<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/NCT02204943</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00053925</org_study_id>
    <nct_id>NCT02204943</nct_id>
  </id_info>
  <brief_title>Pharmacodynamic Study of Radium-223 in Men With Bone Metastatic Castration-Resistant Prostate Cancer</brief_title>
  <official_title>Pharmacodynamic Study of Radium-223 in Men With Bone Metastatic Castration-Resistant Prostate Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will examine biomarkers involved in osteomimicry in bone metastases and&#xD;
      circulating tumor cells (CTCs) of men with mCRPC before and during therapy with the&#xD;
      bone-targeting radiopharmaceutical radium-223. This study will also examine the&#xD;
      bio-distribution of radium-223 in bone and bone metastases of men with mCRPC.&#xD;
&#xD;
      The investigators hypothesize that bone metastases and CTCs in men with mCRPC will commonly&#xD;
      express markers of EMT/plasticity and osteomimicry, not just in the normal surrounding&#xD;
      osteoblastic stroma but in the epithelial tumor cells themselves and that radium-223 will&#xD;
      target both of these compartments including the more mesenchymal/osteoblastic tumor cells and&#xD;
      the surrounding osteoblasts in the active bone microenvironment, with a relative sparing of&#xD;
      normal bone and bone marrow.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 6, 2015</start_date>
  <completion_date type="Actual">July 31, 2017</completion_date>
  <primary_completion_date type="Actual">July 31, 2017</primary_completion_date>
  <phase>Early Phase 1</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients who overexpress alkaline phosphatase (ALP) in Circulating Tumor Cells (CTCs) at each time point</measure>
    <time_frame>Cycle 1 Day 1, Cycle 3 Day 1 and Cycle 6 Day 1 or disease progression</time_frame>
    <description>The proportion of patients who over-express ALP in the CTCs, defined as any over-expression, will be estimated using descriptive statistics at each time point. ALP expression will be concurrently examined in the bone metastatic biopsies of men as well, if evaluable tissue is available.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in biomarkers of epithelial plasticity and osteomimicry expressed in the bone metastases of men with bone metastatic CRPC</measure>
    <time_frame>At time of optional biopsy, pre- and post-treatment with Radium-223. Post-treatment biopsies will be approximately 10 and 22 weeks after first treatment.</time_frame>
    <description>Summary statistics of other biomarkers involved in epithelial plasticity and osteomimicry in the tumor tissue of men with bone metastatic CRPC including expression of ALP, PSA, CK, O-cadherin, N-cadherin, vimentin, TWIST, SNAIL, beta-catenin, ZEB1, androgen receptor (AR), AR variants (ARv) and γ-H2AX will be completed.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Bone Metastatic Castration-Resistant Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Bone Biopsy and Circulating Tumor Cell Samples</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Biomarker analysis</intervention_name>
    <description>Pharmacodynamic study of Radium-223 in bone biopsy and circulating tumor cell samples</description>
    <arm_group_label>Bone Biopsy and Circulating Tumor Cell Samples</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Administration of radium-223</intervention_name>
    <description>Subjects will receive radium-223 treatment for their disease as standard of care in this protocol. They will be receiving this treatment regardless of their participation in this protocol.</description>
    <arm_group_label>Bone Biopsy and Circulating Tumor Cell Samples</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years.&#xD;
&#xD;
          2. Life expectancy of at least 12 weeks (3 months).&#xD;
&#xD;
          3. Subjects must be able to understand and be willing to sign the written informed&#xD;
             consent form. A signed informed consent form must be appropriately obtained prior to&#xD;
             the conduct of any trial-specific procedure.&#xD;
&#xD;
          4. Histologically confirmed diagnosis of adenocarcinoma of the prostate. Histologic&#xD;
             variants of prostate cancer, including neuroendocrine features are permitted; however,&#xD;
             pure small cell carcinoma of the prostate is excluded.&#xD;
