<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/NCT04506398</url>
  </required_header>
  <id_info>
    <org_study_id>Renji-IIT-2020-0007</org_study_id>
    <nct_id>NCT04506398</nct_id>
  </id_info>
  <brief_title>Heterogeneity and Evolution of hepatoceLlular Carcinoma in Post-transplant HCC Recurrence</brief_title>
  <acronym>HELP-2020</acronym>
  <official_title>Translational Study of Molecular-subtype Heterogeneity and Evolution Pattern in Patients With hepatoceLlular Carcinoma Post-transplant Relapse - HELP 2020 Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>RenJi Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>RenJi Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objective of Study: This study will evaluate the heterogeneity and evolution pathway between&#xD;
      primary HCC and tumor relapse after liver transplant.&#xD;
&#xD;
      According to the &quot;Seed-Soil&quot; theory, the primary hypothesis of this study is that HCC&#xD;
      patients with different molecular-subtype experience altered different pattern of&#xD;
      post-transplant recurrence, thus may have altered postoperative Recurrence-Free Survival&#xD;
      (RFS). Because the donors' liver construct different microenvironment for CTC(circulating&#xD;
      tumor cells) colonization. The investigators design this translational study to ①explore&#xD;
      potential high recurrent risk HCC molecular-subtypes which might benefit from neoadjuvant&#xD;
      systematic therapy or early adjuvant systematic therapy;②identify the molecular subtype&#xD;
      heterogeneity of primary and recurrent HCC to guide the precision medicine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      40 specimens will be obtained from the primary tumor during liver transplant surgery and&#xD;
      biopsy/specimens from intrahepatic tumor or lung metastasis when the patients experience&#xD;
      postoperative relapse. The molecular-subtype of HCC will be determined via whole exom&#xD;
      sequence(WES), immunohistochemistry(IHC) and RNA-Seq.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 10, 2020</start_date>
  <completion_date type="Anticipated">August 2022</completion_date>
  <primary_completion_date type="Anticipated">August 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Other</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>molecular-subtype heterogeneity between primary HCC and post-transplant HCC recurrence</measure>
    <time_frame>up to 2 years</time_frame>
    <description>It is defined as the change of HCC molecular subtype by comparing the primary tumor with intrahepatic or intrapulmonary recurrent tumor.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>molecular-subtype</measure>
    <time_frame>up to 2 years</time_frame>
    <description>I.Progenitor Type: defined by the transcriptional and protein overexpression of hepatic progenitor markers, inactivating mutations in RPS6KA3 and AXIN1 and hyperphosphorylation of ERK. The main signalling pathways specifically activated in the progenitor subclass are IGF1R and AKT.&#xD;
II.TGFβ-Wnt Type: characterised by activation of both TGFβ and Wnt pathways and an exhausted immune response. Also, an enrichment in TP53 inactivating mutations, amplification of FGF19 and CCND1, as well as frequent activation of pro-survival signalling pathways including cell cycle, mTOR, RAS-MAPK and MET can be detected.&#xD;
III.G4 Type: It frequently harbour a steatohepatitic phenotype, as well as exhibiting activation of the IL6/JAK-STAT pathway.&#xD;
IV.CTNNB1 Type: a subset of HCC harbouring CTNNB1 mutations. TERT promoter mutations are more frequent in this subclass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrence-Free Survival (RFS)</measure>
    <time_frame>up to 3 years</time_frame>
    <description>RFS is defined as the time from inclusion to first documentation of disease recurrence (intrahepatic or intrapulmonary) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death)</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Hepatocellular Carcinoma Recurrent</condition>
  <condition>Liver Transplant; Complications</condition>
  <arm_group>
    <arm_group_label>Retrospective cohort</arm_group_label>
    <description>20 HCC patients experienced post-transplant HCC</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Perspective cohort</arm_group_label>
    <description>20 HCC patients who underwent liver transplant, the patients would be recruited if recurrence would be diagnosed &gt;6 months after liver transplant</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>liver transplant</intervention_name>
    <description>Liver transplantation for hepatocellular carcinoma has the potential to eliminate both the tumor as well as the underlying cirrhosis and is the ideal treatment for HCC in cirrhotic liver as well as massive HCC in noncirrhotic liver.</description>
    <arm_group_label>Perspective cohort</arm_group_label>
    <arm_group_label>Retrospective cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>ctDNA</intervention_name>
    <description>Circulating Tumor DNA Correlates With Microvascular Invasion and Predicts Tumor Recurrence of Hepatocellular Carcinoma</description>
    <arm_group_label>Perspective cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>whole exome sequencing</intervention_name>
    <description>xome sequencing analysis of liver tumors could reveal mutational signatures associated with specific risk factors of recurrence.</description>
    <arm_group_label>Perspective cohort</arm_group_label>
    <arm_group_label>Retrospective cohort</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Cohort 1: HCC patients experienced post-transplant HCC Cohort 2: High recurrence-risk HCC&#xD;
        patients who underwent liver transplant&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have pathologically or cytologically or by radiological criteria proven&#xD;
             hepatocellular carcinoma; known mixed histology (e.g. hepatocellular carcinoma plus&#xD;
             cholangiocarcinoma) or fibrolamellar variant is not allowed&#xD;
&#xD;
          -  Patients have post-transplant HCC recurrence(cohort 1), Indication for being an&#xD;
             candidate in the waiting list for liver transplant according to multidisciplinary&#xD;
             board evaluation(cohort 2)&#xD;
&#xD;
          -  The time frame between liver transplant and diagnosis of post-transplant HCC&#xD;
             recurrence&gt; 6 months&#xD;
&#xD;
          -  No prior hepatectomy or systemic therapy or local therapy (TACE etc.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of oncological systemic treatment&#xD;
&#xD;
          -  early recurrence(&lt;6 months)&#xD;
&#xD;
          -  multiple organ transplantation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hao Feng, M.D., Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>Dept. of Liver surgery, Renji Hospital, Medical School of Shanghai Jiaotong University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zijie Zhang</last_name>
    <phone>008615026626518</phone>
    <email>sjtuzzj@163.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University</name>
      <address>
        <city>Shanghai</city>
        <zip>200127</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hao Feng, MD, PhD</last_name>
      <email>surgeonfeng@live.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>August 6, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>June 21, 2021</last_update_submitted>
  <last_update_submitted_qc>June 21, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 24, 2021</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>
  </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/NCT04506398
org study id: Renji-IIT-2020-0007
nct id: NCT04506398
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Objective of Study: This study will evaluate the heterogeneity and evolution pathway between
      primary HCC and tumor relapse after liver transplant.

