<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/NCT02203695</url>
  </required_header>
  <id_info>
    <org_study_id>J1454</org_study_id>
    <secondary_id>IRB00030471</secondary_id>
    <nct_id>NCT02203695</nct_id>
  </id_info>
  <brief_title>Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy</brief_title>
  <official_title>Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men With High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Astellas Pharma Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medivation, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary hypothesis of this study is that outcomes for patients with biochemically&#xD;
      recurrent prostate cancer following radical prostatectomy will be improved by the addition of&#xD;
      enzalutamide for 6-months compared to standard-of-care salvage radiation therapy to allow for&#xD;
      further study in the definitive phase III setting. This study builds on the prior success of&#xD;
      high-dose bicalutamide (for 24 months) when combined with salvage external radiation therapy&#xD;
      (XRT), while using a newer more potent anti-androgen for a shorter duration of time (6&#xD;
      months) in an effort to minimize adverse effects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly&#xD;
      prolongs survival in patients with metastatic castration-resistant prostate cancer who have&#xD;
      received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells&#xD;
      that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB)&#xD;
      agents, Enzalutamide does not display any agonist properties and blocks translocation of the&#xD;
      ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral&#xD;
      agent that is generally well tolerated and does not require concurrent steroid&#xD;
      administration, which makes it an ideal candidate for combination with salvage radiation&#xD;
      therapy (SRT).&#xD;
&#xD;
      Finally, provocative preliminary Phase II data presented at the American Society of Clinical&#xD;
      Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks&#xD;
      (~6-mos) of enzalutamide alone in prostate cancer of all stages who had never received&#xD;
      hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide&#xD;
      alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but&#xD;
      .in contrast to castration, bone mineral density (BMD) remained stable and metabolic&#xD;
      variables were not substantially impacted.&#xD;
&#xD;
      The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG&#xD;
      05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less&#xD;
      favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG&#xD;
      96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we&#xD;
      are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as&#xD;
      opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD).&#xD;
&#xD;
      This trial is not intended to address the efficacy of SRT alone over observation. The&#xD;
      complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and&#xD;
      durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible&#xD;
      or appropriate to randomize men between observation and SRT. The more important issue is&#xD;
      whether the proportion of durable responses is increased by altering the therapeutic&#xD;
      approach, such as the use of enhanced ARB using enzalutamide.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 28, 2015</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Actual">December 31, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Freedom of PSA (Prostate Specific Antigen) progression</measure>
    <time_frame>2 years from end of therapy</time_frame>
    <description>The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP) at 2-years. FFPP is defined as the time from randomization to the date of PSA progression. A subject who does not have PSA progression at the time of the analysis will be censored at the last date of PSA measurement.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Local recurrence</measure>
    <time_frame>2 years from end of therapy</time_frame>
    <description>Local recurrence within the radiation field (confirmed pathologically) at 2-years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metastatic free survival rate</measure>
    <time_frame>2 years from the time of registration</time_frame>
    <description>Metastasis-free survival (MFS) rates at 2 years. Metastasis-free survival will be defined as the time from the date of registration to date of evidence of systemic disease on bone scan or cross sectional imaging or death, which occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events Encountered</measure>
    <time_frame>At the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months</time_frame>
    <description>Safety as assessed by NCI Common Toxicity Scales (v4.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>How well participants tolerate treatment</measure>
    <time_frame>During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months</time_frame>
    <description>Quality of life (QoL) tools to be used to determine participant tolerability of treatment will include FACT-P, European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) -C30/QLQ-PR25, and SHIM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of achieving stated accrual</measure>
    <time_frame>During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months</time_frame>
    <description>Compare anticipated accrual versus actual.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">96</enrollment>
  <condition>Adenocarcinoma of the Prostate</condition>
  <arm_group>
    <arm_group_label>SRT plus Enzalutamide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm 2 (experimental): (SRT) Salvage radiation therapy (Three dimensional conformal radiation therapy (3D-CRT)/IMRT [Intensity-modulated radiation therapy]) 66.6-70.2 Gy as 1.8 Gy M-F for 37-39 fx PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SRT plus placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Arm 1 (control): Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT (Intensity-modulated radiation therapy)) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enzalutamide</intervention_name>
    <description>Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)</description>
    <arm_group_label>SRT plus Enzalutamide</arm_group_label>
    <other_name>XTANDI</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>SRT</intervention_name>
    <description>Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx</description>
    <arm_group_label>SRT plus placebo</arm_group_label>
