<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/NCT03838796</url>
  </required_header>
  <id_info>
    <org_study_id>Huashan 004</org_study_id>
    <nct_id>NCT03838796</nct_id>
  </id_info>
  <brief_title>Lenvatinib Combined With TACE to Prevent the Recurrence in High-risk Patients With Hepatocellular Carcinoma</brief_title>
  <official_title>A Prospective Cohort Study of the Effect of Lenvatinib Combined With TACE in Preventing the Recurrence in High-risk Patients With Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fudan University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fudan University</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>
      The purpose of the study is to observe the effect of Lenvatinib Combined With TACE in&#xD;
      preventing the recurrence in high-risk patients with hepatocellular carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Postoperative recurrence and metastasis of hepatocellular carcinoma(HCC）is the main problem&#xD;
      during the treatment. Although with the development of medical science, some drugs have been&#xD;
      found for the prevention and treatment of postoperative recurrence of HCC (such as&#xD;
      postoperative application of interferon to prevent early tumor recurrence), but there is&#xD;
      still no drug widely recognized.&#xD;
&#xD;
      Transcatheter arterial chemoembolization (TACE) is a palliative treatment for hepatocellular&#xD;
      carcinoma. TACE can detect the early recurrence of tumor after liver resection, and has a&#xD;
      complementary treatment effect on hidden residual lesions. For patients with high-risk, the&#xD;
      tumor recurrence rate can be significantly reduced, and the tumor-free survival can be&#xD;
      prolonged by TACE. Therefore, patients with high-risk of recurrence after resection were&#xD;
      routinely arranged TACE treatment as an adjuvant treatment after surgery.&#xD;
&#xD;
      Lenvatinib is a multi-target receptor tyrosine kinase inhibitor (TKI), which mainly inhibits&#xD;
      vascular endothelial growth factor(VEGF) receptor-1, 2, 3; fibroblast growth factors(FGF)&#xD;
      receptor-1, 2, 3, 4; platelet derived growth factor receptor(PDGFR)α; RET and KIT, thereby&#xD;
      inhibiting tumor cell proliferation, inducing apoptosis, and acting as an anti-angiogenesis.&#xD;
      The REFLECT study showed that the median overall survival(OS) of the patients in the&#xD;
      lenvatinib group was 13.6 months (95% CI, 12.1-14.9) and that in the sorafenib group was 12.3&#xD;
      months (95% CI, 10.4-13.9) , which reached a non-inferiority end point (HR = 0.92; 95% CI,&#xD;
      0.79-1.06). In addition, all secondary endpoints in the lenvatinib group were significantly&#xD;
      better than the sorafenib group. A subgroup analysis based on Chinese patients showed that&#xD;
      the OS of Lenvatinib was significantly 4.8 months longer than sorafenib group (15.0 months vs&#xD;
      10.2 months). Other three secondary endpoints, progression-free survival(PFS) (9.2 months vs&#xD;
      3.6) and time to progression(TTP)(11.0 months vs 3.7 months) and objective response rate(ORR)&#xD;
      (21.5% vs 8.3%), were also significantly better in Lenvatinib group. Based on the above&#xD;
      datas, lenvatinib will become a new choice for Chinese patients with HCC. It has also been&#xD;
      approved by the FDA and CFDA as the first-line treatment for patients with advanced HCC.&#xD;
&#xD;
      So, this study is to observe the effect of lenvatinib combined with TACE in preventing the&#xD;
      recurrence in high-risk patients with HCC.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 3, 2019</start_date>
  <completion_date type="Anticipated">June 2023</completion_date>
  <primary_completion_date type="Actual">June 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>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease free survival</measure>
    <time_frame>2 years</time_frame>
    <description>the survival time after liver resection without tumor recurrence or metastasis</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>5 years</time_frame>
    <description>the survival time after liver resection</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">297</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>lenvatinib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>use lenvatinib after liver resection in HCC patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>lenvatinib and TACE</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>use lenvatinib and TACE after liver resection in HCC patients</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>lenvatinib</intervention_name>
    <description>for patients &lt;60kg, lenvatinib 8mg bid po for patients &gt;60kg, lenvatinib 12mg bid po</description>
    <arm_group_label>lenvatinib</arm_group_label>
    <arm_group_label>lenvatinib and TACE</arm_group_label>
    <other_name>lenvatinib treatment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>TACE</intervention_name>
