<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/NCT03020342</url>
  </required_header>
  <id_info>
    <org_study_id>201510056RINA</org_study_id>
    <nct_id>NCT03020342</nct_id>
  </id_info>
  <brief_title>HBV-host cfDNA as Minimal Residual Tumor Marker for HBV-related HCC</brief_title>
  <official_title>A New Biomarker for Detection of Minimal Residual Tumor in Hepatitis-B Virus Related Hepatocellular Carcinoma After Curative Therapies: The Cell-free Circulating HBV-host Chimera DNA Fragment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Early stage HCC is treated by curative surgical resection or by local ablation (such as&#xD;
      radio-frequency) as the current standard of care. The complete removal of clinical visible&#xD;
      HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or&#xD;
      PIVKA). However, despite an apparent complete removal of the HCC, those post-curative&#xD;
      patients frequently develop tumor recurrence at a rate ranging 10-50% within the first year.&#xD;
      The high rate of early HCC recurrence indicated a minimal residual HCC after the curative&#xD;
      therapies in a significant proportion of patients. A better and more specific biomarker for&#xD;
      detecting the residual HCC will improve the patients' prognosis prediction and therapeutic&#xD;
      plan.&#xD;
&#xD;
      To detect the minimal residual HCC, a biomarker unique to the tumor is needed. Currently, the&#xD;
      cell-free circulating DNA carrying tumor-specific somatic mutations has been advocated as a&#xD;
      promising one. It has been applied to investigate the tumor responses or resistances to&#xD;
      cancer therapy. However, currently it is restricted to detect or follow only large advanced&#xD;
      cancer, because of the difficulty in separating or enriching the cfDNA with tumor-specific&#xD;
      mutations from the cfDNA from normal cells. In this project, the investigators proposed that&#xD;
      one class of somatic mutation in HBV-related HCC, namely the insertion mutagenesis by&#xD;
      integrated HBV DNA, could be adopted to circumvent this difficulty. HBV DNA integration has&#xD;
      been found in the chromosomes of about 90% of HBV-related HCC and the integration site is&#xD;
      unique to individual HCC. The HBV-host junction DNA fragment from one HCC is therefore a&#xD;
      tumor-specific biomarker. Such fragments can be released into the circulation as cell-free&#xD;
      circulating DNAs, and the detection of the HBV-host chimera DNAs in the circulation is a&#xD;
      reliable evidence for the presence of the tumor in the patient. Therefore the cf circulating&#xD;
      HBV-host chimera DNA is proposed to assay any minimal residual HCC after curative therapies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Development stages:&#xD;
&#xD;
      Stage I: Identification of integrated HBV DNA sites in HBV-related HCC tissues. the&#xD;
      investigators will develop either HBV-specific inverse PCRs or capture-sequencing protocols&#xD;
      to identify HBV integrations sites in the tumor chromosomes. The viral-host junction&#xD;
      sequences of individual HCC identified and used as the template for developing assays for&#xD;
      detecting the same HBV-host chimera DNA fragment in the circulation.&#xD;
&#xD;
      Stage II: New platforms to accurately detect or even quantitate the circulating vh-chimera&#xD;
      DNA fragment.&#xD;
&#xD;
      These tumor-specific vh-chimera DNA will only represent a tiny fraction of total cfDNAs.&#xD;
      However, as these sequences of the tumor-specific vh-chimera DNA have been known from stage&#xD;
      1, the investigators may develop better and more specific assays for quantitation.&#xD;
&#xD;
      Stage III: Assays for cell-free tumor specific vh-chimera DNA applied to the blood samples&#xD;
      from post-curative HCC patients.&#xD;
&#xD;
      To demonstrate the efficacy of these assays, blood samples obtained at 4 weeks after curative&#xD;
      therapies from 50 HBV-related HCC patients, and tested for the presence of cf tumor-specific&#xD;
      vh-chimera DNAs. The presence or absence of such vh-chimera DNA will be correlated with the&#xD;
      early HCC recurrence within the first year to determine any clinical significance. There will&#xD;
      be one blood sampling at the time of HCC recurrence.&#xD;
&#xD;
      Sample collection In stage I and II, the investigators will set up methods for chimera DNA&#xD;
      identification and quantification, which need tumor samples to support the development and&#xD;
      evaluation of the feasibility for each assay. Therefore, the investigators will apply the&#xD;
      approval for use the tissues from the Taiwan Liver Cancer Network (TLCN), including 20 pairs&#xD;
      of HBV-related male HCC, 20 pairs of HBV-related female HCC (for positive control), 20 pairs&#xD;
      of HCV related male HCC, 20 pairs of HCV related female HCC (for negative control), 20 pairs&#xD;
      of HBV- and HCV-related male HCC, and 20 pairs of HBV- and HCV-related female HCC (to see if&#xD;
      vh-chimera DNA is also applicable for HBV- and HCV-related HCC). Both the genomic DNA and RNA&#xD;
      will be applied for these 120 patients in total. Genomic DNA will be used in assay&#xD;
      development, including identification, detection and quantification; whereas RNA will be used&#xD;
      in validation of the insertional mutagenic RNA transcripts, which will provide supporting&#xD;
      evidence for tumor specific integration from transcription level.&#xD;
&#xD;
      In stage III, the investigators will investigate whether there is any correlation between&#xD;
