Perioperative Sintilimab Plus Bevacizumab Biosimilar and TACE-HAIC for HCC Patients With PVTT: A Phase-2 Clinical Trial

Study Overview
=================
Brief Summary
-----------------
Although resection provided survival benefit for selected HCC patients with PVTT, the recurrence rate is still high for those patients. It is still unknown whether perioperative Sintilimab, a PD-1antibody, plus bevacizumab biosimilar and TACE-HAIC will improve the survival for those patients. We initialed this phase 2 clinical trial to prove the perioperative therapy.

Official Title
-----------------
Perioperative Sintilimab Plus Bevacizumab Biosimilar and Transarterial Embolization, Hepatic Artery Infusion Chemotherapy (TACE-HAIC) for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus (PVTT): A Phase-2 Clinical Trial

Conditions
-----------------
Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: Sintilimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinically diagnosed or pathologically confirmed advanced hepatocellular carcinoma (unresectable or metastatic), at least one measurable focus without local treatment (according to mRECIST requirements, the measurable focus spiral CT scan length ≥ 10 mm or enlargement Short diameter of lymph node ≥15 mm); Child-Pugh score ≤ 6 points (Child-Pugh A); BCLC staging is stage C; PVTT classification is combined with PVTT (program classification PVTT ≤ 3), and a single lesion in the liver (or multiple lesions with diameter) ≤ 7cm of primary liver cancer. Newly diagnosed patients who have not received targeted therapy or immunotherapy in the past; ECOG score: 0～1 (see Annex 1 for ECOG scoring criteria); Expected survival period ≥ 12 weeks; The functions of vital organs meet the following requirements (no blood components, cell growth factors and other corrective treatment drugs are allowed within 14 days before the first administration): Exclusion Criteria: The patient has any active autoimmune disease or a history of autoimmune disease; The patient is using immunosuppressive agents or systemic hormone therapy to achieve the purpose of immunosuppression (dose>10mg/day prednisone or other curative hormones), and continues to use it within 2 weeks before enrollment; The number of system treatment lines ≥ 2 lines; Severe allergic reaction to other monoclonal antibodies; Those with a known history of central nervous system metastasis or hepatic encephalopathy; Patients whose liver tumor burden is greater than 50% of the total liver volume, or who have received liver transplantation in the past; Ascites with clinical symptoms, those who need puncture, drainage, or those who have received ascites drainage within the past 3 months, except those who have only a small amount of ascites on imaging but not accompanied by clinical symptoms; Suffer from high blood pressure and cannot be well controlled by antihypertensive drugs (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg); Uncontrolled cardiac clinical symptoms or diseases, such as: NYHA level 2 or higher heart failure, unstable angina pectoris, myocardial infarction occurred within 1 year, clinically significant supraventricular or ventricular arrhythmia requires treatment or intervention , QTc>450ms (male); QTc>470ms (female); Abnormal coagulation function (INR>2.0, PT>16s), have bleeding tendency or are receiving thrombolysis or anticoagulation therapy, and allow the preventive use of low-dose aspirin and low molecular heparin; Significant clinically significant bleeding symptoms or clear bleeding tendency occurred within 3 months before randomization, such as pertussis/hemoptysis 2.5ml or more, gastrointestinal bleeding, esophageal and gastric varices with bleeding risk, hemorrhagic stomach Ulcer or vasculitis, etc., if the stool occult blood is positive at the baseline, it can be re-examined. If it is still positive after the re-examination, a gastroscopy is required. If the gastroscope shows severe esophageal and gastric varices, it cannot be included in the group (3 before the group) Except those who have undergone gastroscopy within a month or less to exclude such cases); Arterial/venous thrombosis events that occurred within 6 months before randomization, such as cerebrovascular accidents (including temporary ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; Known genetic or acquired bleeding and thrombotic tendency (such as hemophilia patients, coagulation dysfunction, thrombocytopenia, etc.); Urine routine test showed urine protein ≥ ++ and confirmed 24-hour urine protein content> 1.0 g; Patients who have previously received radiotherapy, chemotherapy, hormone therapy, and surgery, after the completion of the treatment (last medication) and less than 4 weeks before the study medication; molecular targeted therapy (including other oral targeted drugs used in clinical trials) is less than the first study medication <5 drug half-lives, or patients whose adverse events (except alopecia) caused by previous treatment have not recovered to ≤ CTCAE level 1; The patient suffered from 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); Patients with bone metastases who received palliative radiotherapy within 4 weeks before participating in the study >5% of the bone marrow area; The patient has previously received other anti-PD-1 antibody therapy or other immunotherapy against PD-1/PD-L1, or has previously received apatinib therapy; Live vaccine may be vaccinated less than 4 weeks before study medication or may be administered during the study period; According to the judgment of the investigator, the patient has other factors that may affect the results of the study or cause the study to be terminated halfway, such as alcoholism, drug abuse, other serious diseases (including mental illness) that require combined treatment, and serious laboratory tests

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Two cycles of Sinitilimab plus bevacizumab biosimilar and TACE-HAIC were administrated before resection, six months adjuvant Sinitilimab plus bevacizumab biosimilar.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perioperative of Sinitilimab, bevacizumab biosimilar plus TACE-HAIC for PVTT-HCC<br>Perioperative of Sinitilimab, bevacizumab biosimilar and TACE-HAIC for HCC patients with PVTT | Drug: Sintilimab<br>* Perioperative Sinitilimab, bevacizumab biosimilar and TACE-HAIC<br>* Other names: bevacizumab biosimilar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RFS, recurrence-free survival | RFS was defined as the time from the date of treatment to that of first recurrence or death. | 6 month |