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/NCT06003673</url>
    </required_header>
    <id_info>
      <org_study_id>MRCTA.ECFAH of FMU[2023]405</org_study_id>
      <nct_id>NCT06003673</nct_id>
    </id_info>
    <brief_title>A Clinical Study of Tislelizumab Combined With TACE and Lenvatinib in the Neoadjuvant Treatment of Resectable HCC</brief_title>
    <official_title>A Single-arm Exploratory Clinical Study of Tislelizumab Combined With Transarterial Chemoembolization (TACE) and Lenvatinib in the Neoadjuvant Treatment of Resectable CNLC Stage Ⅱa-Ⅱb Hepatocellular Carcinoma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>First Affiliated Hospital of Fujian Medical University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>First Affiliated Hospital of Fujian Medical 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>
        In order to improve the R0 resection rate, reduce distant metastasis, and lower postoperative&#xD;
        recurrence, there is a growing exploration of surgical treatments for hepatocellular&#xD;
        carcinoma (HCC), including preoperative neoadjuvant therapy and postoperative adjuvant&#xD;
        therapy. This study is a single-arm, prospective, exploratory clinical trial aimed at&#xD;
        evaluating the effectiveness and safety of combining tislelizumab with transarterial&#xD;
        chemoembolization (TACE) and lenvatinib as neoadjuvant therapy for resectable CNLC stage&#xD;
        IIa-IIb HCC patients. The primary research endpoint of this study is recurrence-free survival&#xD;
        (RFS). A total of 20 Chinese HCC patients with stage IIa-IIb and tumors deemed resectable by&#xD;
        the investigator are enrolled in this study. For stage IIa patients, the inclusion criteria&#xD;
        require meeting any of the following: unclear tumor boundaries, proximity to blood vessels,&#xD;
        or suspicious residual margins. The enrolled patients undergo 2 cycles of neoadjuvant&#xD;
        therapy, with each cycle consisting of treatment every 3 weeks. On the first day of the first&#xD;
        treatment cycle, conventional transarterial chemoembolization (TACE) is performed, and&#xD;
        concomitant intravenous infusion of tislelizumab at a dose of 200mg is given, followed by&#xD;
        oral administration of lenvatinib at a dose of 8/12mg once daily. On the first day of the&#xD;
        second cycle, tislelizumab is again administered intravenously at a dose of 200mg, TACE is&#xD;
        not repeated, and lenvatinib treatment is continued. Within 2-4 weeks after the completion of&#xD;
        neoadjuvant therapy, the investigator evaluates the tumor's suitability for surgical&#xD;
        resection based on comprehensive assessment of imaging results. Subsequently, tumor resection&#xD;
        surgery is performed on eligible patients, followed by survival and safety follow-up for the&#xD;
        patients.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        1. Background&#xD;
  &#xD;
             Primary liver cancer is one of the most common malignancies worldwide, ranking sixth in&#xD;
             terms of incidence and third in terms of cancer-related mortality. Hepatocellular&#xD;
             carcinoma (HCC) is the predominant type of primary liver cancer, accounting for 85%-90%&#xD;
             of cases. Treatment options for HCC include hepatectomy, transplantation, local ablation&#xD;
             therapy, transarterial chemoembolization (TACE), radiation therapy, and systemic&#xD;
             therapy. Hepatectomy is currently the preferred treatment for HCC, but the five-year&#xD;
             recurrence rate after surgery is high, and the overall survival rate for early-stage HCC&#xD;
             is relatively low. Therefore, improving the prognosis of HCC is of utmost importance.&#xD;
  &#xD;
             In recent years, there has been increasing exploration of surgical treatments for HCC,&#xD;
             including neoadjuvant therapy and adjuvant therapy, to increase the R0 resection rate,&#xD;
             reduce distant metastasis, and lower the risk of postoperative recurrence. Neoadjuvant&#xD;
             therapy for HCC refers to interventions such as preoperative radiotherapy,&#xD;
             interventional therapy, targeted therapy, immunotherapy, and portal vein embolization&#xD;
             (PVE) administered to patients with resectable HCC who have a high risk of recurrence.&#xD;
             These interventions aim to reduce liver inflammation, shrink tumors, and eliminate&#xD;
             early-stage microlesions, thereby improving the curative resection rate and overall&#xD;
             survival rate.&#xD;
  &#xD;
             However, there is limited research supporting neoadjuvant therapy for HCC, and its role&#xD;
             in HCC treatment remains unclear. Neoadjuvant therapy has shown preliminary efficacy in&#xD;
             various cancers, such as increasing resection rates and preserving sphincter function in&#xD;
             colorectal cancer, demonstrating significant effects in early-stage non-small cell lung&#xD;
             cancer and advanced malignant melanoma, and showing promise in resectable pancreatic&#xD;
             cancer with high-risk factors. Previous explorations of neoadjuvant therapy for HCC have&#xD;
             included hepatic artery chemotherapy, radiation therapy, and systemic therapy.&#xD;
  &#xD;
             With the emergence of immunotherapy and its promising efficacy in advanced liver cancer,&#xD;
             research on immunotherapy as a neoadjuvant treatment has been conducted. Studies have&#xD;
             shown that neoadjuvant treatment with immunotherapy in resectable liver cancer has&#xD;
             achieved significant tumor necrosis and complete pathological responses. However,&#xD;
             current clinical trials have not reached definitive conclusions, and the role of&#xD;
             neoadjuvant therapy in patients with resectable HCC remains controversial. Therefore,&#xD;
             this study aims to evaluate the efficacy and safety of Tislelizumab in combination with&#xD;
             Transarterial Chemoembolization (TACE) and Lenvatinib as neoadjuvant therapy for&#xD;
             patients with resectable CNLC stage IIa-IIb hepatocellular carcinoma (HCC), with the&#xD;
             goal of providing a better treatment strategy to improve the survival outcomes of these&#xD;
             patients.&#xD;
  &#xD;
          2. Study Objectives&#xD;
  &#xD;
             2.1 Primary Objective:&#xD;
  &#xD;
             - To evaluate the recurrence-free survival (RFS) of patients with resectable CNLC stage&#xD;
             IIa-IIb hepatocellular carcinoma (HCC) treated with Tislelizumab in combination with&#xD;
             Transarterial Chemoembolization (TACE) and Lenvatinib as neoadjuvant therapy.&#xD;
  &#xD;
             2.2 Secondary Objectives:&#xD;
  &#xD;
               -  To evaluate the objective response rate (ORR) of patients with resectable CNLC&#xD;
                  stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib&#xD;
                  as neoadjuvant therapy.&#xD;
  &#xD;
               -  To evaluate the pathological complete response (pCR) rate of patients with&#xD;