    <other_name>Salvage Radiation Therapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Willing and able to provide written informed consent and Health Insurance Portability&#xD;
             and Accountability Act (HIPPA) authorization for the release of personal health&#xD;
             information.&#xD;
&#xD;
          -  Males aged 18 years of age and above&#xD;
&#xD;
          -  Patients must have adenocarcinoma of the prostate gland&#xD;
&#xD;
          -  Patients must have received primary treatment with radical prostatectomy.&#xD;
&#xD;
          -  Patients must have evidence of biochemical (PSA) relapse after prostatectomy&#xD;
&#xD;
          -  Patients must have PSA within study range&#xD;
&#xD;
          -  Patients must have non-metastatic (M0) disease, as defined by a lack of metastases&#xD;
             seen on CT scan of the chest/abdomen/pelvis and whole-body radionuclide 99Technetium&#xD;
             (Tc) bone scan, (or sodium fluoride PET scan) taken within 3 months of study entry.&#xD;
&#xD;
          -  Patients must have had node negative (pN0) disease found at the time of surgery.&#xD;
&#xD;
          -  Patients must have non-castrate levels of serum testosterone levels within study&#xD;
             range.&#xD;
&#xD;
          -  Patients must not have previously received hormonal therapy (LHRH agonist,&#xD;
             antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given&#xD;
             in conjunction with prostatectomy.&#xD;
&#xD;
          -  Patients must have Eastern Cooperative Oncology Group (ECOG)performance status of 0-1,&#xD;
             and life expectancy greater 3 years.&#xD;
&#xD;
          -  Patients must have laboratory test results within the certain ranges&#xD;
&#xD;
          -  Patients must be disease-free from prior malignancies for greater than 3 years, with&#xD;
             the exception of non-melanoma skin cancers and superficial urothelial cancers.&#xD;
&#xD;
          -  Patients must have the ability to swallow the study drug whole as a tablet or capsule.&#xD;
&#xD;
          -  Throughout study, male patient and his female partner who is of childbearing potential&#xD;
             must use 2 acceptable methods of birth control (1 of which must include a condom as a&#xD;
             barrier method of contraception) starting at screening and continuing throughout the&#xD;
             study period and for 3 months after final study drug administration or per local&#xD;
             guidelines where these require additional description of contraceptive methods.&#xD;
&#xD;
          -  Throughout the study, patients must use a condom if having sex with a pregnant woman.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently active second malignancy&#xD;
&#xD;
          -  Primary treatment with radiation therapy.&#xD;
&#xD;
          -  Radiographic or clinical evidence of local-regional tumor recurrence,&#xD;
&#xD;
          -  Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase&#xD;
             inhibitors.&#xD;
&#xD;
          -  Use of systemic corticosteroids equivalent to prednisone (inhaled corticosteroids are&#xD;
             permitted).&#xD;
&#xD;
          -  Concurrent use of other anti-cancer agents or treatments.&#xD;
&#xD;
          -  Serious concurrent medical illnesses (including uncontrolled major cardiac, pulmonary,&#xD;
             Child-Pugh C liver or psychiatric diseases) or active major infections (including HIV,&#xD;
             Hepatitis A-C).&#xD;
&#xD;
          -  Clinically significant cardiovascular disease including:&#xD;
&#xD;
               -  Myocardial infarction within 6 months of Screening visit.&#xD;
&#xD;
               -  Uncontrolled angina within 3 months of Screening visit.&#xD;
&#xD;
               -  Congestive heart failure (within certain ranges)&#xD;
&#xD;
               -  History of clinically significant ventricular arrhythmias&#xD;
&#xD;
               -  Prolonged corrected QT interval&#xD;
&#xD;
               -  History of Mobitz II second degree or third degree heart block without a&#xD;
                  permanent pacemaker in place.&#xD;
&#xD;
               -  Hypotension within certain ranges&#xD;
&#xD;
               -  Uncontrolled hypertension within certain ranges&#xD;
&#xD;
          -  Medications which lowers seizure threshold.&#xD;
&#xD;
          -  History of seizure or any condition that may predispose to seizure including, but not&#xD;
             limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or&#xD;
             alcoholism. Also, history of loss of consciousness or transient ischemic attack within&#xD;
             12months of enrollment (Day 1 visit).&#xD;
&#xD;
          -  Patients taking medications that may have adverse interactions with enzalutamide&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Phuoc Tran, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>The SKCCC at Johns Hopkins</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sibley Memorial Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Lafayette</city>
        <state>Indiana</state>
        <zip>47904</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Suburban Hospital</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20814</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan Health System</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</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>Oregon Health Sciences University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah - Huntsman Cancer Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 16, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>May 30, 2023</last_update_submitted>
  <last_update_submitted_qc>May 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Salvage Radiation Therapy (SRT)</keyword>
  <keyword>Enzalutamide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</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/NCT02203695
org study id: J1454
secondary id: IRB00030471
nct id: NCT02203695
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
The primary hypothesis of this study is that outcomes for patients with biochemically
      recurrent prostate cancer following radical prostatectomy will be improved by the addition of
      enzalutamide for 6-months compared to standard-of-care salvage radiation therapy to allow for
      further study in the definitive phase III setting. This study builds on the prior success of
      high-dose bicalutamide (for 24 months) when combined with salvage external radiation therapy
      (XRT), while using a newer more potent anti-androgen for a shorter duration of time (6
      months) in an effort to minimize adverse effects.
Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly
      prolongs survival in patients with metastatic castration-resistant prostate cancer who have
      received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells
      that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB)
      agents, Enzalutamide does not display any agonist properties and blocks translocation of the
      ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral
      agent that is generally well tolerated and does not require concurrent steroid
      administration, which makes it an ideal candidate for combination with salvage radiation
      therapy (SRT).

      Finally, provocative preliminary Phase II data presented at the American Society of Clinical
      Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks
      (~6-mos) of enzalutamide alone in prostate cancer of all stages who had never received
      hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide
      alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but
      .in contrast to castration, bone mineral density (BMD) remained stable and metabolic
      variables were not substantially impacted.

      The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG
      05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less
      favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG
      96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we
      are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as
      opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD).

      This trial is not intended to address the efficacy of SRT alone over observation. The
      complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and
      durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible
      or appropriate to randomize men between observation and SRT. The more important issue is
      whether the proportion of durable responses is increased by altering the therapeutic
      approach, such as the use of enhanced ARB using enzalutamide.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Freedom of PSA (Prostate Specific Antigen) progression
time frame: 2 years from end of therapy
description: The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP) at 2-years. FFPP is defined as the time from randomization to the date of PSA progression. A subject who does not have PSA progression at the time of the analysis will be censored at the last date of PSA measurement.
measure: Local recurrence
time frame: 2 years from end of therapy
description: Local recurrence within the radiation field (confirmed pathologically) at 2-years
measure: Metastatic free survival rate
time frame: 2 years from the time of registration
description: Metastasis-free survival (MFS) rates at 2 years. Metastasis-free survival will be defined as the time from the date of registration to date of evidence of systemic disease on bone scan or cross sectional imaging or death, which occurs first.
measure: Adverse Events Encountered
time frame: At the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months
description: Safety as assessed by NCI Common Toxicity Scales (v4.0)
measure: How well participants tolerate treatment
time frame: During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months
description: Quality of life (QoL) tools to be used to determine participant tolerability of treatment will include FACT-P, European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) -C30/QLQ-PR25, and SHIM.
measure: Feasibility of achieving stated accrual
time frame: During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months
description: Compare anticipated accrual versus actual.
arm group label: SRT plus Enzalutamide
arm group type: Experimental
description: Arm 2 (experimental): (SRT) Salvage radiation therapy (Three dimensional conformal radiation therapy (3D-CRT)/IMRT [Intensity-modulated radiation therapy]) 66.6-70.2 Gy as 1.8 Gy M-F for 37-39 fx PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)
arm group label: SRT plus placebo
arm group type: Placebo Comparator
description: Arm 1 (control): Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT (Intensity-modulated radiation therapy)) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)
intervention type: Drug
intervention name: Enzalutamide
description: Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)
arm group label: SRT plus Enzalutamide
other name: XTANDI
intervention type: Radiation
intervention name: SRT
description: Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx
arm group label: SRT plus placebo
other name: Salvage Radiation Therapy
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Phuoc Tran, M.D.
role: Principal Investigator
affiliation: The SKCCC at Johns Hopkins
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Adenocarcinoma