xml: <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/NCT06041477</url>
    </required_header>
    <id_info>
      <org_study_id>SL-B2022-793-01</org_study_id>
      <secondary_id>2023001</secondary_id>
      <nct_id>NCT06041477</nct_id>
    </id_info>
    <brief_title>Concurrently vs Sequentially Combined HAIC With Targeted and Immunotherapy in Potentially Resectable HCC</brief_title>
    <acronym>HAIC</acronym>
    <official_title>A Randomized Controlled Study of the Efficacy of Hepatic Arterial Perfusion Chemotherapy Concurrently Compared to Sequentially Combined With Targeted and Immunotherapy in Potentially Resectable Intermediate and Advanced HCC</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Sun Yat-sen University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Affiliated Hospital of Guangdong Medical University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>First People's Hospital of Foshan</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Sun Yat-sen 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 goal of this clinical trial is to compare HAIC concurrently with sequentially combined&#xD;
        with targeted and immunotherapies in terms of efficacy and safety in patients with&#xD;
        potentially resectable intermediate and advanced HCC (CNLC stage IIa~IIIa). The main&#xD;
        questions it aims to answer are:&#xD;
  &#xD;
          -  Does a &quot;strong combination&quot; regimen of three simultaneous treatments (HAIC, targeted&#xD;
             agents and immunotherapy) definitely result in a higher surgical conversion rate and&#xD;
             better survival benefit?&#xD;
  &#xD;
          -  Can the combination of targeted and immunotherapies based on patients' response to HAIC&#xD;
             therapy avoid over-treatment of some patients without affecting the surgical conversion&#xD;
             rate and overall survival? Participants will be randomly assigned to receive either HAIC&#xD;
             concurrently or sequentially combined with targeted and immunotherapies.&#xD;
  &#xD;
        Researchers will compare concurrent treatment group with sequential treatment group to see if&#xD;
        there are different in terms of the conversion resection rate, long-term survival, and&#xD;
        safety.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Participants in the concurrent treatment group will receive two cycles of HAIC (the drugs are&#xD;
        oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2&#xD;
        over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination&#xD;
        with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and&#xD;
        frequency according to instructions), then evaluate the response of tumor, those who achieve&#xD;
        complete response (CR) will receive surgical resection or follow-up, those with partial&#xD;
        response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with&#xD;
        progress disease (PD) will be withdrawn and receive other treatments. After four cycles of&#xD;
        combined therapy, second evaluation of efficacy will be performed, those who achieve CR will&#xD;
        receive surgical resection or follow-up observation, and the other patients will be evaluated&#xD;
        for the possibility of surgical resection or the subsequent treatment.&#xD;
  &#xD;
        Participants in the sequential treatment group will receive two cycles of HAIC (drugs of&#xD;
        oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200&#xD;
        mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4&#xD;
        weeks), then evaluate the response of tumor, and those who achieve complete response (CR )&#xD;
        will receive surgical resection or follow-up, while other patients continue to receive two&#xD;
        cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and&#xD;
        immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four&#xD;
        cycles, a second efficacy assessment will be performed, and patients who achieve CR will&#xD;
        undergo surgical resection or follow-up observation, and the other patients will be evaluated&#xD;
        for the possibility of surgical resection or the subsequent treatment.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">July 2030</completion_date>
    <primary_completion_date type="Anticipated">July 2027</primary_completion_date>
    <phase>Phase 3</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>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>OS</measure>
      <time_frame>From date of randomization until the date of death from any cause, assessed at least 36 months</time_frame>
      <description>Overall survival of the participants</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>PFS</measure>