      According to the "Seed-Soil" theory, the primary hypothesis of this study is that HCC
      patients with different molecular-subtype experience altered different pattern of
      post-transplant recurrence, thus may have altered postoperative Recurrence-Free Survival
      (RFS). Because the donors' liver construct different microenvironment for CTC(circulating
      tumor cells) colonization. The investigators design this translational study to ①explore
      potential high recurrent risk HCC molecular-subtypes which might benefit from neoadjuvant
      systematic therapy or early adjuvant systematic therapy;②identify the molecular subtype
      heterogeneity of primary and recurrent HCC to guide the precision medicine.
40 specimens will be obtained from the primary tumor during liver transplant surgery and
      biopsy/specimens from intrahepatic tumor or lung metastasis when the patients experience
      postoperative relapse. The molecular-subtype of HCC will be determined via whole exom
      sequence(WES), immunohistochemistry(IHC) and RNA-Seq.
observational model: Cohort
time perspective: Other
measure: molecular-subtype heterogeneity between primary HCC and post-transplant HCC recurrence
time frame: up to 2 years
description: It is defined as the change of HCC molecular subtype by comparing the primary tumor with intrahepatic or intrapulmonary recurrent tumor.
measure: molecular-subtype
time frame: up to 2 years
description: I.Progenitor Type: defined by the transcriptional and protein overexpression of hepatic progenitor markers, inactivating mutations in RPS6KA3 and AXIN1 and hyperphosphorylation of ERK. The main signalling pathways specifically activated in the progenitor subclass are IGF1R and AKT.
II.TGFβ-Wnt Type: characterised by activation of both TGFβ and Wnt pathways and an exhausted immune response. Also, an enrichment in TP53 inactivating mutations, amplification of FGF19 and CCND1, as well as frequent activation of pro-survival signalling pathways including cell cycle, mTOR, RAS-MAPK and MET can be detected.
III.G4 Type: It frequently harbour a steatohepatitic phenotype, as well as exhibiting activation of the IL6/JAK-STAT pathway.
IV.CTNNB1 Type: a subset of HCC harbouring CTNNB1 mutations. TERT promoter mutations are more frequent in this subclass
measure: Recurrence-Free Survival (RFS)
time frame: up to 3 years
description: RFS is defined as the time from inclusion to first documentation of disease recurrence (intrahepatic or intrapulmonary) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death)
arm group label: Retrospective cohort
description: 20 HCC patients experienced post-transplant HCC
arm group label: Perspective cohort
description: 20 HCC patients who underwent liver transplant, the patients would be recruited if recurrence would be diagnosed >6 months after liver transplant
intervention type: Procedure
intervention name: liver transplant
description: Liver transplantation for hepatocellular carcinoma has the potential to eliminate both the tumor as well as the underlying cirrhosis and is the ideal treatment for HCC in cirrhotic liver as well as massive HCC in noncirrhotic liver.
arm group label: Perspective cohort
arm group label: Retrospective cohort
intervention type: Diagnostic Test
intervention name: ctDNA
description: Circulating Tumor DNA Correlates With Microvascular Invasion and Predicts Tumor Recurrence of Hepatocellular Carcinoma
arm group label: Perspective cohort
intervention type: Diagnostic Test
intervention name: whole exome sequencing
description: xome sequencing analysis of liver tumors could reveal mutational signatures associated with specific risk factors of recurrence.
arm group label: Perspective cohort
arm group label: Retrospective cohort
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Hao Feng, M.D., Ph.D.
role: Study Director
affiliation: Dept. of Liver surgery, Renji Hospital, Medical School of Shanghai Jiaotong University
last name: Zijie Zhang
phone: 008615026626518
email: sjtuzzj@163.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular