<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/NCT03002220</url>
  </required_header>
  <id_info>
    <org_study_id>MedOPP098</org_study_id>
    <secondary_id>2016-001888-36</secondary_id>
    <nct_id>NCT03002220</nct_id>
  </id_info>
  <brief_title>Trial of Rad-223 Activity in Asymptomatic Patients With mCRPC While on Abiraterone or Enzalutamide Besides AR-V7 Status</brief_title>
  <official_title>A Phase II Clinical Trial of Radium-223 Activity in Patients With Metastatic Castration-resistant Prostate Cancer (mCRPC) With Asymptomatic Progression While on Abiraterone Acetate or Enzalutamide Besides AR-V7 Mutational Status</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MedSIR</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>MedSIR</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Radium-223 is indicated for the treatment of patients with mCRPC with symptomatic bone&#xD;
      metastases and no known visceral metastatic disease. However, very few data have been&#xD;
      reported in patients with mCRPC who are asymptomatic or mildly symptomatic. Recently, results&#xD;
      from an International Expanded Access Program have also suggested a benefit of radium-223 in&#xD;
      asymptomatic patients with mCRPC. In addition, the mechanism of action of radium-223 should&#xD;
      not be correlated with the presence/absence of the AR-V7 mutation, although this issue has&#xD;
      not yet been evaluated.&#xD;
&#xD;
      The aim of this study is to assess the efficacy of radium-223 in asymptomatic patients with&#xD;
      mCRPC, and to establish the association between AR-V7 status and radium-223 activity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary objective:&#xD;
&#xD;
      To assess the efficacy of radium-223 in asymptomatic patients with mCRPC who have progressed&#xD;
      while on abiraterone acetate or enzalutamide treatment.&#xD;
&#xD;
      Primary endpoint:&#xD;
&#xD;
      To determine the efficacy of radium-223 in terms of radiological rPFS.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        -  Safety profile.&#xD;
&#xD;
        -  To determine the association between AR-V7 status (positive vs. negative) and PFS.&#xD;
&#xD;
        -  To establish the relationship between CTCs number with radium-223 efficacy.&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
      Safety AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE)&#xD;
      of the US National Cancer Institute (NCI) version 4.0 [20]. Grade 3 or 4 AEs and serious&#xD;
      adverse events (SAEs) will be assessed to determine the safety and tolerability of the&#xD;
      various combinations of drugs.&#xD;
&#xD;
      Efficacy&#xD;
&#xD;
        -  Radiographic progression-free survival (rPFS) depending on AR-V7 status.&#xD;
&#xD;
        -  Overall survival (OS).&#xD;
&#xD;
        -  Time to first symptomatic skeletal event (SSE).&#xD;
&#xD;
        -  Time to PSA progression according to the ALSYMPCA study criteria.&#xD;
&#xD;
        -  Determination percentage of PSA progression.&#xD;
&#xD;
        -  Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level,&#xD;
           according to the ALSYMPCA study criteria.&#xD;
&#xD;
      Molecular aspects&#xD;
&#xD;
        -  Assessment of AR-V7 mutation evolution during the study treatment.&#xD;
&#xD;
        -  Determination changes in CTCs number during the study treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <primary_completion_date type="Actual">May 6, 2020</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assess the efficacy of radium-223 in terms of radiological rPFS</measure>
    <time_frame>From date of first drug administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months</time_frame>
    <description>The primary efficacy endpoint is the median PFS achieved with radium-223 treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability</measure>
    <time_frame>Starting from the first procedure required by the study up to three months after study discontinuation.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic progression-free survival (rPFS) depending on AR-V7 status.</measure>
    <time_frame>From date of inclusion until Radiographic progression, assessed up to 20 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS).</measure>
    <time_frame>From date of inclusion until death from any cause or the last date the patient was known to be alive, assessed up to 20 months.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first symptomatic skeletal event (SSE).</measure>
    <time_frame>From date of first drug administration until SSE, assessed up to 20 months</time_frame>
    <description>Time to first SSE defined as the time from treatment initiation until SSE (pathological fractures, vertebral or non-vertebral, spinal cord compression, radiation or surgery to bone). For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to PSA progression according to the ALSYMPCA study criteria.</measure>
    <time_frame>From date of first study drug administration to when PSA progression is observed, assessed up to 20 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination percentage of PSA progression</measure>
    <time_frame>From date of first study drug administration to when PSA progression is observed, assessed up to 20 months</time_frame>
    <description>PSA progression (defined as PSA elevation ≥ 25% and ≥ 2 ng/mL after 12 weeks).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level</measure>
    <time_frame>From date of first study drug administration until End of Treatment, assessed up to 6 months</time_frame>
    <description>Progression defined as FA elevation ≥ 25% after 12 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of AR-V7 mutation evolution</measure>
    <time_frame>From date of first study drug administration until End of Treatment, assessed up to 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination changes in CTCs number</measure>
    <time_frame>From date of first study drug administration until End of Treatment, assessed up to 6 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>open-label</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient will be treated with radium-223 at a dose of 55 kBq (after 2015 NIST implementation) per kilogram body weight, given at four-week intervals for six intravenous injections.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>radium-223</intervention_name>
    <description>Radium-223 at a dose of 55 kBq</description>
    <arm_group_label>open-label</arm_group_label>
    <other_name>Xofigo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject is an adult ≥ 18 years at the time of informed consent and has signed informed&#xD;
             consent before any trial related activities and according to local guidelines.&#xD;
&#xD;
          -  Subject has histologically confirmed adenocarcinoma of the prostate without&#xD;
             neuroendocrine differentiation or small cell features.&#xD;
&#xD;
          -  Subject has bone metastases due to the prostate cancer and absence of visceral&#xD;
             metastases.&#xD;
&#xD;
          -  Subject has a serum testosterone of ≤ 1.7 nmol/L (or ≤ 50 ng/dL) at screening.&#xD;
&#xD;
          -  Subject must have received a minimum of 24 weeks of treatment with abiraterone acetate&#xD;
             or enzalutamide within its approved label indication and has discontinued use at least&#xD;
             four weeks prior to start of study drug at day 1.&#xD;
&#xD;
          -  Prior use of docetaxel is allowed in castration-naïve patients (maximum of six&#xD;
             cycles).&#xD;
&#xD;
          -  Subject receives and will continue to receive ongoing androgen deprivation with LHRH&#xD;
             analogue therapy throughout the course of the study or has had a bilateral&#xD;
             orchiectomy.&#xD;
&#xD;
          -  Subject is asymptomatic from prostate cancer, defined as patients with the score on&#xD;
             brief pain inventory (short form) (BPI-SF) Question #3 must zero and no use of opiate&#xD;
             analgesics for prostate cancer-related pain currently or anytime within two weeks&#xD;
             prior to screening.&#xD;
&#xD;
          -  Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at&#xD;
             screening.&#xD;
&#xD;
          -  Subject receiving bisphosphonate or other approved bone-targeting therapy must have&#xD;
             been on stable doses for at least four weeks prior to start of study drug at day 1.&#xD;
&#xD;
          -  Subject has a life expectancy of more than or equal to 12 months.&#xD;
&#xD;
          -  Subject agrees not to participate in another interventional study while on study drug.&#xD;
&#xD;
          -  Subject and his female partner who is of childbearing potential must use two&#xD;
             acceptable methods of birth control (one of which must include a condom as a barrier&#xD;
             method of contraception) starting at screening and continuing throughout the study&#xD;
             period and for six months after final study drug administration.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has received any anti-neoplastic therapy (including ketokonazol and&#xD;
             chemotherapy) following abiraterone acetate or enzalutamide discontinuation and prior&#xD;
             to start of study drug at day 1.&#xD;
&#xD;
          -  Subject has known or suspected brain metastases or active leptomeningeal disease.&#xD;
&#xD;
          -  Subject has concurrent disease or any clinically significant abnormality following the&#xD;
             investigator's review of the physical examination and safety laboratory tests at&#xD;
             screening, which in the judgment of the investigator would interfere with the&#xD;
             subject's participation in this study or evaluation of study results.&#xD;
&#xD;
          -  Subject has a history of another invasive cancer within three years prior to&#xD;
             screening, with the exceptions of non-melanoma skin cancers or a non-infiltrating&#xD;
             muscle bladder cancer that have a remote probability of recurrence in the opinion of&#xD;
             the investigator in consultation with the medical monitor.&#xD;
&#xD;
          -  Subject had major surgery within one month prior to screening.&#xD;
&#xD;
          -  Subject has received investigational therapy within 28 days or 5 half lives, whichever&#xD;
             is longer, prior to start of study drug at day 1.&#xD;
&#xD;
          -  Subject has absolute neutrophil count &lt; 1,500/μL, platelet count &lt; 100,000/μL, and&#xD;
             hemoglobin &lt; 6.25 mmol/L (or &lt; 10 g/dL) at screening (Note: Subjects must not have&#xD;
             received any growth factors or blood transfusions within seven days of the hematologic&#xD;
             laboratory values obtained at screening).&#xD;
&#xD;
          -  Subject has total bilirubin &gt; 1.5 times the upper limit of normal (ULN) at screening,&#xD;
             except for subjects with documented Gilbert's syndrome.&#xD;
&#xD;
          -  Subject has creatinine &gt; 2.5 mg/dL at screening.&#xD;
&#xD;
          -  Subject has albumin ≤ 30 g/L (or ≤ 3.0 g/dL) at screening.&#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>Joan Carles Galcerán</last_name>
    <role>Study Director</role>
    <affiliation>H. Vall Hebrón</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>MedSIR Investigative site</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedSIR Investigative site</name>
      <address>
        <city>Cáceres</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedSIR Investigative site</name>
      <address>
        <city>Córdoba</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedSIR Investigative site</name>
      <address>
        <city>Lugo</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedSIR Investigative site</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedSIR investigative site</name>
      <address>
        <city>Palma De Mallorca</city>
        <zip>07120</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>October 20, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>November 25, 2020</last_update_submitted>
  <last_update_submitted_qc>November 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>March 30, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03002220
org study id: MedOPP098
secondary id: 2016-001888-36
nct id: NCT03002220
lead sponsor: 
collaborator: 
has dmc: No
Radium-223 is indicated for the treatment of patients with mCRPC with symptomatic bone
      metastases and no known visceral metastatic disease. However, very few data have been
      reported in patients with mCRPC who are asymptomatic or mildly symptomatic. Recently, results
      from an International Expanded Access Program have also suggested a benefit of radium-223 in
      asymptomatic patients with mCRPC. In addition, the mechanism of action of radium-223 should
      not be correlated with the presence/absence of the AR-V7 mutation, although this issue has
      not yet been evaluated.