                  resectable CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with&#xD;
                  TACE and Lenvatinib as neoadjuvant therapy.&#xD;
  &#xD;
               -  To evaluate the major pathological response (MPR) rate of patients with resectable&#xD;
                  CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and&#xD;
                  Lenvatinib as neoadjuvant therapy.&#xD;
  &#xD;
               -  To evaluate the R0 resection rates of patients with resectable CNLC stage IIa-IIb&#xD;
                  HCC treated with Tislelizumab in combination with TACE and Lenvatinib as&#xD;
                  neoadjuvant therapy.&#xD;
  &#xD;
               -  To evaluate the overall survival (OS) of patients with resectable CNLC stage&#xD;
                  IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib as&#xD;
                  neoadjuvant therapy.&#xD;
  &#xD;
               -  To assess the safety (according to NCI-CTCAE v5.0) of patients with resectable CNLC&#xD;
                  stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib&#xD;
                  as neoadjuvant therapy.&#xD;
  &#xD;
          3. Study Design&#xD;
  &#xD;
             This is a single-arm, prospective, exploratory clinical trial aimed at investigating the&#xD;
             effectiveness and safety of Tislelizumab combined with Transarterial Chemoembolization&#xD;
             (TACE) and Lenvatinib as neoadjuvant therapy in approximately 20 patients with&#xD;
             resectable CNLC stage IIa-IIb hepatocellular carcinoma (HCC) who have not received any&#xD;
             prior treatment. Patients in CNLC stage IIa must meet one of the following criteria:&#xD;
             unclear tumor margins, proximity to blood vessels, or suspicious residual margins. The&#xD;
             primary endpoint of this study is recurrence-free survival (RFS), which will be assessed&#xD;
             by the investigators based on the intention-to-treat (ITT) population assessment.&#xD;
  &#xD;
             Every effort will be made to ensure that the required tests and procedures outlined in&#xD;
             the protocol are conducted according to plan. However, unforeseen circumstances may&#xD;
             arise that are beyond the control of the investigators, making it difficult to perform&#xD;
             the required assessments. In such cases, the investigators will take all necessary&#xD;
             measures to ensure the safety and well-being of the participants. If a required&#xD;
             assessment cannot be performed as specified in the protocol, the investigators will&#xD;
             document the reasons for this occurrence. Additionally, any unexpected situations that&#xD;
             occur will be promptly reported to the research team.&#xD;
  &#xD;
             3.1 Screening Period&#xD;
  &#xD;
             The investigators will enroll participants according to the following steps:&#xD;
  &#xD;
             3.1.1 Obtain informed consent with the participant's signature before conducting any&#xD;
             study-related procedures.&#xD;
  &#xD;
             3.1.2 The principal investigator or designated personnel, who have undergone appropriate&#xD;
             training, will review the inclusion/exclusion criteria to formally determine the&#xD;
             eligibility of participants.&#xD;
  &#xD;
             3.2 Treatment Period&#xD;
  &#xD;
             During the treatment period, relevant physical examinations, laboratory tests, and&#xD;
             collection of adverse events (AEs) and concomitant medication information will be&#xD;
             conducted. The dispensing, retrieval, and inventory of medications will also be&#xD;
             recorded.&#xD;
  &#xD;
             3.2.1 Neoadjuvant Stage&#xD;
  &#xD;
               -  Tislelizumab: 200 mg, administered intravenously on the first day of each treatment&#xD;
                  cycle. Each cycle lasts for 3 weeks, with a total of 2 treatment cycles. The&#xD;
                  initial infusion (first day of the first cycle) should be completed within 60&#xD;
                  minutes. If the infusion is well tolerated, subsequent infusions can be&#xD;
                  administered within 30 minutes, followed by an additional 2-hour patient monitoring&#xD;
                  period.&#xD;
  &#xD;
               -  Lenvatinib: 8 mg per dose (for weight &lt;60 kg) or 12 mg per dose (for weight ≥60&#xD;
                  kg), taken orally once daily until one week before surgery. The medication should&#xD;
                  be taken at the same fixed time each day, with or without food. The tablets should&#xD;
                  be swallowed whole. Alternatively, the tablet (without opening or crushing it) can&#xD;
                  be mixed with one tablespoon of water or apple juice in a glass to form a&#xD;
                  suspension. If a dose is missed and cannot be taken within 12 hours, it should be&#xD;
                  skipped, and the next dose should be taken at the regular scheduled time.&#xD;
  &#xD;
               -  TACE: One session of TACE will be performed on the first day of the neoadjuvant&#xD;
                  treatment, within the first cycle. The conventional TACE (cTACE) technique will be&#xD;
                  used in this study.&#xD;
  &#xD;
             3.2.2 Surgical Stage&#xD;
  &#xD;
             After completing the neoadjuvant treatment, the feasibility of surgery will be assessed&#xD;
             by the investigator. Surgery will be performed for tumor resection within 2-4 weeks&#xD;
             after the neoadjuvant treatment. The investigator and pathology department will conduct&#xD;
             an assessment of neoadjuvant treatment response (MPR and pCR).&#xD;
  &#xD;
             3.2.3 Postoperative Stage&#xD;
  &#xD;
             After the final treatment, patients will enter the treatment follow-up and safety&#xD;
             monitoring period. Patients who discontinue treatment due to disease progression should&#xD;
             continue to be followed up for their survival. Patients who discontinue treatment or&#xD;
             exit the study for reasons other than disease progression will undergo tumor assessment&#xD;
             every 12 weeks until disease progression, death, study completion, or intolerable&#xD;
             toxicity. The investigator may collect information on the patient's survival (date of&#xD;
             death and cause of death) and other anti-tumor treatments after the completion of the&#xD;
             study by conducting telephone interviews with the patient, their family members, or&#xD;
             local physicians. The details of each survival follow-up should be accurately recorded&#xD;
             in the original medical records. Safety follow-up is required for all patients within 90&#xD;
             days after the last treatment.&#xD;
  &#xD;
          4. Efficacy and Safety Assessment&#xD;
  &#xD;
        The ITT population includes all enrolled patients and serves as the primary analysis&#xD;
        population for efficacy. The safety population includes all patients who received at least&#xD;
        one dose of the investigational drugs and will be used for safety analysis.&#xD;
  &#xD;
        4.1 Efficacy Assessment&#xD;
  &#xD;
          -  Recurrence-Free Survival (RFS): The time from the first day of curative surgery to tumor&#xD;
             recurrence or death from any cause.&#xD;
  &#xD;
          -  Objective Response Rate (ORR): The proportion of participants with the best overall&#xD;
             response (BOR) of complete response (CR) or partial response (PR) assessed by the&#xD;
             investigator according to RECIST v1.1 during the neoadjuvant stage.&#xD;
  &#xD;
          -  Pathological Complete Response Rate (pCR): The proportion of patients assessed by the&#xD;
             investigator, after completion of neoadjuvant treatment, with no residual tumor cells in&#xD;
             the resected tumor.&#xD;
  &#xD;
          -  Major Pathological Response Rate (MPR): The proportion of patients assessed by the&#xD;
             investigator, after completion of neoadjuvant treatment, with ≤10% residual viable tumor&#xD;
             cells in the resected tumor.&#xD;
  &#xD;
          -  R0 Resection Rate: The proportion of patients achieving R0 resection among all surgical&#xD;
             patients.&#xD;
  &#xD;
          -  Overall Survival (OS): The time from the start of treatment to death from any cause.&#xD;
  &#xD;
        4.2 Safety Assessment&#xD;
  &#xD;
        Safety will be evaluated by monitoring and recording all adverse events (AEs) and serious&#xD;
        adverse events (SAEs) in terms of their incidence and severity, graded according to NCI-CTCAE&#xD;
        v5.0. Laboratory test results (such as hematology, clinical chemistry, urine analysis), vital&#xD;
        signs, ECOG performance status, and physical examinations will also be used to assess safety.&#xD;
        Descriptive statistics will be used to analyze all safety data in the safety population.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">August 30, 2025</completion_date>
    <primary_completion_date type="Anticipated">August 30, 2024</primary_completion_date>
    <phase>Phase 4</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>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>recurrence-free survival (RFS)</measure>
      <time_frame>up to 36 months</time_frame>
      <description>The period of time from the first day of curative surgery until tumor recurrence or death from any cause.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Objective Response Rate (ORR)</measure>
      <time_frame>10 weeks</time_frame>
      <description>The proportion of participants assessed by the investigators based on RECIST v1.1 criteria, who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) during the neoadjuvant treatment period.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pathological Complete Response Rate (pCR)</measure>
      <time_frame>10 weeks</time_frame>
      <description>The proportion of patients evaluated by the investigators after completion of neoadjuvant treatment, who have no residual tumor cells in the resected tumor.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Major Pathological Response Rate (MPR)</measure>
      <time_frame>10 weeks</time_frame>
      <description>The proportion of patients assessed by the investigators after completion of neoadjuvant treatment, who have residual viable tumor cells of ≤10% in the resected tumor.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>R0 Resection Rate</measure>
      <time_frame>10 weeks</time_frame>
      <description>The proportion of patients who achieve R0 resection among all surgical patients.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Survival (OS)</measure>
      <time_frame>up to 36 months</time_frame>
      <description>The time from the start of treatment to death from any cause.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">20</enrollment>
    <condition>Hepatocellular Carcinoma Resectable</condition>
    <arm_group>
      <arm_group_label>Neoadjuvant therapy group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants will receive a combination treatment of Tislelizumab, Lenvatinib, and Transarterial Chemoembolization (TACE).</description>
    </arm_group>
    <intervention>
      <intervention_type>Combination Product</intervention_type>
      <intervention_name>neoadjuvant therapy</intervention_name>
      <description>The enrolled patients undergo 2 cycles of neoadjuvant therapy, with each cycle consisting of treatment every 3 weeks. On the first day of the first treatment cycle, conventional transarterial chemoembolization (TACE) is performed, and concomitant intravenous infusion of tislelizumab at a dose of 200mg is given, followed by oral administration of lenvatinib at a dose of 8/12mg once daily. On the first day of the second cycle, tislelizumab is again administered intravenously at a dose of 200mg, TACE is not repeated, and lenvatinib treatment is continued. Within 2-4 weeks after the completion of neoadjuvant therapy, the investigator evaluates the tumor's suitability for surgical resection based on a comprehensive assessment of imaging results. Subsequently, eligible patients undergo tumor resection surgery, followed by follow-up for survival and safety monitoring.</description>
      <arm_group_label>Neoadjuvant therapy group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Participants must voluntarily enroll in this study and provide signed informed&#xD;
               consent.&#xD;
  &#xD;
            2. Male or female patients between the ages of 18 and 75 years old.&#xD;
  &#xD;
            3. Patients diagnosed with hepatocellular carcinoma (HCC) confirmed by histopathology or&#xD;
               imaging.&#xD;
  &#xD;
            4. Chinese liver cancer staging of IIa-IIb with hepatocellular carcinoma considered&#xD;
               resectable by the investigator. For IIa-stage patients, they must meet at least one of&#xD;
               the following criteria: unclear tumor margins, proximity to blood vessels, or&#xD;
               suspicious residual margins.&#xD;
  &#xD;
            5. At least one measurable lesion according to the Response Evaluation Criteria in Solid&#xD;
               Tumors (RECIST v1.1) guidelines (measurable lesions with CT scan long diameter ≥ 10 mm&#xD;
               or lymph node lesions with CT scan short diameter ≥ 15 mm, and no prior local&#xD;
               treatment such as radiation or cryotherapy).&#xD;
  &#xD;
            6. Child-Pugh liver function class A.&#xD;
  &#xD;
            7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
  &#xD;
            8. No prior systemic treatment for HCC.&#xD;
  &#xD;
            9. For HBsAg-positive patients, HBV-DNA &lt; 200,000 IU/ml (106 copies/ml), and receiving&#xD;
               routine antiviral therapy.&#xD;
  &#xD;
           10. Expected survival of at least 3 months.&#xD;
  &#xD;
           11. Normal major organ function, meeting the following criteria:&#xD;
  &#xD;
                 -  Hematology criteria:&#xD;
  &#xD;
                 -  Hemoglobin (HB) ≥ 90 g/L;&#xD;
  &#xD;
                 -  Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/m3);&#xD;
  &#xD;
                 -  Platelet count (PLT) ≥ 75 × 109/L.&#xD;
  &#xD;
                 -  Biochemistry criteria:&#xD;
  &#xD;
                 -  Total bilirubin (TBIL) ≤ 2 × ULN;&#xD;
  &#xD;
