Donafenib Plus Sintilimab in Combination With TACE in Patients With Unresectable Hepatocellular Carcinoma

A Prospective, Single-arm, Phase II Clinical Study of the Efficacy and Safety of Donafenib Plus Sintilimab Combined With Transarterial Chemoembolization (TACE) in Patients With BCLC Stage B/C Hepatocellular Carcinoma

To evaluate the efficacy and safety of Donafenib plus Sintilimab in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma(HCC).

Transarterial chemoembolisation (TACE) was effective and safe for hepatocellular carcinoma. Donafenib was better than sorafenib in overall survival in untreated advanced hepatocellular carcinoma, and programmed cell death protein-1 (PD-1) antibody was effective and tolerable in patients with advanced hepatocellular carcinoma. No study has evaluated TACE plus donafenib and sintilimab. Thus, the investigators carried out this prospective, single-arm study to find out it.

Inclusion Criteria:

• The patient voluntarily joins the study and signs an informed consent;
• Aged 18 to 75 years, both men and women;
• Clinically or pathologically confirmed Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC, not suitable for radical treatment, and no prior systemic therapy for liver cancer;
• At least one measurable lesion according to mRECIST, defined as a spiral computed tomography (CT) long diameter ≥10 mm or lymph node short diameter ≥15 mm;
• Child-Pugh score small or equal to 7 points (Child-Pugh A-B);
• Single lesion <10 cm in greatest dimension and tumor burden <50% of liver volume;
• Must be able to swallow tablets;
• ECOG score: 0 to 1 (according to the ECOG score classification);
• The expected survival is longer than 12 weeks;
• The laboratory parameters meets the following requirements: Absolute neutrophil count >= 1.5 x 10^9 / L; Platelets >= 50 x 10^9 / L; Hemoglobin >= 80 g / L; serum albumin >= 28 g / L; Thyroid stimulating hormone (TSH) <= 1 x ULN (if abnormalities should be considered at the same time FT3, FT4 levels, patients with FT3 and FT4 levels in normal range can also be enrolled); bilirubin <= 1.5 x ULN (within 7 days prior to the first dose); ALT <= 5 x ULN and AST <= 5 x ULN (within 7 days prior to the first dose); AKP <= 2.5 x ULN; serum creatinine <= 1.5 x ULN;
• For female that non-surgical sterilization or in childbearing age need to use a medically approved contraceptive (such as an intrauterine device, contraceptive or condom) during the study period and within 3 months after the end of the study treatment period; For female that non-surgical sterilization or in childbearing age must have a negative serum or urine HCG test within 72 hours prior to study enrollment; and must be non-lactating; for male patients whose partner in a childbearing age, effective methods of contraception should be given during the trial and at the end of Sintilimab injection.

Exclusion Criteria:

• Any tumor ≥ 10 cm in greatest dimension or tumor involvement ≥ 50% of the liver volume;
• Receive local treatment for HCC((e.g.,TACE, TAE, HAIC or radiotherapy); Ablation and resection are permitted if performed >4 weeks before the first dose of study intervention;
• The patient has any active auto-immune disease or a history of auto-radioimmune disease;
• Evidence of hepatic decompensation including ascites, gastrointestinal bleeding or hepatic encephalopathy;
• The patient is using immunosuppressive agents or systemic hormonal therapy for immunosuppression purposes (dose > 10 mg/day of prednisone or other therapeutic hormones) and continues to be used within 2 weeks prior to enrollment;
• Known or suspected allergy to the investigational agents or any agent given in association with this trial;
• Known central nervous system tumors including metastatic brain disease;
• History of organ allograft;
• Ascites with clinical symptoms;
• The intrahepatic neoplasms showed diffuse changes;
• Suffering from hypertension, and cannot be well controlled by antihypertensive drugs (systolic blood pressure >= 140mmHg or diastolic blood pressure >=90 mmHg);
• Suffering heart diseases with clinical symptoms or those not well controlled, such as:(1) Heart failure in NYHA class 2 or higher;(2) Unstable angina;(3) Myocardial infarction occurred within 1 year;(4) Clinically symptomatic supraventricular or ventricular arrhythmia requiring treatment or intervention;(5) Tc > 450ms (male); QTc > 470ms (female).
• Abnormal coagulation (INR>2.0, PT extension time >4s), bleeding tendency or being treated with thrombolytic or anticoagulant therapy, allowing prophylactic use of low-dose aspirin and low-molecular-weight heparin;
• Evidence of bleeding diathesis; Patients with clinically significant gastrointestinal bleeding within 3 months prior to study entry.
• Events of arterial/venous thrombosis occurring within the first 6 months of enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
• Known history of hereditary or acquired bleeding and thrombotic tendencies (e.g., hemophiliacs, coagulopathy, thrombocytopenia, etc.);
• Had intestinal obstruction and/or had clinical signs or symptoms of GI obstruction within 6 months prior to the start of study treatment, including incomplete obstruction related to pre-existing conditions or requiring routine parenteral hydration, parenteral nutrition, or tube feeding;
• Urine routine indicates that urine protein >= ++ and 24-hour urine protein amount > 1.0g was confirmed;
• The patient has active infection, unexplained fever (>=38.5 degree C) within 3 days before administration, or baseline white blood cell count > 15 x 10^9/L;
• Patients with congenital or acquired immunodeficiency (such as HIV-infected patients); Concurrent hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection without initiation of antiviral therapy. Subjects who initiated anti-HBV and anti-HCV treatment prior to enrollment are eligible;
• The patient has had other malignant tumors in the past 3 years or at the same time (except for cured skin basal cell carcinoma and cervical carcinoma in situ);
• Palliative radiotherapy for non-target lesions to control symptoms is permitted and must be completed at least 2 weeks prior to the start of the study treatment. The adverse events caused by radiotherapy have not recovered to <= CTCAE 1;
• Patients have previously received other anti-PD-1 antibody therapy or other immunotherapy against PD-1/PD-L1, or have received targeted therapies (e.g., sorafenib, lenvatinib) before;
• Inoculation of a live vaccine within less than 4 weeks prior to study or possibly during the study period;
• Pregnant or lactating women, or women of childbearing age who are unwilling to take contraceptive measures;
• According to the investigators, the patient has other factors that may affect the results of the study or lead to the termination of the study, such as alcohol abuse, drug abuse, other serious diseases (including mental illness) requiring combined treatment, and serious laboratory tests, abnormalities, accompanied by factors such as family or society, which may affect the safety of enrolled patients.