      <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed at least 36 months</time_frame>
      <description>Progression-free survival of the participants</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ORR</measure>
      <time_frame>Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)</time_frame>
      <description>Objective response rates, which means the proportion of patients with efficacy assessment of complete response and partial response for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>DCR</measure>
      <time_frame>Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)</time_frame>
      <description>Disease control rates, which means the proportion of patients with efficacy assessment of complete response, partial response and stable disease for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>CRR</measure>
      <time_frame>This outcome measure will be assessed at the end of Cycle 4 (each cycle is 28 days)</time_frame>
      <description>Conversion resection rate refer to the proportion of patients in both groups who actually underwent subsequent surgical resection.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Safety profiles of all participants</measure>
      <time_frame>This outcome measure will be assessed at the end of Cycle 1 to 4(each cycle is 28 days), and every 3 months through study completion, an average of 3 years</time_frame>
      <description>Adverse Events and Severe Adverse Events evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">540</enrollment>
    <condition>Hepatocellular Carcinoma</condition>
    <condition>Chemotherapy Effect</condition>
    <condition>Chemotherapeutic Toxicity</condition>
    <arm_group>
      <arm_group_label>concurrent treatment group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants receive two cycles of HAIC (the drugs are oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and frequency according to instructions), then evaluate the response of tumor, those who achieve complete response (CR) will receive surgical resection or follow-up, those with partial response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments. After four cycles of combined therapy, second evaluation of efficacy will be performed, those who achieve CR will receive surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>sequential treatment group</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Participants receive two cycles of HAIC (drugs of oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200 mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4 weeks), then evaluate the response of tumor, and those who achieve complete response (CR ) will receive surgical resection or follow-up, while other patients continue to receive two cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four cycles, a second efficacy assessment will be performed, and patients who achieve CR will undergo surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU</intervention_name>
      <description>Hepatic arterial infusion chemotherapy with (oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks)</description>
      <arm_group_label>concurrent treatment group</arm_group_label>
      <arm_group_label>sequential treatment group</arm_group_label>
      <other_name>Hepatic arterial infusion chemotherapy (HAIC)</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Concurrent Lenvatinib</intervention_name>
      <description>Lenvatinib 8mg/day combined with the HAIC from the first cycle</description>
      <arm_group_label>concurrent treatment group</arm_group_label>
      <other_name>Concurrent targeted therapy</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Concurrent PD-1 antibody</intervention_name>
      <description>PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the first cycle (dosage and frequency according to instructions)</description>
      <arm_group_label>concurrent treatment group</arm_group_label>
      <other_name>Concurrent immunotherapy</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sequential Lenvatinib</intervention_name>
      <description>Lenvatinib 8mg/day combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR)</description>
      <arm_group_label>sequential treatment group</arm_group_label>
      <other_name>Sequential targeted therapy</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sequential PD-1 antibody</intervention_name>
      <description>PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR) (dosage and frequency according to instructions)</description>
      <arm_group_label>sequential treatment group</arm_group_label>
      <other_name>Sequential immunotherapy</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age ≥18 and ≤75 years;&#xD;