                 -  ALT, ALP, and AST ≤ 5 × ULN;&#xD;
  &#xD;
                 -  Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 ml/min&#xD;
                    (calculated using the Cockcroft-Gault formula: CrCL (mL/min) = [(140 - age) ×&#xD;
                    body weight (kg) × F] / (SCr(mg/dL) × 72). Where F=1 for males and F=0.85 for&#xD;
                    females; SCr=serum creatinine).&#xD;
  &#xD;
                 -  Coagulation function: International Normalized Ratio (INR) ≤ 2.3.&#xD;
  &#xD;
           12. Blood pressure (BP) controlled with a maximum of 3 antihypertensive medications,&#xD;
               defined as BP ≤ 150/90 mmHg at screening, and no changes in antihypertensive treatment&#xD;
               within one week before Cycle 1/Day 1.&#xD;
  &#xD;
           13. Doppler echocardiography: Left Ventricular Ejection Fraction (LVEF) ≥ lower limit of&#xD;
               normal (50%).&#xD;
  &#xD;
           14. Women of childbearing potential must use reliable contraceptive methods or undergo&#xD;
               pregnancy testing (serum or urine) within 7 days before enrollment, with negative&#xD;
               results, and agree to use appropriate contraceptive methods during the trial and for 8&#xD;
               weeks after the last dose of investigational drugs. For males, they must agree to use&#xD;
               appropriate contraceptive methods during the trial and for 8 weeks after the last dose&#xD;
               of investigational drugs or have undergone surgical sterilization.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Extrahepatic metastasis of primary liver cancer.&#xD;
  &#xD;
            2. Diffuse liver cancer with tumor burden ≥ 50% of liver volume; and/or macrovascular&#xD;
               invasion of the portal vein classified as Type IV; and/or inferior vena cava tumor&#xD;
               thrombosis.&#xD;
  &#xD;
            3. Prior treatment with targeted immunotherapy agents, including but not limited to&#xD;
               anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated antigen 4&#xD;
               (anti-CTLA-4) antibodies.&#xD;
  &#xD;
            4. Contraindications for Transarterial Chemoembolization (TACE) treatment.&#xD;
  &#xD;
            5. Participation in other investigational drug trials within the past 4 weeks.&#xD;
  &#xD;
            6. Medical history and comorbidities:1)Active, known, or suspected autoimmune diseases,&#xD;
               including a history of allogeneic organ transplantation, allogeneic hematopoietic stem&#xD;
               cell transplantation, HIV positive history, or acquired immunodeficiency syndrome&#xD;
               (AIDS) history. 2)Severe cardiovascular diseases: Grade II or higher myocardial&#xD;
               ischemia or myocardial infarction, poorly controlled arrhythmia; NYHA Class III-IV&#xD;
               heart failure, or left ventricular ejection fraction (LVEF) &lt; 50% based on&#xD;
               echocardiography. 3)Active infections. 4)Known allergies to components of Tislelizumab&#xD;
               or Lenvatinib. 5)History of substance abuse, alcoholism, or drug addiction.&#xD;
  &#xD;
            7. Ineligibility as determined by the investigator.&#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>Zhang Zhibo, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>First Affiliated Hospital of Fujian Medical University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Zhang Zhibo, PhD</last_name>
      <phone>008618559853003</phone>
      <email>wql0211@gmail.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>The First Affiliated Hospital of Fujian Medical University</name>
        <address>
          <city>Fuzhou</city>
          <state>Fujian</state>
          <zip>350000</zip>
          <country>China</country>
        </address>
      </facility>
      <contact>
        <last_name>Zhang Zhibo, PhD</last_name>
        <phone>008618559853003</phone>
        <email>wql0211@gmail.com</email>
      </contact>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 14, 2023</study_first_submitted>
    <study_first_submitted_qc>August 19, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 22, 2023</study_first_posted>
    <last_update_submitted>August 19, 2023</last_update_submitted>
    <last_update_submitted_qc>August 19, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 22, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>First Affiliated Hospital of Fujian Medical University</investigator_affiliation>
      <investigator_full_name>Zhang Zhibo</investigator_full_name>
      <investigator_title>Director of Hepatobiliary and Pancreatic Surgery Department</investigator_title>
    </responsible_party>
    <keyword>hepatocellular carcinoma</keyword>
    <keyword>resectable</keyword>
    <keyword>CNLC stage IIa-IIb</keyword>
    <keyword>neoadjuvant therapy</keyword>
    <keyword>Tislelizumab</keyword>
    <keyword>Lenvatinib</keyword>
    <keyword>Transarterial Chemoembolization (TACE)</keyword>
    <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>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </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/NCT06003673
  org study id: MRCTA.ECFAH of FMU[2023]405
  nct id: NCT06003673
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  In order to improve the R0 resection rate, reduce distant metastasis, and lower postoperative
        recurrence, there is a growing exploration of surgical treatments for hepatocellular
        carcinoma (HCC), including preoperative neoadjuvant therapy and postoperative adjuvant
        therapy. This study is a single-arm, prospective, exploratory clinical trial aimed at
        evaluating the effectiveness and safety of combining tislelizumab with transarterial
        chemoembolization (TACE) and lenvatinib as neoadjuvant therapy for resectable CNLC stage
        IIa-IIb HCC patients. The primary research endpoint of this study is recurrence-free survival
        (RFS). A total of 20 Chinese HCC patients with stage IIa-IIb and tumors deemed resectable by
        the investigator are enrolled in this study. For stage IIa patients, the inclusion criteria
        require meeting any of the following: unclear tumor boundaries, proximity to blood vessels,
        or suspicious residual margins. The enrolled patients undergo 2 cycles of neoadjuvant
        therapy, with each cycle consisting of treatment every 3 weeks. On the first day of the first
        treatment cycle, conventional transarterial chemoembolization (TACE) is performed, and
        concomitant intravenous infusion of tislelizumab at a dose of 200mg is given, followed by
        oral administration of lenvatinib at a dose of 8/12mg once daily. On the first day of the
        second cycle, tislelizumab is again administered intravenously at a dose of 200mg, TACE is
        not repeated, and lenvatinib treatment is continued. Within 2-4 weeks after the completion of
        neoadjuvant therapy, the investigator evaluates the tumor's suitability for surgical
        resection based on comprehensive assessment of imaging results. Subsequently, tumor resection
        surgery is performed on eligible patients, followed by survival and safety follow-up for the
        patients.
  1. Background
  
