<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/NCT03839706</url>
  </required_header>
  <id_info>
    <org_study_id>17-6065</org_study_id>
    <nct_id>NCT03839706</nct_id>
  </id_info>
  <brief_title>Relationship Between 18FDG PET/MRI Patterns and ctDNA to Predict HCC Recurrence After Liver Transplantation</brief_title>
  <acronym>PETMRIinHCC</acronym>
  <official_title>Relationship Between 18F-Fluorodeoxyglucose Positron Emission Tomography Magnetic Resonance Imaging Patterns and Circulating Tumor DNA to Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation (PET MRI in HCC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</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>
      Liver transplantation is the standard treatment for patients with early-stage Hepatocellular&#xD;
      Carcinoma (HCC). Currently, important treatment decisions, like the selection of patients for&#xD;
      transplantation, are made on crude, static tumour characteristics such as the size and number&#xD;
      of lesions that do not reflect other aspects of tumour biology. To date, pre-transplantation&#xD;
      percutaneous biopsy is the best strategy to assess tumoral differentiation and, consequently,&#xD;
      tumor biological behavior. Previous studies have demonstrated that 18F-Fluorodeoxyglucose&#xD;
      Positron Emission Tomography Magnetic Resonance Imaging (18F-FDG PET/MRI) may have role in&#xD;
      assessing the HCC tumoral differentiation and predict survival after LT. The Investigators&#xD;
      will assess the accuracy of 18F-FDG PET/MRI as a tool to predict HCC recurrence after liver&#xD;
      transplant. To understand the role of 18F-FDG PET/MRI in prediction of HCC's biological&#xD;
      behavior and upon recurrence, the investigators will try to assess whether the findings in&#xD;
      18F-FDG PET/MRI can predict HCC poor tumoral differentiation, if the findings in 18F-FDG&#xD;
      PET/MRI are related to presence of circulating tumoral DNA in plasma and try to determine the&#xD;
      role of 18F-FDG PET/MRI in predicting HCC recurrence after resection. These findings may&#xD;
      impact the selection criteria for liver transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hepatocellular Carcinoma (HCC) is the third leading cause of death by cancer worldwide, being&#xD;
      responsible for nearly 700,000 deaths in 2012. Liver transplantation (LT) provides the best&#xD;
      results as a curative treatment for patients with early-stage HCC. Other curative treatment&#xD;
      strategies for early stages HCC include resection and ablation. However, the recurrence rates&#xD;
      are higher than LT. Due to organ shortage, better criteria for recipient selection are&#xD;
      necessary. The first widely accepted criteria for graft allocation in HCC patients is the&#xD;
      so-called Milan Criteria (MC): single HCC nodule ≤ 5 cm or 3 nodules all ≤ 3 cm, achieving a&#xD;
      4-y survival of 85%. Recently, MC is seen as too restrictive, its inclusion preventing&#xD;
      patients who might have better survival following LT when compared to other therapies.&#xD;
      Reluctant to have sizing-only criteria, the University of Toronto, since 2004, has applied&#xD;
      the so-called Extended Toronto Criteria (ETC) to LT, which offers transplant to patients with&#xD;
      any size and any number of tumors provide they do not have systemic cancer-related symptoms,&#xD;
      extrahepatic disease, vascular invasion or poorly differentiated tumors. A recent prospective&#xD;
      study conducted at University Health Network (UHN) has shown 5-years survival rates of 68%&#xD;
      when ECT are applied. Recent studies have demonstrated the need to use, besides the lesion&#xD;
      size, variables which can predict the biological behavior of the tumor.&#xD;
&#xD;
      Currently, important treatment decisions, like the selection of patients for transplantation,&#xD;
      are made on crude, static tumour characteristics such as the size and number of lesions, but&#xD;
      do not reflect other aspects of tumour biology. To date, pre-transplantation percutaneous&#xD;
      biopsy is the best strategy to assess tumor differentiation and, consequently, tumor&#xD;
      biological behavior. However, HCC is a very complex disease. Microscopic and molecular&#xD;
      analyses have demonstrated a highly heterogeneous degree of cell differentiation. Patients&#xD;
      with more than one tumor may have two or three degrees of cell differentiation between the&#xD;
      tumors. Even within a single HCC nodule, more than one clonal mutations can be present. To&#xD;
      date, there is not a precise method to determinate the degree of differentiation of each&#xD;
      patient's disease and percutaneous core biopsy, an invasive method, is the best estimative&#xD;
      the investigators can reach.&#xD;
&#xD;
      Since it is impossible to precisely determine the degree of differentiation of HCC with one&#xD;
      single tissue sample, the use of imaging becomes necessary. Magnetic resonance imaging (MRI)&#xD;
      and enhanced computed tomography (CT) are extensively validated as staging methods for HCC.&#xD;
      The use of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Magnetic Resonance&#xD;
      Imaging (PET/MRI) is still underevaluated in the field of HCC. However, previous studies have&#xD;