    <description>The patient underwent transfemoral hepatic artery angiography one month after surgery to observe whether there was tumor staining in the liver. If there was suspicious tumor staining, micro-catheter was superselected to the tumor blood vessel, the embolization agents and chemotherapy drugs were injected. If there was no tumor staining, a small amount of embolization agents were slowly injected into the artery.</description>
    <arm_group_label>lenvatinib and TACE</arm_group_label>
    <other_name>transcatheter arterial chemoembolization</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The characteristics of the treatment history:&#xD;
&#xD;
        No lenvatinib treatment history, no sorafenib allergies.&#xD;
&#xD;
          -  The characteristics of the tumor:&#xD;
&#xD;
        The pathological results is hepatocellular carcinoma.&#xD;
&#xD;
        Meet any of the following articles:&#xD;
&#xD;
        Pathological prompt microvascular invasion(MVI) class II, and incorporate any of the&#xD;
        following:Tumor number≥3,Tumor size≥8cm,Tumor margin is not clear and no complete capsule.&#xD;
&#xD;
        With the embolus in Portal vein, hepatic vein or bile duct. Preoperative rupture or&#xD;
        invasion the adjacent organs.&#xD;
&#xD;
          -  The characteristics of the patients:&#xD;
&#xD;
        The patient age was between 18-75. The American Society of Anesthesiologists(ASA）score was&#xD;
        I-III. The Child-pugh score was A. Total bilirubin≤3.0 mg/dL, albumin≥28 g/L, AST, ALT,&#xD;
        ALP≤5 times the upper limit of normal value.&#xD;
&#xD;
        Routine blood test: the neutrophil≥1.5×10^9/L, Hb≥8.5g/L，PLT≥75×10^9/L. The INR≤2.3. The&#xD;
        Eastern Cooperative Oncology Group(ECOG) score was less than 2 points&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  R1/2 or palliative rescted tumor&#xD;
&#xD;
          -  Pregnant or lactating women.&#xD;
&#xD;
          -  Patients with other malignant tumor.&#xD;
&#xD;
          -  Patients with mental illness.&#xD;
&#xD;
          -  Patients participated in other clinical trials in last three months.&#xD;
&#xD;
          -  Residual lesions showed by Postoperative digital subtraction angiography(DSA).&#xD;
&#xD;
          -  Postoperative patients treated with other targeted drugs, PD1 antibody and other&#xD;
             immunotherapies, FOLFOX systemic chemotherapy, and HuaiErKeLi drug treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lunxiu Qin, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of general surgery, Huashan hospital, Fudan University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Huashan hospital</name>
      <address>
        <city>Shanghai</city>
        <zip>200040</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <results_reference>
    <citation>Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003 Dec 6;362(9399):1907-17. doi: 10.1016/S0140-6736(03)14964-1.</citation>
    <PMID>14667750</PMID>
  </results_reference>
  <results_reference>
    <citation>Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006 Jul;132(7):458-65. doi: 10.1007/s00432-006-0091-y. Epub 2006 Mar 24.</citation>
    <PMID>16557381</PMID>
  </results_reference>
  <results_reference>
    <citation>Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study. Clin Cancer Res. 2018 May 1;24(9):2074-2081. doi: 10.1158/1078-0432.CCR-17-2899. Epub 2018 Feb 2.</citation>
    <PMID>29420221</PMID>
  </results_reference>
  <results_reference>
    <citation>Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.</citation>
    <PMID>29433850</PMID>
  </results_reference>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>February 11, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>July 29, 2022</last_update_submitted>
  <last_update_submitted_qc>July 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fudan University</investigator_affiliation>
    <investigator_full_name>Lunxiu Qin</investigator_full_name>
    <investigator_title>Director of the general surgery department, Huashan hospital</investigator_title>
  </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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lenvatinib</mesh_term>
  </intervention_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/NCT03838796
org study id: Huashan 004
nct id: NCT03838796
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of the study is to observe the effect of Lenvatinib Combined With TACE in
      preventing the recurrence in high-risk patients with hepatocellular carcinoma.
Postoperative recurrence and metastasis of hepatocellular carcinoma(HCC）is the main problem
      during the treatment. Although with the development of medical science, some drugs have been
      found for the prevention and treatment of postoperative recurrence of HCC (such as
      postoperative application of interferon to prevent early tumor recurrence), but there is
      still no drug widely recognized.