      tumor-specific vh-chimera DNA level and recurrence-free survival using the assays the&#xD;
      investigators developed in stage I and II. Therefore, the investigators will collect the&#xD;
      Tumor (T) and non-Tumor (NT) tissue pairs from 50 HBV-related HCC patients that receive&#xD;
      surgical removal of tumor, and also the peripheral blood at 4w after surgery. T and NT&#xD;
      tissues are for vh-chimera DNA identification, peripheral blood will be used for vh-chimera&#xD;
      DNA detection and quantification. On the other hand, clinical information including tumor&#xD;
      size, tumor grade, serum markers from routine liver function test (ALT, AST), current HCC&#xD;
      marker (AFP), and recurrence-free survival time will be collected for correlation study. All&#xD;
      data will be stored in computer with password protection.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2016</start_date>
  <completion_date type="Anticipated">January 2019</completion_date>
  <primary_completion_date type="Anticipated">January 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>vh-chimera DNA</measure>
    <time_frame>week 4 after surgery.</time_frame>
    <description>Detection of the HBV-host chimera DNA in blood sample.----- one blood sampling at the time of HCC recurrence.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tumor size (measured in the longest dimension in cm)</measure>
    <time_frame>after medical imaging or pathology report completion, up to 2 weeks.</time_frame>
    <description>clinical information about HCC recurrence. detection by CT or MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tumor grade (Grades I-IV)</measure>
    <time_frame>after medical imaging or pathology report completion, up to 2 weeks.</time_frame>
    <description>clinical information about HCC recurrence. detection by CT or MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>recurrence-free survival time ----measurement in weeks</measure>
    <time_frame>from the date of surgery until the date of first documented HCC recurrence or date of death from any cause, whichever came first, assessed up to 24 months</time_frame>
    <description>clinical information about HCC recurrence.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Routine liver function test (ALT in IU/L)</measure>
    <time_frame>week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.</time_frame>
    <description>serum markers.</description>
  </other_outcome>
  <other_outcome>
    <measure>Routine liver function test (AST in IU/L)</measure>
    <time_frame>week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.</time_frame>
    <description>serum markers.</description>
  </other_outcome>
  <other_outcome>
    <measure>current HCC marker (AFP ng/ml)</measure>
    <time_frame>week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.</time_frame>
    <description>serum markers.(ALT and AFP)</description>
  </other_outcome>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Carcinoma, Hepatocellular</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Tumor (T) and non-Tumor (NT) tissue, and peripheral blood.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HBV-related HCC patients that receive surgical removal of tumor.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HBV-related HCC patients that receive surgical removal of tumor.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  unsuitable for surgery.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pei-Jer Chen, MD-PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Pei-Jer Chen, MD-PhD</last_name>
    <phone>+886-2-23123456</phone>
    <phone_ext>67072</phone_ext>
    <email>peijerchen@ntu.edu.tw</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shiou-Hwei Yeh, Ph.D.</last_name>
    <phone>+886-2-23123456</phone>
    <phone_ext>66644</phone_ext>
    <email>shyeh@ntu.edu.tw</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pei-Jer Chen, MD/PhD</last_name>
      <phone>+886-2-23123456</phone>
      <phone_ext>67072</phone_ext>
      <email>peijerchen@ntu.edu.tw</email>
    </contact>
    <contact_backup>
      <last_name>Shiou-Hwei Yeh, PhD</last_name>
      <phone>+886-2-23123456</phone>
      <phone_ext>66644</phone_ext>
      <email>shyeh@ntu.edu.tw</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>June 22, 2016</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <last_update_submitted>January 11, 2017</last_update_submitted>
  <last_update_submitted_qc>January 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HCC</keyword>
  <keyword>chimera DNA</keyword>
  <keyword>circulating DNA</keyword>
  <keyword>biomarker</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    <mesh_term>Neoplasm, Residual</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03020342
org study id: 201510056RINA
nct id: NCT03020342
lead sponsor: 
has dmc: No
Early stage HCC is treated by curative surgical resection or by local ablation (such as
      radio-frequency) as the current standard of care. The complete removal of clinical visible
      HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or
      PIVKA). However, despite an apparent complete removal of the HCC, those post-curative
      patients frequently develop tumor recurrence at a rate ranging 10-50% within the first year.
      The high rate of early HCC recurrence indicated a minimal residual HCC after the curative
      therapies in a significant proportion of patients. A better and more specific biomarker for
      detecting the residual HCC will improve the patients' prognosis prediction and therapeutic
      plan.