             Primary liver cancer is one of the most common malignancies worldwide, ranking sixth in
             terms of incidence and third in terms of cancer-related mortality. Hepatocellular
             carcinoma (HCC) is the predominant type of primary liver cancer, accounting for 85%-90%
             of cases. Treatment options for HCC include hepatectomy, transplantation, local ablation
             therapy, transarterial chemoembolization (TACE), radiation therapy, and systemic
             therapy. Hepatectomy is currently the preferred treatment for HCC, but the five-year
             recurrence rate after surgery is high, and the overall survival rate for early-stage HCC
             is relatively low. Therefore, improving the prognosis of HCC is of utmost importance.
  
             In recent years, there has been increasing exploration of surgical treatments for HCC,
             including neoadjuvant therapy and adjuvant therapy, to increase the R0 resection rate,
             reduce distant metastasis, and lower the risk of postoperative recurrence. Neoadjuvant
             therapy for HCC refers to interventions such as preoperative radiotherapy,
             interventional therapy, targeted therapy, immunotherapy, and portal vein embolization
             (PVE) administered to patients with resectable HCC who have a high risk of recurrence.
             These interventions aim to reduce liver inflammation, shrink tumors, and eliminate
             early-stage microlesions, thereby improving the curative resection rate and overall
             survival rate.
  