      Transcatheter arterial chemoembolization (TACE) is a palliative treatment for hepatocellular
      carcinoma. TACE can detect the early recurrence of tumor after liver resection, and has a
      complementary treatment effect on hidden residual lesions. For patients with high-risk, the
      tumor recurrence rate can be significantly reduced, and the tumor-free survival can be
      prolonged by TACE. Therefore, patients with high-risk of recurrence after resection were
      routinely arranged TACE treatment as an adjuvant treatment after surgery.

      Lenvatinib is a multi-target receptor tyrosine kinase inhibitor (TKI), which mainly inhibits
      vascular endothelial growth factor(VEGF) receptor-1, 2, 3; fibroblast growth factors(FGF)
      receptor-1, 2, 3, 4; platelet derived growth factor receptor(PDGFR)α; RET and KIT, thereby
      inhibiting tumor cell proliferation, inducing apoptosis, and acting as an anti-angiogenesis.
      The REFLECT study showed that the median overall survival(OS) of the patients in the
      lenvatinib group was 13.6 months (95% CI, 12.1-14.9) and that in the sorafenib group was 12.3
      months (95% CI, 10.4-13.9) , which reached a non-inferiority end point (HR = 0.92; 95% CI,
      0.79-1.06). In addition, all secondary endpoints in the lenvatinib group were significantly
      better than the sorafenib group. A subgroup analysis based on Chinese patients showed that
      the OS of Lenvatinib was significantly 4.8 months longer than sorafenib group (15.0 months vs
      10.2 months). Other three secondary endpoints, progression-free survival(PFS) (9.2 months vs
      3.6) and time to progression(TTP)(11.0 months vs 3.7 months) and objective response rate(ORR)
      (21.5% vs 8.3%), were also significantly better in Lenvatinib group. Based on the above
      datas, lenvatinib will become a new choice for Chinese patients with HCC. It has also been
      approved by the FDA and CFDA as the first-line treatment for patients with advanced HCC.

      So, this study is to observe the effect of lenvatinib combined with TACE in preventing the
      recurrence in high-risk patients with HCC.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Disease free survival
time frame: 2 years
description: the survival time after liver resection without tumor recurrence or metastasis
measure: Overall survival
time frame: 5 years
description: the survival time after liver resection
arm group label: lenvatinib
arm group type: Active Comparator
description: use lenvatinib after liver resection in HCC patients
arm group label: lenvatinib and TACE
arm group type: Active Comparator
description: use lenvatinib and TACE after liver resection in HCC patients
intervention type: Drug
intervention name: lenvatinib
description: for patients <60kg, lenvatinib 8mg bid po for patients >60kg, lenvatinib 12mg bid po
arm group label: lenvatinib
arm group label: lenvatinib and TACE
other name: lenvatinib treatment
intervention type: Procedure
intervention name: TACE
description: The patient underwent transfemoral hepatic artery angiography one month after surgery to observe whether there was tumor staining in the liver. If there was suspicious tumor staining, micro-catheter was superselected to the tumor blood vessel, the embolization agents and chemotherapy drugs were injected. If there was no tumor staining, a small amount of embolization agents were slowly injected into the artery.
arm group label: lenvatinib and TACE
other name: transcatheter arterial chemoembolization
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Lunxiu Qin, MD
role: Principal Investigator
affiliation: Department of general surgery, Huashan hospital, Fudan University
facility: 
country: China
citation: Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003 Dec 6;362(9399):1907-17. doi: 10.1016/S0140-6736(03)14964-1.
PMID: 14667750
citation: Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006 Jul;132(7):458-65. doi: 10.1007/s00432-006-0091-y. Epub 2006 Mar 24.
PMID: 16557381
citation: Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study. Clin Cancer Res. 2018 May 1;24(9):2074-2081. doi: 10.1158/1078-0432.CCR-17-2899. Epub 2018 Feb 2.
PMID: 29420221
citation: Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
PMID: 29433850
responsible party type: Principal Investigator
investigator affiliation: Fudan University
investigator full name: Lunxiu Qin
investigator title: Director of the general surgery department, Huashan hospital
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Recurrence
mesh term: Lenvatinib
sharing ipd: No