      To detect the minimal residual HCC, a biomarker unique to the tumor is needed. Currently, the
      cell-free circulating DNA carrying tumor-specific somatic mutations has been advocated as a
      promising one. It has been applied to investigate the tumor responses or resistances to
      cancer therapy. However, currently it is restricted to detect or follow only large advanced
      cancer, because of the difficulty in separating or enriching the cfDNA with tumor-specific
      mutations from the cfDNA from normal cells. In this project, the investigators proposed that
      one class of somatic mutation in HBV-related HCC, namely the insertion mutagenesis by
      integrated HBV DNA, could be adopted to circumvent this difficulty. HBV DNA integration has
      been found in the chromosomes of about 90% of HBV-related HCC and the integration site is
      unique to individual HCC. The HBV-host junction DNA fragment from one HCC is therefore a
      tumor-specific biomarker. Such fragments can be released into the circulation as cell-free
      circulating DNAs, and the detection of the HBV-host chimera DNAs in the circulation is a
      reliable evidence for the presence of the tumor in the patient. Therefore the cf circulating
      HBV-host chimera DNA is proposed to assay any minimal residual HCC after curative therapies.
Development stages:

      Stage I: Identification of integrated HBV DNA sites in HBV-related HCC tissues. the
      investigators will develop either HBV-specific inverse PCRs or capture-sequencing protocols
      to identify HBV integrations sites in the tumor chromosomes. The viral-host junction
      sequences of individual HCC identified and used as the template for developing assays for
      detecting the same HBV-host chimera DNA fragment in the circulation.

      Stage II: New platforms to accurately detect or even quantitate the circulating vh-chimera
      DNA fragment.

      These tumor-specific vh-chimera DNA will only represent a tiny fraction of total cfDNAs.
      However, as these sequences of the tumor-specific vh-chimera DNA have been known from stage
      1, the investigators may develop better and more specific assays for quantitation.

      Stage III: Assays for cell-free tumor specific vh-chimera DNA applied to the blood samples
      from post-curative HCC patients.