  &#xD;
            2. ECOG PS score of 0~1;&#xD;
  &#xD;
            3. Clinical or pathological diagnosis of hepatocellular carcinoma and meeting the stage&#xD;
               IIa-IIIa of CNLC staging according to the relevant definitions in the 2015 edition of&#xD;
               the Guidelines for Standardized Pathological Diagnosis of Primary Liver Cancer;&#xD;
  &#xD;
            4. Not having received previous treatment against hepatocellular carcinoma;&#xD;
  &#xD;
            5. Those who cannot be surgically resected after discussion by the multidisciplinary team&#xD;
               of the participating centers , but have a potential chance of resection after&#xD;
               conversion therapy, including: multiple tumors located in one lobe of the liver;&#xD;
               portal vein cancer thrombus not reaching the main trunk, which can be resected&#xD;
               together with the primary focus;&#xD;
  &#xD;
            6. Laboratory tests meet the following conditions, or the following conditions can be&#xD;
               achieved with short-term treatment:&#xD;
  &#xD;
               Neutrophil count ≥2.0×109/L; Hemoglobin ≥ 100 g/L; Platelet count ≥ 75 × 109/L; Plasma&#xD;
               albumin level ≥ 35 g/L; Plasma total bilirubin less than 2 times the upper limit of&#xD;
               normal; Plasma alanine aminotransferase (ALT) less than 3 times the upper limit of&#xD;
               normal; Plasma aspartate aminotransferase (AST) less than 3 times the upper limit of&#xD;
               normal; Plasma creatinine less than 1.5 times the upper limit of normal; Plasma&#xD;
               prothrombin time is normal or exceeds the upper limit of normal value by ≤ 4 seconds;&#xD;
               Prothrombinogen international normalized ratio (INR) ≤ 2.2;&#xD;
  &#xD;
            7. Patients were fully informed about the study and signed an informed consent form.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Those with severe comorbidity including cardiac, cerebral, pulmonary, renal, and other&#xD;
               vital organ function damage, combined with severe infections or other serious&#xD;
               concomitant diseases (&gt; grade 2 CTCAE Version 5.0 adverse events), who cannot tolerate&#xD;
               the treatment;&#xD;
  &#xD;
            2. Those with a history of other malignant tumors;&#xD;
  &#xD;
            3. Those with a history of related drug allergy;&#xD;
  &#xD;
            4. Those with known hypersensitivity to any component of the targeted and immunologic&#xD;
               drugs to be applied;&#xD;
  &#xD;
            5. Those with a history of organ transplantation;&#xD;
  &#xD;
            6. Those who have received previous treatment targeting hepatocellular carcinoma&#xD;
               (including interferon);&#xD;
  &#xD;
            7. Those with co-infection with HIV;&#xD;
  &#xD;
            8. Those with drugs abuse;&#xD;
  &#xD;
            9. Those who have had gastrointestinal bleeding or cardiovascular events within the last&#xD;
               30 days;&#xD;
  &#xD;
           10. Pregnant or breastfeeding women, or women of childbearing age who do not wish to use&#xD;
               contraception;&#xD;
  &#xD;
           11. Persons with concomitant psychiatric disorders that preclude informed consent or&#xD;
               affect acceptance of treatment;&#xD;
  &#xD;
           12. Other factors that may affect patient enrollment and assessment results.&#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>Wei Wei, Ph.D, M,D</last_name>
      <role>Principal Investigator</role>
      <affiliation>Sun Yat-sen University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Shao Hua Li, Ph.D, M,D</last_name>
      <phone>008615088064187</phone>
      <email>lishaoh@sysucc.org.cn</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Rong Ping Guo, M,D</last_name>
      <phone>008618819809988</phone>
      <email>guorp@sysucc.org.cn</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>SUN Yat-sen University Cancer Center</name>
        <address>
          <city>Guangzhou</city>
          <state>Guangdong</state>
          <zip>510060</zip>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Shao Hua Li, Ph.D, M.D</last_name>
        <phone>008615088064187</phone>
        <email>lishaoh@sysucc.org.cn</email>
      </contact>
      <contact_backup>
        <last_name>Wei Wei, Ph.D, M.D</last_name>
        <phone>008613725208259</phone>
        <email>weiwei@sysucc.org.cn</email>
      </contact_backup>
      <investigator>
        <last_name>Wei Wei, Ph.D, M.D</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <results_reference>
      <citation>Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.</citation>