             However, there is limited research supporting neoadjuvant therapy for HCC, and its role
             in HCC treatment remains unclear. Neoadjuvant therapy has shown preliminary efficacy in
             various cancers, such as increasing resection rates and preserving sphincter function in
             colorectal cancer, demonstrating significant effects in early-stage non-small cell lung
             cancer and advanced malignant melanoma, and showing promise in resectable pancreatic
             cancer with high-risk factors. Previous explorations of neoadjuvant therapy for HCC have
             included hepatic artery chemotherapy, radiation therapy, and systemic therapy.
  
             With the emergence of immunotherapy and its promising efficacy in advanced liver cancer,
             research on immunotherapy as a neoadjuvant treatment has been conducted. Studies have
             shown that neoadjuvant treatment with immunotherapy in resectable liver cancer has
             achieved significant tumor necrosis and complete pathological responses. However,
             current clinical trials have not reached definitive conclusions, and the role of
             neoadjuvant therapy in patients with resectable HCC remains controversial. Therefore,
             this study aims to evaluate the efficacy and safety of Tislelizumab in combination with
             Transarterial Chemoembolization (TACE) and Lenvatinib as neoadjuvant therapy for
             patients with resectable CNLC stage IIa-IIb hepatocellular carcinoma (HCC), with the
             goal of providing a better treatment strategy to improve the survival outcomes of these
             patients.
  
