TACE Combined With Lenvatinib Versus TACE Sequential Lenvatinib in the Treatment of Intermediate/Advanced Liver Cancer

Inclusion Criteria:

• Provision of signed and dated, written informed consent form (ICF) and any locallyrequired authorization obtained from the patient prior to any mandatory study specificprocedures, sampling, and analyses.
• Provision of signed and dated written genetic informed consent prior to optionalcollection of sample for genetic analysis.
• Patients with BCLC stage C hepatocellular carcinoma confirmed by pathology orclinically diagnosed
• Anticipated life expectancy ≥ 12 months
• Eligible for TACE treatment, including BCLC-B, and BCLC-C only for Eastern CooperativeOncology Group (ECOG) Performance Status 0-1
• No prior systemic therapy (including systemic investigational agents) for HCC,especially immunotherapy
• Age ≥18 years and < 75 years at the time of screening.
• Portal vein invasion or extrahepatic oligosaccharides were detected by baselineimaging. Oligosaccharides were defined as no more than two extrahepatic organs and nomore than three tumors.
• Portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp1 andVp2 are included
• Patients who have previously undergone surgical resection, thermal ablation and otherradical therapies for liver cancer may be enrolled. Prior TACE therapy must be used aspart of the radical therapy (e.g. in combination with thermal ablation or surgery),but not as the sole form of previous treatment. These treatments need to be completedone month before enrollment.
• Child-Pugh score class A to B7
• No local antitumor therapy for hepatocellular carcinoma was received within 4 weeksprior to enrollment
• No evidence of extrahepatic disease on any available imaging
• No previous systemic antitumor therapy for hepatocellular carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
• The expected survival time is no less than 3 months
• BCLC Stage B: Patients with Intermediate HCC exceeding the "up-to-seven" criteria [i.e., the sum of tumor number (number) and maximum tumor diameter (cm) exceeds 7]
• Patients with HBV infection, which is characterized by positive hepatitis B surfaceantigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBVDNA (≥10 IU/ml or above the limit of detection per local lab standard), must betreated with antiviral therapy, as per institutional practice. HBV antiviral therapymust be initiated prior to randomization and patients must remain on antiviral therapyfor the study duration and for 6 months after the last dose of study medication.Patients must show evidence HBV stabilization or signs of viral response (e.g.,reduction HBV DNA levels) prior to starting IP. Patients who test positive foranti-hepatitis B core (HBc) with undetectable HBV DNA (<10 IU/ml or under the limit ofdetection per local lab standard) do not require anti-viral therapy prior torandomization. These subjects will be tested at every cycle to monitor HBV DNA levelsand initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit ofdetection per local lab standard). HBV DNA detectable subjects must initiate andremain on antiviral therapy for the study duration and for 6 months after the lastdose of study medication.
• Patients with HCV infection must have management of this disease per localinstitutional practice throughout the study. HCV diagnosis is characterized by thepresence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody uponenrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according tothe following mRECIST criteria: （1）Liver lesions that show typical features of HCC onIV contrast-enhanced CT or MRI scans, ie, hypervascularity in the arterial phase withwashout in the portal or the late venous phase；（2）Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria "a," "b," "c," and "f"may not be met with transfusions, infusions, or growth factor support administeredwithin 14 days of starting the first dose. Hemoglobin ≥9.0 g/dL、Absolute neutrophil count ≥1000/µL、Platelet count ≥50000/µL、Totalbilirubin ≤2.0 × the upper limit of normal (ULN)、alanine aminotransferase (ALT) andaspartate aminotransferase (AST) ≤5 × ULN、Albumin ≥2.8 g/dL、International normalized ratio ≤1.6、2+ proteinuria or less urine dipstick reading、Calculated creatinine clearance (CL) ≥30mL/min as determined by Cockcroft-Gault (using actual body weight) or 24hour urinecreatinine CL Males: Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL) Females: Creatinine CL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)
• Must have a life expectancy of at least 12 weeks.
• Body weight >30 kg

Exclusion Criteria:

• Evidence of macrovascular invasion (MVI).
• Evidence of extrahepatic spread (EHS)
• Being a candidate for curative treatments (e.g. surgical resection, RFA or livertransplantation).
• Any condition representing a contraindication to TACE as determined by theinvestigators(for example, the main portal vein obstruction without collateral vesselsformed, etc.);
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC;Historyof leptomeningeal disease;
• Allergy to TACE process medications (such as contrast agents) or to Lenvatinib isknown or suspected
• There are obvious arteriovenous fistula or portal vein fistula in the liver.
• Tumor invasion or oppression of the common bile duct, resulting in malignantobstructive jaundice;
• Tumor volume of 70% or more of the liver;
• Previous history of molecular targeted therapy, such as sorafenib, apatinib, etc.
• Patients who had previously used systemic therapy (e.g., immunotherapy, targetedtherapy) were excluded from the study
• Severe heart conditions, such as congestive heart failure & GT; New York HeartAssociation (NYHA) Class II, active coronary artery disease (patients with myocardialinfarction that occurred 6 months prior to enrollment), arrhythmias requiringtreatment (other than beta-blockers, calcium antagonists, or digoxin); Uncontrolledhypertension (diastolic blood pressure not below 90mmHg even after treatment with 3antihypertensive drugs;
• Active clinical severe infection (> Level 2 NCI-CTCAE version 4.0);
• Presence of active pulmonary tuberculosis or inability to exclude intrapulmonarylesions of old pulmonary tuberculosis.
• Known tumors of the central nervous system, including brain metastases;
• Clinically significant gastrointestinal bleeding within 30 days prior to enrollment;
• Autoimmune disease (HIV);
• Pregnant or breast-feeding patients;
• Prior history of liver transplantation;
• Any unstable condition or condition that may compromise the patient's safety andhis/her compliance with the study.