&#xD;
          5. Presence of &gt;2 sites of metastatic disease in bone as determined by bone scan or CT,&#xD;
             and for men who opt-in for bone biopsy, they must have at least one site amenable to&#xD;
             radiographically-guided metastatic biopsy as determined by the study radiologist.&#xD;
&#xD;
          6. Symptomatic castration-resistant bone metastatic disease as determined by the&#xD;
             provider.&#xD;
&#xD;
          7. Prior or concurrent therapy with either abiraterone acetate or enzalutamide.&#xD;
&#xD;
          8. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g.&#xD;
             degarelix) must continue on therapy unless prior bilateral orchiectomy has been&#xD;
             performed.&#xD;
&#xD;
          9. Current evidence of disease progression as evidenced by one of the following:&#xD;
&#xD;
               1. 2 consecutive rising PSA levels separated at least 1 week apart above nadir PSA&#xD;
                  on last systemic therapy. If no nadir, then 2 rising PSA values greater than&#xD;
                  baseline pretreatment value is required from the most immediate prior therapy, OR&#xD;
&#xD;
               2. CT or bone scan based evidence of disease progression with bone metastasis (new&#xD;
                  lesions or growth of existing lesions), OR&#xD;
&#xD;
               3. Evidence of symptomatic progression (increased pain in an area with known lesions&#xD;
                  confirmed on imaging).&#xD;
&#xD;
         10. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 2&#xD;
             or less.&#xD;
&#xD;
         11. Men of childbearing potential must agree to use adequate contraception beginning at&#xD;
             the signing of the ICF until at least 30 days after the last dose of study drug. The&#xD;
             definition of adequate contraception will be based on the judgment of the principal&#xD;
             investigator or a designated associate.&#xD;
&#xD;
         12. Acceptable hematology and serum biochemistry screening values:&#xD;
&#xD;
               -  White Blood Cell Count (WBC) ≥ 3,000/mm3&#xD;
&#xD;
               -  Absolute Neutrophil Count (ANC) ≥ 1,500/mm3&#xD;
&#xD;
               -  Platelet (PLT) count ≥ 100,000/mm3&#xD;
&#xD;
               -  Hemoglobin (HGB) ≥ 9.0 g/dl&#xD;
&#xD;
               -  Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN&#xD;
&#xD;
               -  Creatinine ≤ 1.5 x ULN&#xD;
&#xD;
               -  Albumin &gt; 2.5 g/dL&#xD;
&#xD;
         13. Willing and able to comply with the protocol, including follow-up visits and&#xD;
             examinations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Treatment with cytotoxic chemotherapy within previous 4 weeks, or failure to recover&#xD;
             from AEs down to grade 2 or less due to cytotoxic chemotherapy administered more than&#xD;
             4 weeks previous (however, ongoing neuropathy is permitted)&#xD;
&#xD;
          2. Receiving concurrent systemic therapy with radionuclides (e.g., strontium-89,&#xD;
             samarium-153, rhenium-186, or rhenium-188) for the treatment of bony metastases. Prior&#xD;
             therapy with radium-223 is not permitted.&#xD;
&#xD;
          3. Other malignancy treated within the last 3 years (except non melanoma skin cancer or&#xD;
             low-grade superficial bladder cancer)&#xD;
&#xD;
          4. Visceral (i.e. liver, lung, etc) metastases (pulmonary nodules ≤1cm are permitted) as&#xD;
             assessed by chest, abdominal or pelvic computed tomography (CT) (or other imaging&#xD;
             modality)&#xD;
&#xD;
          5. Presence of active untreated CNS parenchymal or epidural spinal metastases&#xD;
&#xD;
          6. Lymphadenopathy exceeding 3 cm in short-axis diameter&#xD;
&#xD;
          7. Imminent spinal cord compression based on clinical findings and/or magnetic resonance&#xD;
             imaging (MRI). Treatment should be completed for spinal cord compression.&#xD;
&#xD;
          8. Any other serious illness or medical condition, such as but not limited to:&#xD;
&#xD;
               -  Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse&#xD;
                  Events (NCI-CTCAE) version 4.0 Grade 2&#xD;
&#xD;
               -  Cardiac failure New York Heart Association (NYHA) III or IV&#xD;
&#xD;
               -  Crohn's disease or ulcerative colitis&#xD;