          2. Study Objectives
  
             2.1 Primary Objective:
  
             - To evaluate the recurrence-free survival (RFS) of patients with resectable CNLC stage
             IIa-IIb hepatocellular carcinoma (HCC) treated with Tislelizumab in combination with
             Transarterial Chemoembolization (TACE) and Lenvatinib as neoadjuvant therapy.
  
             2.2 Secondary Objectives:
  
               -  To evaluate the objective response rate (ORR) of patients with resectable CNLC
                  stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib
                  as neoadjuvant therapy.
  
               -  To evaluate the pathological complete response (pCR) rate of patients with
                  resectable CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with
                  TACE and Lenvatinib as neoadjuvant therapy.
  
               -  To evaluate the major pathological response (MPR) rate of patients with resectable
                  CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and
                  Lenvatinib as neoadjuvant therapy.
  
               -  To evaluate the R0 resection rates of patients with resectable CNLC stage IIa-IIb
                  HCC treated with Tislelizumab in combination with TACE and Lenvatinib as
                  neoadjuvant therapy.
  
               -  To evaluate the overall survival (OS) of patients with resectable CNLC stage
                  IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib as
                  neoadjuvant therapy.
  
               -  To assess the safety (according to NCI-CTCAE v5.0) of patients with resectable CNLC
                  stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib
                  as neoadjuvant therapy.
  
          3. Study Design
  
             This is a single-arm, prospective, exploratory clinical trial aimed at investigating the
             effectiveness and safety of Tislelizumab combined with Transarterial Chemoembolization
             (TACE) and Lenvatinib as neoadjuvant therapy in approximately 20 patients with
             resectable CNLC stage IIa-IIb hepatocellular carcinoma (HCC) who have not received any
             prior treatment. Patients in CNLC stage IIa must meet one of the following criteria:
             unclear tumor margins, proximity to blood vessels, or suspicious residual margins. The
             primary endpoint of this study is recurrence-free survival (RFS), which will be assessed
             by the investigators based on the intention-to-treat (ITT) population assessment.
  
             Every effort will be made to ensure that the required tests and procedures outlined in
             the protocol are conducted according to plan. However, unforeseen circumstances may
             arise that are beyond the control of the investigators, making it difficult to perform
             the required assessments. In such cases, the investigators will take all necessary
             measures to ensure the safety and well-being of the participants. If a required
             assessment cannot be performed as specified in the protocol, the investigators will
             document the reasons for this occurrence. Additionally, any unexpected situations that
             occur will be promptly reported to the research team.
  
             3.1 Screening Period
  
             The investigators will enroll participants according to the following steps:
  
             3.1.1 Obtain informed consent with the participant's signature before conducting any
             study-related procedures.
  
             3.1.2 The principal investigator or designated personnel, who have undergone appropriate
             training, will review the inclusion/exclusion criteria to formally determine the
             eligibility of participants.
  
             3.2 Treatment Period
  
             During the treatment period, relevant physical examinations, laboratory tests, and
             collection of adverse events (AEs) and concomitant medication information will be
             conducted. The dispensing, retrieval, and inventory of medications will also be
             recorded.
  
             3.2.1 Neoadjuvant Stage
  
               -  Tislelizumab: 200 mg, administered intravenously on the first day of each treatment
                  cycle. Each cycle lasts for 3 weeks, with a total of 2 treatment cycles. The
                  initial infusion (first day of the first cycle) should be completed within 60
                  minutes. If the infusion is well tolerated, subsequent infusions can be
                  administered within 30 minutes, followed by an additional 2-hour patient monitoring
                  period.
  
               -  Lenvatinib: 8 mg per dose (for weight <60 kg) or 12 mg per dose (for weight ≥60
                  kg), taken orally once daily until one week before surgery. The medication should
                  be taken at the same fixed time each day, with or without food. The tablets should
                  be swallowed whole. Alternatively, the tablet (without opening or crushing it) can
                  be mixed with one tablespoon of water or apple juice in a glass to form a
                  suspension. If a dose is missed and cannot be taken within 12 hours, it should be
                  skipped, and the next dose should be taken at the regular scheduled time.
  
               -  TACE: One session of TACE will be performed on the first day of the neoadjuvant
                  treatment, within the first cycle. The conventional TACE (cTACE) technique will be
                  used in this study.
  
             3.2.2 Surgical Stage
  
             After completing the neoadjuvant treatment, the feasibility of surgery will be assessed
             by the investigator. Surgery will be performed for tumor resection within 2-4 weeks
             after the neoadjuvant treatment. The investigator and pathology department will conduct
             an assessment of neoadjuvant treatment response (MPR and pCR).
  