      demonstrated that 18F-FDG PET/CT may have role in assessing the HCC tumoral differentiation&#xD;
      and predict survival after LT. There is no investigation on use of 18F-FDG PET/MRI as a tool&#xD;
      to predict biological behavior in HCC.&#xD;
&#xD;
      Recently, the Pugh Lab has developed a circulating tumor DNA (ctDNA) sequencing assay that&#xD;
      combines a hybrid-capture method with a novel bioinformatics algorithm to enable full-length&#xD;
      sequence analysis of all exons in genes of interest or any other arbitrary genomic region,&#xD;
      rather than mutation hotspots13. With the availability of these technologies in our group,&#xD;
      the investigators next sought to determine whether these methods were applicable to HCC&#xD;
      patients, gathering two innovative tools in transplant patients' care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 22, 2018</start_date>
  <completion_date type="Anticipated">April 2023</completion_date>
  <primary_completion_date type="Actual">July 30, 2022</primary_completion_date>
  <phase>N/A</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>18F-FDG PET/MRI results can identify aggressive HCC behavior and recurrence post transplant</measure>
    <time_frame>3 years</time_frame>
    <description>PET scan results will be compared with pathology at the time of transplant. Patients will be followed-up 2 years post transplant for recurrence. PET scan results will be compared for Recurrent/non-recurrent patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>18F-FDG PET/MRI can predict HCC's poor tumoral differentiation</measure>
    <time_frame>3 years</time_frame>
    <description>PET/MRI reports will be compared with pathology at the time of transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>18F-FDG PET/MRI are related to presence of circulating tumor DNA in plasma</measure>
    <time_frame>3 years</time_frame>
    <description>18F-FDG PET/MRI scan results will be compared with levels of ctDNA identified in plasma</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>PET MRI Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient enrolled in the study will have a PET MRI exam scheduled before transplant</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>PET MRI</intervention_name>
    <description>18F-Fluorodeoxyglucose Positron Emission Tomography combined with Primovist MRI</description>
    <arm_group_label>PET MRI Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological or radiological diagnosis of HCC (AASLD guidelines)&#xD;
&#xD;
          -  Listed for LT at UHN&#xD;
&#xD;
          -  Enrolled in ctDNA study (15-5925)&#xD;
&#xD;
          -  Able to undergo PET and MRI examination,&#xD;
&#xD;
          -  Willingness and ability of patient to provide signed voluntary informed consent.&#xD;
&#xD;
          -  Adults (age ≥ 18-years old)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any contraindication to undergoing venipuncture.&#xD;
&#xD;
          -  Patients with previous history of cancer diagnosed and/or treated within last 5 years,&#xD;
             with the exception of non-melanomatous skin cancers and intraepithelial cancers such&#xD;
             as cervical intraepithelial neoplasia that were properly treated, are not eligible.&#xD;
&#xD;
          -  Inability to lie supine for at least 30 minutes.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2N2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 12, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>October 31, 2022</last_update_submitted>
  <last_update_submitted_qc>October 31, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 1, 2022</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    <mesh_term>Recurrence</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/NCT03839706
org study id: 17-6065
nct id: NCT03839706
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Liver transplantation is the standard treatment for patients with early-stage Hepatocellular
      Carcinoma (HCC). Currently, important treatment decisions, like the selection of patients for
      transplantation, are made on crude, static tumour characteristics such as the size and number
      of lesions that do not reflect other aspects of tumour biology. To date, pre-transplantation
      percutaneous biopsy is the best strategy to assess tumoral differentiation and, consequently,
      tumor biological behavior. Previous studies have demonstrated that 18F-Fluorodeoxyglucose
      Positron Emission Tomography Magnetic Resonance Imaging (18F-FDG PET/MRI) may have role in
      assessing the HCC tumoral differentiation and predict survival after LT. The Investigators
      will assess the accuracy of 18F-FDG PET/MRI as a tool to predict HCC recurrence after liver
      transplant. To understand the role of 18F-FDG PET/MRI in prediction of HCC's biological
      behavior and upon recurrence, the investigators will try to assess whether the findings in
      18F-FDG PET/MRI can predict HCC poor tumoral differentiation, if the findings in 18F-FDG
      PET/MRI are related to presence of circulating tumoral DNA in plasma and try to determine the
      role of 18F-FDG PET/MRI in predicting HCC recurrence after resection. These findings may
      impact the selection criteria for liver transplantation.