      To demonstrate the efficacy of these assays, blood samples obtained at 4 weeks after curative
      therapies from 50 HBV-related HCC patients, and tested for the presence of cf tumor-specific
      vh-chimera DNAs. The presence or absence of such vh-chimera DNA will be correlated with the
      early HCC recurrence within the first year to determine any clinical significance. There will
      be one blood sampling at the time of HCC recurrence.

      Sample collection In stage I and II, the investigators will set up methods for chimera DNA
      identification and quantification, which need tumor samples to support the development and
      evaluation of the feasibility for each assay. Therefore, the investigators will apply the
      approval for use the tissues from the Taiwan Liver Cancer Network (TLCN), including 20 pairs
      of HBV-related male HCC, 20 pairs of HBV-related female HCC (for positive control), 20 pairs
      of HCV related male HCC, 20 pairs of HCV related female HCC (for negative control), 20 pairs
      of HBV- and HCV-related male HCC, and 20 pairs of HBV- and HCV-related female HCC (to see if
      vh-chimera DNA is also applicable for HBV- and HCV-related HCC). Both the genomic DNA and RNA
      will be applied for these 120 patients in total. Genomic DNA will be used in assay
      development, including identification, detection and quantification; whereas RNA will be used
      in validation of the insertional mutagenic RNA transcripts, which will provide supporting
      evidence for tumor specific integration from transcription level.

      In stage III, the investigators will investigate whether there is any correlation between
      tumor-specific vh-chimera DNA level and recurrence-free survival using the assays the
      investigators developed in stage I and II. Therefore, the investigators will collect the
      Tumor (T) and non-Tumor (NT) tissue pairs from 50 HBV-related HCC patients that receive
      surgical removal of tumor, and also the peripheral blood at 4w after surgery. T and NT
      tissues are for vh-chimera DNA identification, peripheral blood will be used for vh-chimera
      DNA detection and quantification. On the other hand, clinical information including tumor
      size, tumor grade, serum markers from routine liver function test (ALT, AST), current HCC
      marker (AFP), and recurrence-free survival time will be collected for correlation study. All
      data will be stored in computer with password protection.
observational model: Case-Only
time perspective: Prospective
measure: vh-chimera DNA
time frame: week 4 after surgery.
description: Detection of the HBV-host chimera DNA in blood sample.----- one blood sampling at the time of HCC recurrence.
measure: Tumor size (measured in the longest dimension in cm)
time frame: after medical imaging or pathology report completion, up to 2 weeks.
description: clinical information about HCC recurrence. detection by CT or MRI.
measure: tumor grade (Grades I-IV)
time frame: after medical imaging or pathology report completion, up to 2 weeks.
description: clinical information about HCC recurrence. detection by CT or MRI.
measure: recurrence-free survival time ----measurement in weeks
time frame: from the date of surgery until the date of first documented HCC recurrence or date of death from any cause, whichever came first, assessed up to 24 months
description: clinical information about HCC recurrence.
measure: Routine liver function test (ALT in IU/L)
time frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.
description: serum markers.
measure: Routine liver function test (AST in IU/L)
time frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.
description: serum markers.
measure: current HCC marker (AFP ng/ml)
time frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence.
description: serum markers.(ALT and AFP)
Tumor (T) and non-Tumor (NT) tissue, and peripheral blood.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Pei-Jer Chen, MD-PhD
role: Principal Investigator
affiliation: National Taiwan University Hospital
last name: Pei-Jer Chen, MD-PhD
phone: +886-2-23123456
phone ext: 67072
email: peijerchen@ntu.edu.tw
last name: Shiou-Hwei Yeh, Ph.D.
phone: +886-2-23123456
phone ext: 66644
email: shyeh@ntu.edu.tw
facility: 
status: Recruiting
contact: 
contact backup: 
country: Taiwan
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Neoplasm, Residual
sharing ipd: Undecided