<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/NCT03814811</url>
  </required_header>
  <id_info>
    <org_study_id>SNUH-IRB-1706069859</org_study_id>
    <nct_id>NCT03814811</nct_id>
  </id_info>
  <brief_title>Circulating Osteocalcin-positive Cells in Breast Cancer Bone Metastasis</brief_title>
  <acronym>COP-BREAST</acronym>
  <official_title>Circulating Osteocalcin-positive Cells as a Cell-Based Biomarker of Breast Cancer Bone Metastasis Progression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Center, Korea</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Seoul National University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Bone metastasis (i.e. cancer cell spreading to bone) is the major clinical problem of&#xD;
      advanced breast cancer patients. Bone metastasis is not curable nor preventable. Currently&#xD;
      available therapeutic approaches are only palliative. The major hurdle for improving bone&#xD;
      metastasis treatment is lack of sensitive diagnostic tools. Diagnosis of bone metastasis is&#xD;
      heavily dependent on radiographic imaging of bone destruction that are detectable only when&#xD;
      the lesion is significantly large. Accordingly, if bone metastasis can be detected at an&#xD;
      earlier time point when bone destruction is minimal or incipient, treatments can be given&#xD;
      earlier and the patients can expect better outcomes. We and others previously have found that&#xD;
      a subset of bone-forming cells (i.e. circulating osteocalcin-positive cells) exists in the&#xD;
      blood stream of the patients with bone diseases (e.g. bone metastasis and inflammation) or&#xD;
      active bone formation (e.g. adolescence) in mouse models anf human samples. Extended from&#xD;
      this laboratory observation, this clinical study proposes to test the hypothesis that&#xD;
      circulating osteocalcin-positive cells are the early biomarker of breast cancer bone&#xD;
      metastasis. For this aim, this study will measure circulating osteocalcin-positive cells in&#xD;
      the blood samples of breast cancer patient, and examine whether the measure sensitively&#xD;
      detects bone metastasis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Bone is the most common site of breast cancer metastasis, and the skeletal-related events&#xD;
      (SRE) of bone metastasis such as pathologic fractures, cord compression, hypercalcemia and&#xD;
      severe pain, accounting for poor quality of life in the terminal stage of the afflicted&#xD;
      patients. Since previous SREs are the major risk factors for subsequent SREs related to&#xD;
      serious morbidity and mortality, the early detection of bone metastasis prior to clinical&#xD;
      symptoms is essential to the better management of breast cancer patients. Currently,&#xD;
      diagnosis of bone metastasis is dependent on imaging modalities such as whole-body bone&#xD;
      scintigraphy (WBBS). However, detectability of radionuclide activity in the WBBS depends on&#xD;
      gross structural bone destruction resulting from considerable progression of&#xD;
      macro-metastasis.&#xD;
&#xD;
      Circulating osteoprogenitor cells that is defined a small monocytic cells expressing&#xD;
      osteocalcin, a late osteoblast differentiation marker, had been identified in human&#xD;
      peripheral blood mononuclear cells (PBMCs). Flow cytometric analyses of the PBMCs using&#xD;
      anti-osteocalcin antibody demonstrated that adolescents who are in the period of rapid bone&#xD;
      growth showed higher fractions of osteocalcin-positive cells than adults. Moreover, these&#xD;
      cells also positively correlated with pathologic changes of bone turnover in such conditions&#xD;
      as fracture, hypoparathyroidism, or diabetes. Collectively, circulating osteoprogenitor cells&#xD;
      reflects changes of bone turnover in either physiologic or pathologic status.&#xD;
&#xD;
      The scientific hypothesis of this study is that circulating osteoprogenitor cells increases&#xD;
      in the early phase of bone micro-metastasis, and the aim of this clinical study is to&#xD;
      investigate the difference of circulating osteoprogenitor cells in metastatic breast cancer&#xD;
      with or without bone metastasis. This study will also examine whether the patients who have&#xD;
      higher number of osteocalcin-positive cells develop bone metastasis at an earlier time point,&#xD;
      to validate the value of circulating osteoprogenitor cells in monitoring and/or predictinng&#xD;
      the progression of bone metastasis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">September 30, 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Progression of bone metastasis</measure>
    <time_frame>18 months after enrollment</time_frame>
    <description>Metastatic bone lesions will be re-evaluated at 18 months using imaging studies such as bone scan, CT, MRI, or PET or incidence of active skeletal-related events (SREs) such as pathologic fracture or progressive neurologic signs</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Diagnosis of new bone metastasis</measure>
    <time_frame>18 months after enrollment</time_frame>
    <description>De novo bone metastasis will be diagnosed using imaging studies</description>
  </primary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Breast Neoplasms</condition>
  <condition>Bone Metastases</condition>
  <arm_group>
    <arm_group_label>Bone metastasis(+) with low cOC</arm_group_label>
    <description>Patients who have bone metastasis with low number of circulating osteocalcin-positive (cOC) cells</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bone metastasis(+) with high cOC</arm_group_label>
    <description>Patients who have bone metastasis with high number of circulating osteocalcin-positive (cOC) cells</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bone metastasis(-) with low cOC</arm_group_label>
