<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/NCT03275376</url>
  </required_header>
  <id_info>
    <org_study_id>CF16263B</org_study_id>
    <nct_id>NCT03275376</nct_id>
  </id_info>
  <brief_title>Statin Combination Therapy in Patients Receiving Sorafenib for Advanced Hepatocellular Carcinoma</brief_title>
  <official_title>Statin Combination Therapy in Patients Receiving Sorafenib for Advanced Hepatocellular Carcinoma: A Randomized Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Taichung Veterans General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Taichung Veterans General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Target therapy with sorafenib is the standard of treatment for advanced Hepatocellular&#xD;
      carcinoma (HCC), but the patient survival time is still unsatisfactory. The aims of this&#xD;
      study are to prove statins improve the tumor responses and overall survival for patients who&#xD;
      receive sorafenib therapy for advanced HCC by a prospective randomized controlled study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide,&#xD;
      including the condition in Taiwan, and the management of HCC is an important challenge in&#xD;
      public health. Target therapy with sorafenib is the standard of treatment for advanced HCC&#xD;
      (vascular invasion or extrahepatic metastasis), but the patient survival time is still&#xD;
      unsatisfactory. In recent years, growing evidences, including mechanism analysis, have&#xD;
      suggested the anitneoplastic effects of statin, and a recent pooled analysis found that&#xD;
      statin use may be associated with improved survival in patients with metastatic rencal cell&#xD;
      carcinoma. However, a prospective clinical trial of statin sorafenib combination therapy in&#xD;
      the treatment of advanced HCC is lacking.&#xD;
&#xD;
      Aims:&#xD;
&#xD;
        1. To prove statins improve the overall survival for patients who receive sorafenib therapy&#xD;
           for advanced HCC by a prospective randomized controlled study.&#xD;
&#xD;
        2. To prove statin can improve tumor responses and the progression free survival for&#xD;
           patients who receive sorafenib therapy for advanced HCC by a prospective randomized&#xD;
           controlled study.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      This randomized placebo-controlled study will prospectively enroll patients who receiving&#xD;
      sorafenib therapy for advanced HCC in the Taichung Veterans General Hospital, and statin or&#xD;
      placebo will be statin or placebo will be administered according to randomized allocations.&#xD;
      Tumor responses, time to tumor progression, and survival time will be followed and recorded&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow in patient enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">December 21, 2017</start_date>
  <completion_date type="Actual">March 13, 2021</completion_date>
  <primary_completion_date type="Actual">December 21, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Three year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best tumor response</measure>
    <time_frame>Three year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Three year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Overall Survival</condition>
  <condition>Tumor Responses</condition>
  <arm_group>
    <arm_group_label>Statin treated group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin 10mg</intervention_name>
    <description>Atorvastatin or placebo will be administered according to randomized allocations.</description>
    <arm_group_label>Statin treated group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Atorvastatin or placebo will be administered according to randomized allocations.</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients more than 40 years old&#xD;
&#xD;
          2. HCCs diagnosed by AASLD image criteria or pathology&#xD;
&#xD;
          3. HCCs in BCLC advanced stage, with portal vein thrombosis (VP3 or VP4) or extrahepatic&#xD;
             metastasis&#xD;
&#xD;
          4. Not suitable or failed to locoreginal treatments for HCC&#xD;
&#xD;
          5. Child-Pugh score = or &lt; 6&#xD;
&#xD;
          6. ECOG performance status (PST) 0-2&#xD;
&#xD;
          7. Serum bilirubin &lt; 2 mg/dL and prothrombin time (PT) prolongation &lt; 3 seconds&#xD;
&#xD;
          8. Will receive sorafenib therapy&#xD;
&#xD;
          9. Life expectancy &gt; 3 months&#xD;
&#xD;
         10. Will follow the pregnancy prevention protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. HCC is considered for curative therapy&#xD;
&#xD;
          2. HCC with brain metastasis&#xD;
&#xD;
          3. History of systemic therapy for HCC&#xD;
&#xD;
          4. Indications for statin use, such as hyperlipidemia in cardiovascular diseases&#xD;
&#xD;
          5. Any local treatment for HCC within 4 weeks&#xD;
&#xD;
          6. Any active gastrointestinal bleeding within 4 weeks&#xD;
&#xD;
          7. Liver transplant history or concomitant immunosuppressive therapy&#xD;
&#xD;
          8. Concurrent any other malignancy&#xD;
&#xD;
          9. Allergy to sorafenib or statins&#xD;
&#xD;
         10. Pregnancy or lactation&#xD;
&#xD;
         11. Serum AST or ALT &gt; 5x upper limit of normal&#xD;
&#xD;
         12. Known HIV infection&#xD;
&#xD;
         13. eGFR &lt; 30 ml/min&#xD;
&#xD;
         14. Abnormal medical conditions that are unsuitable for study, such as uncontrolled&#xD;
             hypertension, coronary arterial disease, or arrhythmia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Teng-Yu Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Taichung Veterans General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Taichung Veterans General Hospital</name>
      <address>
        <city>Taichung</city>
        <zip>40705</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <reference>
    <citation>1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. 2. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. 3. Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-179. 4. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31:3509-3516. 5. Singh S, Singh PP, Roberts LR, et al. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2014;11:45-54. 6. Demierre MF, Higgins PD, Gruber SB, et al. Statins and cancer prevention. Nat Rev Cancer 2005;5:930-942. 7. Wu J, Wong WW, Khosravi F, et al. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res 2004;64:6461-6468. 8. Rao S, Porter DC, Chen X, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A 1999;96:7797-7802. 9. El-Serag HB, Johnson ML, Hachem C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-1608. 10. Tsan YT, Lee CH, Wang JD, et al. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012;30:623-630. 11. Chiu HF, Ho SC, Chen CC, et al. Statin use and the risk of liver cancer: a population-based case-control study. Am J Gastroenterol 2011;106:894-898.</citation>
  </reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <last_update_submitted>March 14, 2021</last_update_submitted>
  <last_update_submitted_qc>March 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Taichung Veterans General Hospital</investigator_affiliation>
    <investigator_full_name>Teng-Yu Lee</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</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/NCT03275376
org study id: CF16263B
nct id: NCT03275376
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Target therapy with sorafenib is the standard of treatment for advanced Hepatocellular
      carcinoma (HCC), but the patient survival time is still unsatisfactory. The aims of this
      study are to prove statins improve the tumor responses and overall survival for patients who
      receive sorafenib therapy for advanced HCC by a prospective randomized controlled study.
Background:

      Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide,
      including the condition in Taiwan, and the management of HCC is an important challenge in
      public health. Target therapy with sorafenib is the standard of treatment for advanced HCC
      (vascular invasion or extrahepatic metastasis), but the patient survival time is still
      unsatisfactory. In recent years, growing evidences, including mechanism analysis, have
      suggested the anitneoplastic effects of statin, and a recent pooled analysis found that
      statin use may be associated with improved survival in patients with metastatic rencal cell
      carcinoma. However, a prospective clinical trial of statin sorafenib combination therapy in
      the treatment of advanced HCC is lacking.

      Aims:

        1. To prove statins improve the overall survival for patients who receive sorafenib therapy
           for advanced HCC by a prospective randomized controlled study.

        2. To prove statin can improve tumor responses and the progression free survival for
           patients who receive sorafenib therapy for advanced HCC by a prospective randomized
           controlled study.

      Methods:

      This randomized placebo-controlled study will prospectively enroll patients who receiving
      sorafenib therapy for advanced HCC in the Taichung Veterans General Hospital, and statin or
      placebo will be statin or placebo will be administered according to randomized allocations.
      Tumor responses, time to tumor progression, and survival time will be followed and recorded
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Overall survival
time frame: Three year
measure: Best tumor response
time frame: Three year
measure: Progression free survival
time frame: Three year
arm group label: Statin treated group
arm group type: Experimental
arm group label: Control group
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Atorvastatin 10mg
description: Atorvastatin or placebo will be administered according to randomized allocations.
arm group label: Statin treated group
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Atorvastatin or placebo will be administered according to randomized allocations.
arm group label: Control group
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Teng-Yu Lee, MD
role: Principal Investigator
affiliation: Taichung Veterans General Hospital
facility: 
country: Taiwan
citation: 1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. 2. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. 3. Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-179. 4. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31:3509-3516. 5. Singh S, Singh PP, Roberts LR, et al. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2014;11:45-54. 6. Demierre MF, Higgins PD, Gruber SB, et al. Statins and cancer prevention. Nat Rev Cancer 2005;5:930-942. 7. Wu J, Wong WW, Khosravi F, et al. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res 2004;64:6461-6468. 8. Rao S, Porter DC, Chen X, et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A 1999;96:7797-7802. 9. El-Serag HB, Johnson ML, Hachem C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-1608. 10. Tsan YT, Lee CH, Wang JD, et al. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012;30:623-630. 11. Chiu HF, Ho SC, Chen CC, et al. Statin use and the risk of liver cancer: a population-based case-control study. Am J Gastroenterol 2011;106:894-898.
responsible party type: Principal Investigator
investigator affiliation: Taichung Veterans General Hospital
investigator full name: Teng-Yu Lee
investigator title: MD, PhD
mesh term: Carcinoma, Hepatocellular
mesh term: Atorvastatin
sharing ipd: No