Hepatocellular Carcinoma (HCC) is the third leading cause of death by cancer worldwide, being
      responsible for nearly 700,000 deaths in 2012. Liver transplantation (LT) provides the best
      results as a curative treatment for patients with early-stage HCC. Other curative treatment
      strategies for early stages HCC include resection and ablation. However, the recurrence rates
      are higher than LT. Due to organ shortage, better criteria for recipient selection are
      necessary. The first widely accepted criteria for graft allocation in HCC patients is the
      so-called Milan Criteria (MC): single HCC nodule ≤ 5 cm or 3 nodules all ≤ 3 cm, achieving a
      4-y survival of 85%. Recently, MC is seen as too restrictive, its inclusion preventing
      patients who might have better survival following LT when compared to other therapies.
      Reluctant to have sizing-only criteria, the University of Toronto, since 2004, has applied
      the so-called Extended Toronto Criteria (ETC) to LT, which offers transplant to patients with
      any size and any number of tumors provide they do not have systemic cancer-related symptoms,
      extrahepatic disease, vascular invasion or poorly differentiated tumors. A recent prospective
      study conducted at University Health Network (UHN) has shown 5-years survival rates of 68%
      when ECT are applied. Recent studies have demonstrated the need to use, besides the lesion
      size, variables which can predict the biological behavior of the tumor.

      Currently, important treatment decisions, like the selection of patients for transplantation,
      are made on crude, static tumour characteristics such as the size and number of lesions, but
      do not reflect other aspects of tumour biology. To date, pre-transplantation percutaneous
      biopsy is the best strategy to assess tumor differentiation and, consequently, tumor
      biological behavior. However, HCC is a very complex disease. Microscopic and molecular
      analyses have demonstrated a highly heterogeneous degree of cell differentiation. Patients
      with more than one tumor may have two or three degrees of cell differentiation between the
      tumors. Even within a single HCC nodule, more than one clonal mutations can be present. To
      date, there is not a precise method to determinate the degree of differentiation of each
      patient's disease and percutaneous core biopsy, an invasive method, is the best estimative
      the investigators can reach.

      Since it is impossible to precisely determine the degree of differentiation of HCC with one
      single tissue sample, the use of imaging becomes necessary. Magnetic resonance imaging (MRI)
      and enhanced computed tomography (CT) are extensively validated as staging methods for HCC.
      The use of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Magnetic Resonance
      Imaging (PET/MRI) is still underevaluated in the field of HCC. However, previous studies have
      demonstrated that 18F-FDG PET/CT may have role in assessing the HCC tumoral differentiation
      and predict survival after LT. There is no investigation on use of 18F-FDG PET/MRI as a tool
      to predict biological behavior in HCC.

      Recently, the Pugh Lab has developed a circulating tumor DNA (ctDNA) sequencing assay that
      combines a hybrid-capture method with a novel bioinformatics algorithm to enable full-length
      sequence analysis of all exons in genes of interest or any other arbitrary genomic region,
      rather than mutation hotspots13. With the availability of these technologies in our group,
      the investigators next sought to determine whether these methods were applicable to HCC
      patients, gathering two innovative tools in transplant patients' care.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: 18F-FDG PET/MRI results can identify aggressive HCC behavior and recurrence post transplant
time frame: 3 years
description: PET scan results will be compared with pathology at the time of transplant. Patients will be followed-up 2 years post transplant for recurrence. PET scan results will be compared for Recurrent/non-recurrent patients.
measure: 18F-FDG PET/MRI can predict HCC's poor tumoral differentiation
time frame: 3 years
description: PET/MRI reports will be compared with pathology at the time of transplant.
measure: 18F-FDG PET/MRI are related to presence of circulating tumor DNA in plasma
time frame: 3 years
description: 18F-FDG PET/MRI scan results will be compared with levels of ctDNA identified in plasma
arm group label: PET MRI Arm
arm group type: Experimental
description: Patient enrolled in the study will have a PET MRI exam scheduled before transplant
intervention type: Device
intervention name: PET MRI
description: 18F-Fluorodeoxyglucose Positron Emission Tomography combined with Primovist MRI
arm group label: PET MRI Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Recurrence