&#xD;
               -  Bone marrow dysplasia&#xD;
&#xD;
               -  Fecal incontinence&#xD;
&#xD;
          9. Inability to comply with the protocol and/or not willing or not available for&#xD;
             follow-up assessments.&#xD;
&#xD;
         10. Any condition which, in the investigator's opinion, makes the subject unsuitable for&#xD;
             trial participation.&#xD;
&#xD;
         11. Concurrent cytotoxic chemotherapy or anticancer therapies other than abiraterone,&#xD;
             prednisone or other glucocorticoids, enzalutamide, androgen deprivation therapy,&#xD;
             bisphosphonates, and denosumab.&#xD;
&#xD;
         12. Concurrent use of another investigational drug or device therapy (i.e., outside of&#xD;
             study treatment) during, or within 2 weeks of treatment initiation.&#xD;
&#xD;
         13. Major surgery within 30 days prior to start of study drug.&#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>Andrew Armstrong, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>July 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 31, 2014</study_first_posted>
  <last_update_submitted>June 7, 2018</last_update_submitted>
  <last_update_submitted_qc>June 7, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2018</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>
  <!-- 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/NCT02204943
org study id: Pro00053925
nct id: NCT02204943
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
is unapproved device: Yes
This study will examine biomarkers involved in osteomimicry in bone metastases and
      circulating tumor cells (CTCs) of men with mCRPC before and during therapy with the
      bone-targeting radiopharmaceutical radium-223. This study will also examine the
      bio-distribution of radium-223 in bone and bone metastases of men with mCRPC.

      The investigators hypothesize that bone metastases and CTCs in men with mCRPC will commonly
      express markers of EMT/plasticity and osteomimicry, not just in the normal surrounding
      osteoblastic stroma but in the epithelial tumor cells themselves and that radium-223 will
      target both of these compartments including the more mesenchymal/osteoblastic tumor cells and
      the surrounding osteoblasts in the active bone microenvironment, with a relative sparing of
      normal bone and bone marrow.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Proportion of patients who overexpress alkaline phosphatase (ALP) in Circulating Tumor Cells (CTCs) at each time point
time frame: Cycle 1 Day 1, Cycle 3 Day 1 and Cycle 6 Day 1 or disease progression
description: The proportion of patients who over-express ALP in the CTCs, defined as any over-expression, will be estimated using descriptive statistics at each time point. ALP expression will be concurrently examined in the bone metastatic biopsies of men as well, if evaluable tissue is available.
measure: Change in biomarkers of epithelial plasticity and osteomimicry expressed in the bone metastases of men with bone metastatic CRPC
time frame: At time of optional biopsy, pre- and post-treatment with Radium-223. Post-treatment biopsies will be approximately 10 and 22 weeks after first treatment.
description: Summary statistics of other biomarkers involved in epithelial plasticity and osteomimicry in the tumor tissue of men with bone metastatic CRPC including expression of ALP, PSA, CK, O-cadherin, N-cadherin, vimentin, TWIST, SNAIL, beta-catenin, ZEB1, androgen receptor (AR), AR variants (ARv) and γ-H2AX will be completed.
arm group label: Bone Biopsy and Circulating Tumor Cell Samples
arm group type: Experimental
intervention type: Device
intervention name: Biomarker analysis
description: Pharmacodynamic study of Radium-223 in bone biopsy and circulating tumor cell samples
arm group label: Bone Biopsy and Circulating Tumor Cell Samples
intervention type: Drug
intervention name: Administration of radium-223
description: Subjects will receive radium-223 treatment for their disease as standard of care in this protocol. They will be receiving this treatment regardless of their participation in this protocol.
arm group label: Bone Biopsy and Circulating Tumor Cell Samples
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrew Armstrong, MD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Prostatic Neoplasms