             3.2.3 Postoperative Stage
  
             After the final treatment, patients will enter the treatment follow-up and safety
             monitoring period. Patients who discontinue treatment due to disease progression should
             continue to be followed up for their survival. Patients who discontinue treatment or
             exit the study for reasons other than disease progression will undergo tumor assessment
             every 12 weeks until disease progression, death, study completion, or intolerable
             toxicity. The investigator may collect information on the patient's survival (date of
             death and cause of death) and other anti-tumor treatments after the completion of the
             study by conducting telephone interviews with the patient, their family members, or
             local physicians. The details of each survival follow-up should be accurately recorded
             in the original medical records. Safety follow-up is required for all patients within 90
             days after the last treatment.
  
          4. Efficacy and Safety Assessment
  
        The ITT population includes all enrolled patients and serves as the primary analysis
        population for efficacy. The safety population includes all patients who received at least
        one dose of the investigational drugs and will be used for safety analysis.
  
        4.1 Efficacy Assessment
  
          -  Recurrence-Free Survival (RFS): The time from the first day of curative surgery to tumor
             recurrence or death from any cause.
  
          -  Objective Response Rate (ORR): The proportion of participants with the best overall
             response (BOR) of complete response (CR) or partial response (PR) assessed by the
             investigator according to RECIST v1.1 during the neoadjuvant stage.
  
          -  Pathological Complete Response Rate (pCR): The proportion of patients assessed by the
             investigator, after completion of neoadjuvant treatment, with no residual tumor cells in
             the resected tumor.
  
          -  Major Pathological Response Rate (MPR): The proportion of patients assessed by the
             investigator, after completion of neoadjuvant treatment, with ≤10% residual viable tumor
             cells in the resected tumor.
  
          -  R0 Resection Rate: The proportion of patients achieving R0 resection among all surgical
             patients.
  
          -  Overall Survival (OS): The time from the start of treatment to death from any cause.
  
        4.2 Safety Assessment
  
        Safety will be evaluated by monitoring and recording all adverse events (AEs) and serious
        adverse events (SAEs) in terms of their incidence and severity, graded according to NCI-CTCAE
        v5.0. Laboratory test results (such as hematology, clinical chemistry, urine analysis), vital
        signs, ECOG performance status, and physical examinations will also be used to assess safety.
        Descriptive statistics will be used to analyze all safety data in the safety population.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: recurrence-free survival (RFS)
  time frame: up to 36 months
  description: The period of time from the first day of curative surgery until tumor recurrence or death from any cause.
  measure: Objective Response Rate (ORR)
  time frame: 10 weeks
  description: The proportion of participants assessed by the investigators based on RECIST v1.1 criteria, who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) during the neoadjuvant treatment period.
  measure: Pathological Complete Response Rate (pCR)
  time frame: 10 weeks
  description: The proportion of patients evaluated by the investigators after completion of neoadjuvant treatment, who have no residual tumor cells in the resected tumor.
  measure: Major Pathological Response Rate (MPR)
  time frame: 10 weeks
  description: The proportion of patients assessed by the investigators after completion of neoadjuvant treatment, who have residual viable tumor cells of ≤10% in the resected tumor.
  measure: R0 Resection Rate
  time frame: 10 weeks
  description: The proportion of patients who achieve R0 resection among all surgical patients.
  measure: Overall Survival (OS)
  time frame: up to 36 months
  description: The time from the start of treatment to death from any cause.
  arm group label: Neoadjuvant therapy group
  arm group type: Experimental
  description: Participants will receive a combination treatment of Tislelizumab, Lenvatinib, and Transarterial Chemoembolization (TACE).
  intervention type: Combination Product
  intervention name: neoadjuvant therapy
  description: The enrolled patients undergo 2 cycles of neoadjuvant therapy, with each cycle consisting of treatment every 3 weeks. On the first day of the first treatment cycle, conventional transarterial chemoembolization (TACE) is performed, and concomitant intravenous infusion of tislelizumab at a dose of 200mg is given, followed by oral administration of lenvatinib at a dose of 8/12mg once daily. On the first day of the second cycle, tislelizumab is again administered intravenously at a dose of 200mg, TACE is not repeated, and lenvatinib treatment is continued. Within 2-4 weeks after the completion of neoadjuvant therapy, the investigator evaluates the tumor's suitability for surgical resection based on a comprehensive assessment of imaging results. Subsequently, eligible patients undergo tumor resection surgery, followed by follow-up for survival and safety monitoring.
  arm group label: Neoadjuvant therapy group
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Zhang Zhibo, PhD
  role: Principal Investigator
  affiliation: First Affiliated Hospital of Fujian Medical University
  last name: Zhang Zhibo, PhD
  phone: 008618559853003
  email: wql0211@gmail.com
  facility: 
  contact: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: First Affiliated Hospital of Fujian Medical University
  investigator full name: Zhang Zhibo
  investigator title: Director of Hepatobiliary and Pancreatic Surgery Department
  mesh term: Carcinoma
  mesh term: Carcinoma, Hepatocellular
  sharing ipd: No