cTACE Plus Sintilimab for Unresectable Intermediate-stage HCC With Beyond Up-to-seven Criteria

Inclusion Criteria:

1. Age ≥20 and ≤75 years old

2. Clinically diagnosed or pathologically confirmed advanced hepatocellular carcinoma. ( Fibrolamellae and mixed hepatocellular/cholangiocarcinoma subtypes are notincluded)

3. CNLC stage IIa/IIb or BCLC stage B, not eligible for resection or local ablation,beyond up-to-seven criteria (hepatocellular carcinomas with seven as the sum of thesize of the largest tumor [in cm] and the number of tumors)

4. Newly diagnosed or recurrent more than half a year after radical surgery

5. No prior TACE treatment,

6. Child-Pugh A, ECOG PS: 0-1

7. Patients with chronic HBV infection must have HBV DNA viral load < 500 IU/mL atscreening. In addition, they must be on antiviral therapy per regional standard ofcare guidelines prior to initiation of study therapy.

8. At least one measurable site of disease as defined by modified RECIST (mRECIST) andRECICL criteria with spiral CT scan or MRI.

9. Life expectancy of at least 3 months.

10. Adequate blood count, liver-enzymes, and renal function: Haemoglobin ≥ 8.5 g/dL,absolute neutrophil count ≥ 1,500/L, platelets ≥70 x103/L; Total bilirubin ≤ 3xupper normal limit; Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25;Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinineclearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula )

11. Patients are willing and able to comply with the protocol for the duration of thestudy including undergoing treatment, adherence to contraceptive measures, scheduledvisits and examinations including follow up.

12. Normal T3 and T4. (T3 and T4 controlled in the normal range through treatment isalso eligible.)

13. Female patients with reproductive potential must have a negative urine or serumpregnancy test within 7 days prior to start of trial.

Exclusion Criteria:

1. Diffuse HCC or presence of vascular invasion or extrahepatic spread.

2. The patient suffered from other malignant tumors in the past 3 years or at the sametime (except for cured skin basal cell carcinoma and cervical carcinoma in situ).

3. Known history of hepatic encephalopathy within 6 months

4. Known history of cardiac disease within 12 months before the first dose of studydrug.

5. Clinically significant hemoptysis or tumor bleeding of any reason within 2 weeksbefore the first dose of study drug.

6. Severe unhealed wounds, ulcers, or fractures

7. Prior systemic anti-cancer therapy.

8. Prior treatment with TACE.

9. Suffer from high blood pressure and cannot be well controlled by antihypertensivedrugs (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg)

10. Any active autoimmune disease or a history of autoimmune disease.

11. Major surgery within 4 weeks of starting the study treatment OR subjects who havenot recovered from effects of major surgery.

12. History of allogeneic tissue/solid organ transplant.

13. Urine routine test showed urine protein ≥ ++ and confirmed 24-hour urine proteincontent> 1.0 g.

14. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1,anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a memberof the Tumor Necrosis Factor Receptor (TNFR) family), or anti-CytotoxicT-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab orany other antibody or drug specifically targeting T-cell co-stimulation orcheckpoint pathways).

15. Female patients who are pregnant, breast-feeding.