      <PMID>33538338</PMID>
    </results_reference>
    <results_reference>
      <citation>Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015 Sep;35(9):2155-66. doi: 10.1111/liv.12818. Epub 2015 Mar 25.</citation>
      <PMID>25752327</PMID>
    </results_reference>
    <results_reference>
      <citation>Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5.</citation>
      <PMID>29307467</PMID>
    </results_reference>
    <results_reference>
      <citation>Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol. 2002 Oct;3(10):593-603. doi: 10.1016/s1470-2045(02)00873-2.</citation>
      <PMID>12372721</PMID>
    </results_reference>
    <results_reference>
      <citation>Shi HY, Wang SN, Wang SC, Chuang SC, Chen CM, Lee KT. Preoperative transarterial chemoembolization and resection for hepatocellular carcinoma: a nationwide Taiwan database analysis of long-term outcome predictors. J Surg Oncol. 2014 Apr;109(5):487-93. doi: 10.1002/jso.23521. Epub 2013 Nov 30.</citation>
      <PMID>24293372</PMID>
    </results_reference>
    <results_reference>
      <citation>He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):953-960. doi: 10.1001/jamaoncol.2019.0250.</citation>
      <PMID>31070690</PMID>
    </results_reference>
    <results_reference>
      <citation>Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, Xie Q, Guo R, Shi M, Xu L, Cai X, Wu P, Zhao M. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):60-69. doi: 10.1016/j.jhep.2018.02.008. Epub 2018 Feb 20.</citation>
      <PMID>29471013</PMID>
    </results_reference>
    <results_reference>
      <citation>He MK, Le Y, Li QJ, Yu ZS, Li SH, Wei W, Guo RP, Shi M. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017 Oct 23;36(1):83. doi: 10.1186/s40880-017-0251-2.</citation>
      <PMID>29061175</PMID>
    </results_reference>
    <results_reference>
      <citation>Li S, Mei J, Wang Q, Guo Z, Lu L, Ling Y, Xu L, Chen M, Zheng L, Lin W, Zou J, Wen Y, Wei W, Guo R. Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial. Ann Surg Oncol. 2020 Dec;27(13):5183-5190. doi: 10.1245/s10434-020-08601-8. Epub 2020 May 16. Erratum In: Ann Surg Oncol. 2021 Dec;28(Suppl 3):874.</citation>
      <PMID>32418078</PMID>
    </results_reference>
    <results_reference>
      <citation>Li SH, Mei J, Cheng Y, Li Q, Wang QX, Fang CK, Lei QC, Huang HK, Cao MR, Luo R, Deng JD, Jiang YC, Zhao RC, Lu LH, Zou JW, Deng M, Lin WP, Guan RG, Wen YH, Li JB, Zheng L, Guo ZX, Ling YH, Chen HW, Zhong C, Wei W, Guo RP. Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study. J Clin Oncol. 2023 Apr 1;41(10):1898-1908. doi: 10.1200/JCO.22.01142. Epub 2022 Dec 16.</citation>
      <PMID>36525610</PMID>
    </results_reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 23, 2023</study_first_submitted>
    <study_first_submitted_qc>September 11, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 18, 2023</study_first_posted>
    <last_update_submitted>September 11, 2023</last_update_submitted>
    <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
      <investigator_full_name>Wei Wei</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>Hepatic artery infusion chemotherapy</keyword>
    <keyword>Tyrosine kinase inhibitors</keyword>
    <keyword>Immune checkpoint inhibitors</keyword>
    <keyword>Intermediate and advanced stage hepatocellular carcinoma</keyword>
    <keyword>combined therapy</keyword>
    <keyword>conversion resection</keyword>
    <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>Leucovorin</mesh_term>
      <mesh_term>Folic Acid</mesh_term>
      <mesh_term>Oxaliplatin</mesh_term>
      <mesh_term>Lenvatinib</mesh_term>
      <mesh_term>Antibodies</mesh_term>
      <mesh_term>Immunoglobulins</mesh_term>
      <mesh_term>Immunologic Factors</mesh_term>
      <mesh_term>Immunomodulating Agents</mesh_term>
      <mesh_term>Levoleucovorin</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>From the perspective of protecting the privacy of participants, there was no participant data (IPD) plan in this study.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06041477
  org study id: SL-B2022-793-01
  secondary id: 2023001
  nct id: NCT06041477
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this clinical trial is to compare HAIC concurrently with sequentially combined
        with targeted and immunotherapies in terms of efficacy and safety in patients with
        potentially resectable intermediate and advanced HCC (CNLC stage IIa~IIIa). The main
        questions it aims to answer are:
  
          -  Does a "strong combination" regimen of three simultaneous treatments (HAIC, targeted
             agents and immunotherapy) definitely result in a higher surgical conversion rate and
             better survival benefit?
