Overview

This study is a single-arm, open-label, exploratory clinical trial designed to assess the effectiveness and safety of the combination therapy of Cadonilimab and Lenvatinib for conversion treatment in unresectable hepatocellular carcinoma. Eligible patients, meeting the inclusion criteria and providing informed consent, will undergo 3-4 cycles of Cadonilimab and Lenvatinib conversion therapy. A single imaging assessment will be conducted, and successfully converted patients will proceed to surgical treatment, with pathological evaluation of intraoperative specimens. Post-surgery, patients will choose an appropriate adjuvant treatment based on prior treatment benefits, disease baseline, and personal preferences.

Patients who do not successfully convert and experience disease progression will exit the study for alternative treatment. Those who do not successfully convert but do not exhibit disease progression will continue conversion treatment with Cadonilimab and Lenvatinib±TACE/HAIC, with tumor imaging assessments every 3 cycles. Successfully converted patients will undergo surgery, followed by the selection of an appropriate adjuvant treatment based on prior treatment benefits, disease baseline, and personal preferences.

Patients who do not successfully convert and experience disease progression will exit the study for alternative treatment. Those who do not successfully convert but do not exhibit disease progression will continue conversion treatment with Cadonilimab and Lenvatinib±TACE/HAIC until disease progression or intolerable toxicity occurs, with a maximum treatment duration of 2 years. Efficacy assessment will use mRECIST and RECIST v1.1 criteria, and safety evaluation will follow CTCAE 5.0 standards. Adverse events will be recorded throughout the study, with a period extending to 60 days after treatment completion for serious adverse events or those related to Enfortumab Vedotin, and in some cases extended to 90 days post-treatment.

Eligibility

Inclusion Criteria:

• Participants must sign a written informed consent form before enrollment. Age >18 and ≤75 years, both genders are eligible. Patients with histologically or pathologically confirmed hepatocellular carcinoma (HCC) or meeting the clinical diagnostic criteria for HCC according to the American Association for the Study of Liver Diseases (AASLD).

