergo an additional set of targeted&#xD;
      tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The&#xD;
      prostatectomy specimen will be additionally sampled, ex vivo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in&#xD;
      early prostate cancer could lead to improved patient selection for treatment.&#xD;
&#xD;
      Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA&#xD;
      interaction and gene expression.&#xD;
&#xD;
      Study design: A phase II prospective single-arm analysis. With a power of 80% to detect an&#xD;
      expected reduction in positive surgical margin rate from 34% to 17% the investigators will&#xD;
      have to included 55 men. For the AR/DNA interaction patients will serve as there own control&#xD;
      since biopsies will be taken before and after enzalutamide treatment.&#xD;
&#xD;
      Study population: Patients over 18 years of age with localized prostate cancer that are&#xD;
      planned for prostatectomy.&#xD;
&#xD;
      Intervention : Men with localized prostate cancer will undergo an additional set of targeted&#xD;
      tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The&#xD;
      prostatectomy specimen will be additionally sampled, ex vivo.&#xD;
&#xD;
      Main study parameters/endpoints: 1. The effects of neoadjuvant androgen ablation on tumor&#xD;
      downstaging. 2. The genetic and transcriptional changes caused by neoadjuvant androgen&#xD;
      ablation by enzalutamide.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: Burden and risks: Patients will be submitted to an additional set of 4 tumor&#xD;
      targeted biopsies under local anesthesia and antibiotic prophylaxis. This comprises a 5&#xD;
      minute intervention with an elevated (2%) risk of postbiopsy urinary tract infection.&#xD;
      Additionally oral enzalutamide treatment for a period of 3 months will result in temporary&#xD;
      signs of androgen ablation such as: hot flushes (20%), headache (12%), diarrhea (1%), and&#xD;
      seizures (0.9%). Benefits: neoadjuvant enzalutamide treatment has been shown to result in&#xD;
      tumor and prostate downsizing. Earlier neoadjuvant androgen ablation studies with other&#xD;
      agents have shown a reduced positive surgical margin rate and reduced intraoperative blood&#xD;
      loss&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 28, 2014</start_date>
  <completion_date type="Actual">April 1, 2017</completion_date>
  <primary_completion_date type="Actual">April 1, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A phase II prospective single-arm analysis. With a power of 80% to detect an expected reduction in positive surgical margin rate from 34% to 17% we will have to included 55 men. For the AR/DNA interaction patients will serve as there own control since biopsies will be taken before and after enzalutamide treatment.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effects of enzalutamide on tumor downstaging</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>To study the effects of enzalutamide on surgical margin status and AR / DNA interaction and gene expression.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Genetic and transcriptional changes caused by enzalutamide</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>The genetic and transcriptional changes caused by neoadjuvant androgen ablation by enzalutamide.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical down-staging of enzalutamide pretreatment</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>To assess the effects of 3 months enzalutamide pretreatment on clinical down-staging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AR-chromatin binding alterations and Ki-67 expression</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>Study the correlation between AR-chromatin binding alterations and Ki-67 expression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AR-dependant genes such as PSA, human kallikrein and PSMA</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>Compare the AR-chromatin binding with expression alterations of known AR-dependent genes such as PSA, human kallikrein and PSMA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gleason grading</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>Compare AR-chromatin binding patterns with Gleason grading.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Find associated genes in prostate tissue, using tissue microarray (TMA).</measure>
    <time_frame>From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).</time_frame>
    <description>Find associated genes on TMA derived from prostatectomy specimens.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Prostate Cancer</condition>
  <condition>DNA</condition>
  <condition>Androgen Receptor Abnormal</condition>
  <arm_group>
    <arm_group_label>Prostatectomy after enzalutamide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a single-arm study. Patients will have biopsies, after which they will receive enzalutamide for 3 months.&#xD;
After 3 months they will have a prostatectomy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzalutamide</intervention_name>
    <description>Men with localized prostate cancer will undergo an additional set of targeted tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The prostatectomy specimen will be additionally sampled, ex vivo.</description>
    <arm_group_label>Prostatectomy after enzalutamide</arm_group_label>
    <other_name>Xtandi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men over 18 years of age.&#xD;
&#xD;
          2. clinically non-metastasized prostate cancer, tumor that can be imaged (TRUS or MRI) in&#xD;
             order to allow for accurate preoperative biopsies.&#xD;
&#xD;
          3. Gleason score 7-10&#xD;
&#xD;
          4. written informed consent&#xD;
&#xD;
          5. WHO performance 0-1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. A history of seizures.&#xD;
&#xD;
          2. Clinically nodal metastases.&#xD;
&#xD;
          3. Prostatitis or urinary tract infection.&#xD;
&#xD;
          4. Androgen ablative therapy within 6 weeks of inclusion (including 5 alpha-reductase&#xD;
             inhibitors).&#xD;
&#xD;
          5. Tumor of the prostate that can not be visualized by TRUS or MRI.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>April 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <last_update_submitted>September 28, 2017</last_update_submitted>
  <last_update_submitted_qc>September 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 29, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Prostate Cancer</keyword>
  <keyword>Androgen Receptor Genomics</keyword>
  <keyword>Enzalutamide</keyword>
  <keyword>Prostatectomy</keyword>
  <keyword>Neoadjuvant androgen ablation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03297385
org study id: N14DAR
nct id: NCT03297385
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in
      early prostate cancer could lead to improved patient selection for treatment.

      Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA
      interaction and gene expression.

      Intervention : Men with localized prostate cancer will undergo an additional set of targeted
      tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The
      prostatectomy specimen will be additionally sampled, ex vivo.
Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in
      early prostate cancer could lead to improved patient selection for treatment.

      Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA
      interaction and gene expression.

      Study design: A phase II prospective single-arm analysis. With a power of 80% to detect an
      expected reduction in positive surgical margin rate from 34% to 17% the investigators will
      have to included 55 men. For the AR/DNA interaction patients will serve as there own control
      since biopsies will be taken before and after enzalutamide treatment.

      Study population: Patients over 18 years of age with localized prostate cancer that are
      planned for prostatectomy.

      Intervention : Men with localized prostate cancer will undergo an additional set of targeted
      tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The
      prostatectomy specimen will be additionally sampled, ex vivo.

      Main study parameters/endpoints: 1. The effects of neoadjuvant androgen ablation on tumor
      downstaging. 2. The genetic and transcriptional changes caused by neoadjuvant androgen
      ablation by enzalutamide.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: Burden and risks: Patients will be submitted to an additional set of 4 tumor
      targeted biopsies under local anesthesia and antibiotic prophylaxis. This comprises a 5
      minute intervention with an elevated (2%) risk of postbiopsy urinary tract infection.
      Additionally oral enzalutamide treatment for a period of 3 months will result in temporary
      signs of androgen ablation such as: hot flushes (20%), headache (12%), diarrhea (1%), and
      seizures (0.9%). Benefits: neoadjuvant enzalutamide treatment has been shown to result in
      tumor and prostate downsizing. Earlier neoadjuvant androgen ablation studies with other
      agents have shown a reduced positive surgical margin rate and reduced intraoperative blood
      loss
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A phase II prospective single-arm analysis. With a power of 80% to detect an expected reduction in positive surgical margin rate from 34% to 17% we will have to included 55 men. For the AR/DNA interaction patients will serve as there own control since biopsies will be taken before and after enzalutamide treatment.
primary purpose: Treatment
masking: None (Open Label)
measure: Effects of enzalutamide on tumor downstaging
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: To study the effects of enzalutamide on surgical margin status and AR / DNA interaction and gene expression.
measure: Genetic and transcriptional changes caused by enzalutamide
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: The genetic and transcriptional changes caused by neoadjuvant androgen ablation by enzalutamide.
measure: Clinical down-staging of enzalutamide pretreatment
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: To assess the effects of 3 months enzalutamide pretreatment on clinical down-staging
measure: AR-chromatin binding alterations and Ki-67 expression
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: Study the correlation between AR-chromatin binding alterations and Ki-67 expression.
measure: AR-dependant genes such as PSA, human kallikrein and PSMA
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: Compare the AR-chromatin binding with expression alterations of known AR-dependent genes such as PSA, human kallikrein and PSMA.
measure: Gleason grading
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: Compare AR-chromatin binding patterns with Gleason grading.
measure: Find associated genes in prostate tissue, using tissue microarray (TMA).
time frame: From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months).
description: Find associated genes on TMA derived from prostatectomy specimens.
arm group label: Prostatectomy after enzalutamide
arm group type: Experimental
description: This is a single-arm study. Patients will have biopsies, after which they will receive enzalutamide for 3 months.
After 3 months they will have a prostatectomy.
intervention type: Drug
intervention name: Enzalutamide
description: Men with localized prostate cancer will undergo an additional set of targeted tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The prostatectomy specimen will be additionally sampled, ex vivo.
arm group label: Prostatectomy after enzalutamide
other name: Xtandi
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
responsible party type: Sponsor
mesh term: Prostatic Neoplasms