  
          -  Can the combination of targeted and immunotherapies based on patients' response to HAIC
             therapy avoid over-treatment of some patients without affecting the surgical conversion
             rate and overall survival? Participants will be randomly assigned to receive either HAIC
             concurrently or sequentially combined with targeted and immunotherapies.
  
        Researchers will compare concurrent treatment group with sequential treatment group to see if
        there are different in terms of the conversion resection rate, long-term survival, and
        safety.
  Participants in the concurrent treatment group will receive two cycles of HAIC (the drugs are
        oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2
        over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination
        with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and
        frequency according to instructions), then evaluate the response of tumor, those who achieve
        complete response (CR) will receive surgical resection or follow-up, those with partial
        response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with
        progress disease (PD) will be withdrawn and receive other treatments. After four cycles of
        combined therapy, second evaluation of efficacy will be performed, those who achieve CR will
        receive surgical resection or follow-up observation, and the other patients will be evaluated
        for the possibility of surgical resection or the subsequent treatment.
  
        Participants in the sequential treatment group will receive two cycles of HAIC (drugs of
        oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200
        mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4
        weeks), then evaluate the response of tumor, and those who achieve complete response (CR )
        will receive surgical resection or follow-up, while other patients continue to receive two
        cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and
        immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four
        cycles, a second efficacy assessment will be performed, and patients who achieve CR will
        undergo surgical resection or follow-up observation, and the other patients will be evaluated
        for the possibility of surgical resection or the subsequent treatment.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: OS
  time frame: From date of randomization until the date of death from any cause, assessed at least 36 months
  description: Overall survival of the participants
  measure: PFS
  time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed at least 36 months
  description: Progression-free survival of the participants
  measure: ORR
  time frame: Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)
  description: Objective response rates, which means the proportion of patients with efficacy assessment of complete response and partial response for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively.
  measure: DCR
  time frame: Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)
  description: Disease control rates, which means the proportion of patients with efficacy assessment of complete response, partial response and stable disease for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively.
  measure: CRR
  time frame: This outcome measure will be assessed at the end of Cycle 4 (each cycle is 28 days)
  description: Conversion resection rate refer to the proportion of patients in both groups who actually underwent subsequent surgical resection.
  measure: Safety profiles of all participants
  time frame: This outcome measure will be assessed at the end of Cycle 1 to 4(each cycle is 28 days), and every 3 months through study completion, an average of 3 years
  description: Adverse Events and Severe Adverse Events evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
  arm group label: concurrent treatment group
  arm group type: Experimental
  description: Participants receive two cycles of HAIC (the drugs are oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and frequency according to instructions), then evaluate the response of tumor, those who achieve complete response (CR) will receive surgical resection or follow-up, those with partial response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments. After four cycles of combined therapy, second evaluation of efficacy will be performed, those who achieve CR will receive surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.
  arm group label: sequential treatment group
  arm group type: Active Comparator
  description: Participants receive two cycles of HAIC (drugs of oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200 mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4 weeks), then evaluate the response of tumor, and those who achieve complete response (CR ) will receive surgical resection or follow-up, while other patients continue to receive two cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four cycles, a second efficacy assessment will be performed, and patients who achieve CR will undergo surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.