      The aim of this study is to assess the efficacy of radium-223 in asymptomatic patients with
      mCRPC, and to establish the association between AR-V7 status and radium-223 activity.
Primary objective:

      To assess the efficacy of radium-223 in asymptomatic patients with mCRPC who have progressed
      while on abiraterone acetate or enzalutamide treatment.

      Primary endpoint:

      To determine the efficacy of radium-223 in terms of radiological rPFS.

      Secondary objectives:

        -  Safety profile.

        -  To determine the association between AR-V7 status (positive vs. negative) and PFS.

        -  To establish the relationship between CTCs number with radium-223 efficacy.

      Secondary endpoints:

      Safety AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE)
      of the US National Cancer Institute (NCI) version 4.0 [20]. Grade 3 or 4 AEs and serious
      adverse events (SAEs) will be assessed to determine the safety and tolerability of the
      various combinations of drugs.

      Efficacy

        -  Radiographic progression-free survival (rPFS) depending on AR-V7 status.

        -  Overall survival (OS).

        -  Time to first symptomatic skeletal event (SSE).

        -  Time to PSA progression according to the ALSYMPCA study criteria.

        -  Determination percentage of PSA progression.

        -  Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level,
           according to the ALSYMPCA study criteria.

      Molecular aspects

        -  Assessment of AR-V7 mutation evolution during the study treatment.

        -  Determination changes in CTCs number during the study treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Assess the efficacy of radium-223 in terms of radiological rPFS
time frame: From date of first drug administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months
description: The primary efficacy endpoint is the median PFS achieved with radium-223 treatment
measure: AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability
time frame: Starting from the first procedure required by the study up to three months after study discontinuation.
measure: Radiographic progression-free survival (rPFS) depending on AR-V7 status.
time frame: From date of inclusion until Radiographic progression, assessed up to 20 months
measure: Overall survival (OS).
time frame: From date of inclusion until death from any cause or the last date the patient was known to be alive, assessed up to 20 months.
measure: Time to first symptomatic skeletal event (SSE).
time frame: From date of first drug administration until SSE, assessed up to 20 months
description: Time to first SSE defined as the time from treatment initiation until SSE (pathological fractures, vertebral or non-vertebral, spinal cord compression, radiation or surgery to bone). For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.
measure: Time to PSA progression according to the ALSYMPCA study criteria.
time frame: From date of first study drug administration to when PSA progression is observed, assessed up to 20 months
measure: Determination percentage of PSA progression
time frame: From date of first study drug administration to when PSA progression is observed, assessed up to 20 months
description: PSA progression (defined as PSA elevation ≥ 25% and ≥ 2 ng/mL after 12 weeks).
measure: Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level
time frame: From date of first study drug administration until End of Treatment, assessed up to 6 months
description: Progression defined as FA elevation ≥ 25% after 12 weeks
measure: Assessment of AR-V7 mutation evolution
time frame: From date of first study drug administration until End of Treatment, assessed up to 6 months
measure: Determination changes in CTCs number
time frame: From date of first study drug administration until End of Treatment, assessed up to 6 months
arm group label: open-label
arm group type: Experimental
description: Patient will be treated with radium-223 at a dose of 55 kBq (after 2015 NIST implementation) per kilogram body weight, given at four-week intervals for six intravenous injections.
intervention type: Drug
intervention name: radium-223
description: Radium-223 at a dose of 55 kBq
arm group label: open-label
other name: Xofigo
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joan Carles Galcerán
role: Study Director
affiliation: H. Vall Hebrón
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
sharing ipd: No
submitted: March 30, 2023