    <description>Patients who have metastasis only in extraskeletal sites with low number of circulating osteocalcin-positive (cOC) cells</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bone metastasis(-) with high cOC</arm_group_label>
    <description>Patients who have metastasis only in extraskeletal sites with high number of circulating osteocalcin-positive (cOC) cells</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Circulating Osteocalcin-positive (cOC) cells</intervention_name>
    <description>Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry</description>
    <arm_group_label>Bone metastasis(+) with high cOC</arm_group_label>
    <arm_group_label>Bone metastasis(+) with low cOC</arm_group_label>
    <arm_group_label>Bone metastasis(-) with high cOC</arm_group_label>
    <arm_group_label>Bone metastasis(-) with low cOC</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        -  Patients in Seoul National University Hospital or Korea University Anam Hospital,&#xD;
             Seoul, Korea&#xD;
&#xD;
          -  Residents of the Republic of Korea&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stages 2A-4 breast cancer patients who are subject to adjuvant chemotherapy or&#xD;
             radiotherapy&#xD;
&#xD;
          -  20 years of age or greater&#xD;
&#xD;
          -  Female&#xD;
&#xD;
          -  Ability to understand the study objectives and willingness to sign written consent&#xD;
&#xD;
          -  ECOG status 0, 1 or 2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of primary cancer diagnosis in other sites than breast within 5 years&#xD;
&#xD;
          -  Diseases of bone metabolism including primary hyperparathyroidism, Paget's disease,&#xD;
             osteomalacia, osteogenesis imperfecta&#xD;
&#xD;
          -  ECOG status 3 or 4&#xD;
&#xD;
          -  Retraction of written consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Only females are eligible.</gender_description>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sun Wook Cho, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seoul National University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sun Wook Cho, M.D., Ph.D.</last_name>
    <phone>+82-2-2072-4761</phone>
    <email>swchomd@snu.ac.kr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Young Shin Song, M.D., Ph.D.</last_name>
    <phone>+82-2-2072-4761</phone>
    <email>yssongmd@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Korea University Anam Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>02841</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kyung Hwa Park, M.D., Ph.D.</last_name>
      <phone>+82-2-920-6841</phone>
      <email>katyoncopark@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sun Wook Cho, M.D., Ph.D.</last_name>
      <phone>+82-2-2072-4761</phone>
      <email>swchomd@snu.ac.kr</email>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Jeong HM, Cho SW, Park SI. Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment. Endocrinol Metab (Seoul). 2016 Dec;31(4):485-492. doi: 10.3803/EnM.2016.31.4.485.</citation>
    <PMID>28029019</PMID>
  </reference>
  <reference>
    <citation>Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med. 2005 May 12;352(19):1959-66. doi: 10.1056/NEJMoa044264.</citation>
    <PMID>15888696</PMID>
  </reference>
  <reference>
    <citation>Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar;9(3):162-74. doi: 10.1038/nri2506.</citation>
    <PMID>19197294</PMID>
  </reference>
  <reference>
    <citation>Manavalan JS, Cremers S, Dempster DW, Zhou H, Dworakowski E, Kode A, Kousteni S, Rubin MR. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012 Sep;97(9):3240-50. doi: 10.1210/jc.2012-1546. Epub 2012 Jun 27.</citation>
    <PMID>22740707</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 21, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>January 21, 2019</last_update_submitted>
  <last_update_submitted_qc>January 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 24, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <keyword>Bone</keyword>
  <keyword>Metastasis</keyword>
  <keyword>Osteoblast</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Bone Neoplasms</mesh_term>
    <mesh_term>Bone Marrow Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03814811
org study id: SNUH-IRB-1706069859
nct id: NCT03814811
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Bone metastasis (i.e. cancer cell spreading to bone) is the major clinical problem of
      advanced breast cancer patients. Bone metastasis is not curable nor preventable. Currently
      available therapeutic approaches are only palliative. The major hurdle for improving bone
      metastasis treatment is lack of sensitive diagnostic tools. Diagnosis of bone metastasis is
      heavily dependent on radiographic imaging of bone destruction that are detectable only when
      the lesion is significantly large. Accordingly, if bone metastasis can be detected at an
      earlier time point when bone destruction is minimal or incipient, treatments can be given
      earlier and the patients can expect better outcomes. We and others previously have found that
      a subset of bone-forming cells (i.e. circulating osteocalcin-positive cells) exists in the
      blood stream of the patients with bone diseases (e.g. bone metastasis and inflammation) or
      active bone formation (e.g. adolescence) in mouse models anf human samples. Extended from
      this laboratory observation, this clinical study proposes to test the hypothesis that
      circulating osteocalcin-positive cells are the early biomarker of breast cancer bone
      metastasis. For this aim, this study will measure circulating osteocalcin-positive cells in
      the blood samples of breast cancer patient, and examine whether the measure sensitively
      detects bone metastasis.