  intervention type: Drug
  intervention name: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU
  description: Hepatic arterial infusion chemotherapy with (oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks)
  arm group label: concurrent treatment group
  arm group label: sequential treatment group
  other name: Hepatic arterial infusion chemotherapy (HAIC)
  intervention type: Drug
  intervention name: Concurrent Lenvatinib
  description: Lenvatinib 8mg/day combined with the HAIC from the first cycle
  arm group label: concurrent treatment group
  other name: Concurrent targeted therapy
  intervention type: Drug
  intervention name: Concurrent PD-1 antibody
  description: PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the first cycle (dosage and frequency according to instructions)
  arm group label: concurrent treatment group
  other name: Concurrent immunotherapy
  intervention type: Drug
  intervention name: Sequential Lenvatinib
  description: Lenvatinib 8mg/day combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR)
  arm group label: sequential treatment group
  other name: Sequential targeted therapy
  intervention type: Drug
  intervention name: Sequential PD-1 antibody
  description: PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR) (dosage and frequency according to instructions)
  arm group label: sequential treatment group
  other name: Sequential immunotherapy
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Wei Wei, Ph.D, M,D
  role: Principal Investigator
  affiliation: Sun Yat-sen University
  last name: Shao Hua Li, Ph.D, M,D
  phone: 008615088064187
  email: lishaoh@sysucc.org.cn
  last name: Rong Ping Guo, M,D
  phone: 008618819809988
  email: guorp@sysucc.org.cn
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  country: China
  citation: Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
  PMID: 33538338
  citation: Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015 Sep;35(9):2155-66. doi: 10.1111/liv.12818. Epub 2015 Mar 25.
  PMID: 25752327
  citation: Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5.
  PMID: 29307467
  citation: Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol. 2002 Oct;3(10):593-603. doi: 10.1016/s1470-2045(02)00873-2.
  PMID: 12372721
  citation: Shi HY, Wang SN, Wang SC, Chuang SC, Chen CM, Lee KT. Preoperative transarterial chemoembolization and resection for hepatocellular carcinoma: a nationwide Taiwan database analysis of long-term outcome predictors. J Surg Oncol. 2014 Apr;109(5):487-93. doi: 10.1002/jso.23521. Epub 2013 Nov 30.
  PMID: 24293372
  citation: He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):953-960. doi: 10.1001/jamaoncol.2019.0250.
  PMID: 31070690
  citation: Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, Xie Q, Guo R, Shi M, Xu L, Cai X, Wu P, Zhao M. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):60-69. doi: 10.1016/j.jhep.2018.02.008. Epub 2018 Feb 20.
  PMID: 29471013
  citation: He MK, Le Y, Li QJ, Yu ZS, Li SH, Wei W, Guo RP, Shi M. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017 Oct 23;36(1):83. doi: 10.1186/s40880-017-0251-2.
  PMID: 29061175
  citation: Li S, Mei J, Wang Q, Guo Z, Lu L, Ling Y, Xu L, Chen M, Zheng L, Lin W, Zou J, Wen Y, Wei W, Guo R. Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial. Ann Surg Oncol. 2020 Dec;27(13):5183-5190. doi: 10.1245/s10434-020-08601-8. Epub 2020 May 16. Erratum In: Ann Surg Oncol. 2021 Dec;28(Suppl 3):874.
  PMID: 32418078
  citation: Li SH, Mei J, Cheng Y, Li Q, Wang QX, Fang CK, Lei QC, Huang HK, Cao MR, Luo R, Deng JD, Jiang YC, Zhao RC, Lu LH, Zou JW, Deng M, Lin WP, Guan RG, Wen YH, Li JB, Zheng L, Guo ZX, Ling YH, Chen HW, Zhong C, Wei W, Guo RP. Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study. J Clin Oncol. 2023 Apr 1;41(10):1898-1908. doi: 10.1200/JCO.22.01142. Epub 2022 Dec 16.
  PMID: 36525610
  responsible party type: Principal Investigator
  investigator affiliation: Sun Yat-sen University
  investigator full name: Wei Wei
  investigator title: Professor
  mesh term: Carcinoma, Hepatocellular
  mesh term: Leucovorin
  mesh term: Folic Acid
  mesh term: Oxaliplatin
  mesh term: Lenvatinib
  mesh term: Antibodies
  mesh term: Immunoglobulins
  mesh term: Immunologic Factors
  mesh term: Immunomodulating Agents
  mesh term: Levoleucovorin
  sharing ipd: No
  ipd description: From the perspective of protecting the privacy of participants, there was no participant data (IPD) plan in this study.