        BCLC stage C without distant or lymphatic metastasis, or BCLC stage B ineligible for
        curative surgical treatment.
        Presence of measurable lesions (according to RECIST 1.1 criteria, CT scan long diameter ≥10
        mm for non-lymph node lesions, CT scan short diameter ≥15 mm for lymph node lesions).
        No prior systemic anticancer therapy. No prior local treatment for target lesions,
        including TAE, TACE, TARE, surgery, ablation, PEI, or radiotherapy.
        Child-Pugh score <7. ECOG PS score: 0-1. At least one untreated measurable lesion according
        to RECIST v1.1, or a measurable lesion with confirmed progression after local treatment
        (e.g., radiofrequency ablation, ethanol or acetic acid injection, cryoablation,
        high-intensity focused ultrasound, arterial embolization, arterial chemoembolization, etc.)
        per mRECIST criteria.
        Expected survival >12 weeks. Non-surgically sterilized or premenopausal female patients
        must use a medically approved contraceptive measure during the study treatment period and
        within 3 months after the end of the study treatment. Pregnancy tests for non-surgically
        sterilized premenopausal female patients must be negative within 7 days before study entry,
        and they must not be lactating. Non-surgically sterilized or fertile male patients must
        agree to use a medically approved contraceptive measure with their female partners during
        the study treatment period and within 3 months after the end of the study treatment.
        Adequate organ function, excluding any blood component and growth factor use within 14
        days:
        Hematology: ANC ≥1.5×10^9/L, PLT ≥50×10^9/L, HGB ≥90g/L. Liver function: TBIL ≤3×ULN, ALT
        and AST ≤5×ULN, serum albumin ≥28 g/L, ALP ≤5×ULN, and must be stable for at least 1 week
        after routine liver protection treatment as assessed by the investigator.
        Renal function: Cr ≤1.5×ULN or creatinine clearance ≥50 mL/min (using the standard
        Cockcroft-Gault formula), and urine protein <2+; for patients with baseline urine protein
        ≥2+, a 24-hour urine collection and quantitative measurement with <1g of protein is
        required.
        Coagulation function: INR and APTT ≤1.5×ULN; for subjects receiving anticoagulant therapy,
        PT and INR should be within the planned range.
        Exclusion Criteria:
          -  Previously histologically/cytologically confirmed hepatocellular carcinoma with
             fibrolamellar components, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma,
             etc.
        Prior local or systemic anti-tumor therapy. History of hepatic encephalopathy. History of
        liver transplantation. Clinically significant pericardial effusion requiring drainage or
        clinically symptomatic pleural effusion.
        Clinically evident ascites defined as detectable on physical examination or requiring
        drainage during screening.
        Concurrent HBV and HCV infection (HCV RNA negative patients with a history of HCV infection
        are considered uninfected).
        Central nervous system metastasis or leptomeningeal metastasis. History of esophageal or
        gastric variceal bleeding due to portal hypertension in the first 6 months before the
        initial dose. Participants must have undergone esophagogastroduodenoscopy within 6 months
        before the first dose; participants with severe (Grade 3) varices are not allowed to
        participate in the study.
        Patients with any bleeding diathesis signs or history, experiencing any bleeding or
        hemorrhagic events ≥CTCAE Grade 3 within the first 4 weeks before the initial dose.
        Occurrence of arterial or venous thromboembolic events in the first 6 months before the
        initial dose, including myocardial infarction, unstable angina, cerebrovascular accident or
        transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any severe history
        of thromboembolism. Exclusion criteria do not apply to stable thrombosis after routine
        anticoagulation therapy for implanted venous infusion ports or catheter-related thrombosis.
        Uncontrolled hypertension, with systolic blood pressure >150 mmHg or diastolic blood
        pressure >90 mmHg after optimal medical treatment, hypertensive crisis, or a history of
        hypertensive encephalopathy.
        Symptomatic congestive heart failure (New York Heart Association Class II-IV) or
        echocardiographic left ventricular ejection fraction (EF) <50%. Symptomatic or poorly
        controlled arrhythmias, including atrial fibrillation or flutter with a ventricular rate
        >100 beats/min, a history of congenital long QT syndrome, or a corrected QT interval (QTc)
        >450 ms (male) or QTc >470 ms (female) on screening (using the Fridericia method). A
        history of myocarditis, cardiomyopathy, or malignant arrhythmias.
        Severe bleeding tendency or coagulation disorders, or receiving thrombolytic therapy.
        Currently using or recently used (within 10 days before the first dose of study treatment)
        aspirin (>325 mg/day) or anticoagulants requiring INR monitoring (such as warfarin).
        History of gastrointestinal perforation and/or fistula within the first 6 months before the
        initial dose, history of bowel obstruction (including incomplete bowel obstruction
        requiring parenteral nutrition), extensive colon resection (partial colon resection or
        extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative
        colitis, or long-term chronic diarrhea.
        Received radiation therapy within the first 3 weeks before the initial dose. Patients who
        received radiation therapy more than 7 days before the first dose can be enrolled. Presence
        of interstitial lung disease or interstitial lung disease requiring steroid treatment,
        either past or current.
        Active pulmonary tuberculosis (TB), receiving anti-TB treatment, or having received anti-TB
        treatment within the past 1 year before the initial dose.
        Subjects with any active autoimmune disease or a history of autoimmune disease (including
        but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis,
        hepatitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, and those who have
        undergone thyroid surgery cannot be included). Subjects with resolved childhood asthma
        without the need for intervention can be included; subjects with asthma requiring
        bronchodilators for medical intervention cannot be included.
        Subjects using immunosuppressive agents, either systemic or locally absorbable steroids for
        immunosuppressive purposes (dose >10 mg/day prednisone or equivalent), and still continuing
        within the last 2 weeks before enrollment.
        Subjects with active infection or unexplained fever >38.5°C during screening or within the
        first 4 weeks before the initial dose (subjects with fever related to tumor-induced fever
        can be included according to the investigator's judgment).
        Patients with objective evidence of past or present lung fibrosis, interstitial pneumonia,
        pneumoconiosis, radiation pneumonitis, drug-related pneumonia, or severe impairment of lung
        function.
        Subjects with congenital or acquired immunodeficiency, such as HIV infection. Subjects who
        have not received live vaccines within 4 weeks before the study medication or may receive
        live vaccines during the study period.
        Subjects with a known history of substance abuse, alcohol abuse, or drug abuse. Patients
        unable to take oral medication. The investigator deems it necessary to exclude subjects
        from this study. For instance, based on the investigator's judgment, if a participant has
        other factors that could potentially lead to the premature termination of the study, such
        as the presence of other serious illnesses (including mental disorders) requiring
        concurrent treatment, severe gastroesophageal varices, significant laboratory
        abnormalities, or factors related to family or social circumstances that could impact the
        safety of the participant or the collection of data and samples.