Bone is the most common site of breast cancer metastasis, and the skeletal-related events
      (SRE) of bone metastasis such as pathologic fractures, cord compression, hypercalcemia and
      severe pain, accounting for poor quality of life in the terminal stage of the afflicted
      patients. Since previous SREs are the major risk factors for subsequent SREs related to
      serious morbidity and mortality, the early detection of bone metastasis prior to clinical
      symptoms is essential to the better management of breast cancer patients. Currently,
      diagnosis of bone metastasis is dependent on imaging modalities such as whole-body bone
      scintigraphy (WBBS). However, detectability of radionuclide activity in the WBBS depends on
      gross structural bone destruction resulting from considerable progression of
      macro-metastasis.

      Circulating osteoprogenitor cells that is defined a small monocytic cells expressing
      osteocalcin, a late osteoblast differentiation marker, had been identified in human
      peripheral blood mononuclear cells (PBMCs). Flow cytometric analyses of the PBMCs using
      anti-osteocalcin antibody demonstrated that adolescents who are in the period of rapid bone
      growth showed higher fractions of osteocalcin-positive cells than adults. Moreover, these
      cells also positively correlated with pathologic changes of bone turnover in such conditions
      as fracture, hypoparathyroidism, or diabetes. Collectively, circulating osteoprogenitor cells
      reflects changes of bone turnover in either physiologic or pathologic status.

      The scientific hypothesis of this study is that circulating osteoprogenitor cells increases
      in the early phase of bone micro-metastasis, and the aim of this clinical study is to
      investigate the difference of circulating osteoprogenitor cells in metastatic breast cancer
      with or without bone metastasis. This study will also examine whether the patients who have
      higher number of osteocalcin-positive cells develop bone metastasis at an earlier time point,
      to validate the value of circulating osteoprogenitor cells in monitoring and/or predictinng
      the progression of bone metastasis.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Progression of bone metastasis
time frame: 18 months after enrollment
description: Metastatic bone lesions will be re-evaluated at 18 months using imaging studies such as bone scan, CT, MRI, or PET or incidence of active skeletal-related events (SREs) such as pathologic fracture or progressive neurologic signs
measure: Diagnosis of new bone metastasis
time frame: 18 months after enrollment
description: De novo bone metastasis will be diagnosed using imaging studies
arm group label: Bone metastasis(+) with low cOC
description: Patients who have bone metastasis with low number of circulating osteocalcin-positive (cOC) cells
arm group label: Bone metastasis(+) with high cOC
description: Patients who have bone metastasis with high number of circulating osteocalcin-positive (cOC) cells
arm group label: Bone metastasis(-) with low cOC
description: Patients who have metastasis only in extraskeletal sites with low number of circulating osteocalcin-positive (cOC) cells
arm group label: Bone metastasis(-) with high cOC
description: Patients who have metastasis only in extraskeletal sites with high number of circulating osteocalcin-positive (cOC) cells
intervention type: Diagnostic Test
intervention name: Circulating Osteocalcin-positive (cOC) cells
description: Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry
arm group label: Bone metastasis(+) with high cOC
arm group label: Bone metastasis(+) with low cOC
arm group label: Bone metastasis(-) with high cOC
arm group label: Bone metastasis(-) with low cOC
Blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
gender description: Only females are eligible.
minimum age: 20 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Sun Wook Cho, M.D., Ph.D.
role: Principal Investigator
affiliation: Seoul National University Hospital
last name: Sun Wook Cho, M.D., Ph.D.
phone: +82-2-2072-4761
email: swchomd@snu.ac.kr
last name: Young Shin Song, M.D., Ph.D.
phone: +82-2-2072-4761
email: yssongmd@gmail.com
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Korea, Republic of
citation: Jeong HM, Cho SW, Park SI. Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment. Endocrinol Metab (Seoul). 2016 Dec;31(4):485-492. doi: 10.3803/EnM.2016.31.4.485.
PMID: 28029019
citation: Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med. 2005 May 12;352(19):1959-66. doi: 10.1056/NEJMoa044264.
PMID: 15888696
citation: Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar;9(3):162-74. doi: 10.1038/nri2506.
PMID: 19197294
citation: Manavalan JS, Cremers S, Dempster DW, Zhou H, Dworakowski E, Kode A, Kousteni S, Rubin MR. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012 Sep;97(9):3240-50. doi: 10.1210/jc.2012-1546. Epub 2012 Jun 27.
PMID: 22740707
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Bone Neoplasms
mesh term: Bone Marrow Diseases
sharing ipd: No