This study aims to evaluate the efficacy and safety of sorafenib plus toripalimab for unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).

Investigators aimed to conduct an exploratory study- an open-label, single-arm and multi-center -to evaluate the efficacy and safety of sorafenib plus toripalimab for unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). The primary objectives are 6-month progression free survival (PFS) rate and safety. Secondary objectives include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and duration of response. The study is divided into dose escalation stage and expansion stage.

Stage I (escalation stage) was designed to identify the dose-limiting toxicity (DLT) of the combination therapy. Subjects enrolled were divided into two cohorts. Subjects (n=3) in cohort A received oral sorafenib at doses of 400 mg once daily, in combination with intravenous toripalimab 240 mg on the first day, every 3 weeks. Subjects (n=3) in cohort B received oral sorafenib at doses of 400 mg twice daily, in combination with intravenous toripalimab 240 mg on the first day, every 3 weeks. If DLT does not occur within 42 days of the first administration, the dose is escalated. If one subject experienced DLTs, additional 3 subjects are enrolled at that level. Unless no DLT occurs, the next dose level test is continued.

Once ≥2 subjects in cohort A experienced DLT, the study is suspended in advance. If ≥2 subjects in cohort B experienced DLT, the dose of cohort A is recommended in expansion stage. If DLT does not occur in cohort B or only 1 of 6 subjects suffered DLT, the dose of cohort B is recommended in expansion stage.

For subjects who experienced DLT, if adverse events (AEs) return to normal or common terminology criteria for adverse events (CTCAE) level 1 within 2 weeks and researchers believe continuing treatment is beneficial to the subjects, they can continue treatment after dose adjustment. Otherwise, termination of treatment is suggested.

According to CTCAE version 4.0, DLT was defined as any grade ≥3 treatment-related toxicity occurring within the first 42 days of administration. Six to twelve patients will be included in this stage.

Stage II (Expansion stage): According to the expansion dose based on stage I, subjects are enlarged to 39. Subjects enrolled are treated with oral sorafenib in combination with toripalimab (every 3 weeks) until suffering progressive disease (PD) or un-tolerated toxicities. Previous literature indicated 6-month PFS rate for HCC with PVTT treated with sorafenib is about 20%. Investigators hypothesize sorafenib plus toripalimab could improve 6-month PFS rate to 40%. Software (PASS) is used to calculate the sample size (β=0.2，α=0.05). According to the results, 35 subjects should be enrolled. When 10% missing rate is considered, total subjects is 39.

Inclusion Criteria:

1. Histologic or cytologic diagnosis of unresectable hepatocellular carcinoma, or confirmed clinically in accordance with Chinese Association for the Study of Liver Diseases criteria (v2017)
2. Radiographically measurable disease by RECIST version 1.1 in at least one site
3. Radiographic evidence of portal vein cancer thrombus
4. Survival expectation ≥3 months
5. Eastern Cooperative Oncology Group: 0 or 1
6. Child-Pugh score A or B: score ≤7
7. Not previously treated with any systemic anti-cancer treatment (i.e. chemotherapy, target drugs, immune checkpoint inhibitors); Subjects who have received local hepatic therapy such as surgery, ablation, radiotherapy or transcatheter arterial chemoembolization, progression of target lesions after local treatment is required to increase by 25%, or target lesions are untreated, and the end of local treatment is more than 4 weeks.
8. All eligible patients have adequate organ function (ANC ≥1.5× 10⁹ / L, PLT ≥75 × 10⁹ /L, HGB≥90 g/L (no blood transfusion or EPO tolerance within 7 days), Cr≤1.5 times the ULN, TBN ≤1.5 times ULN, ALT and AST ≤3 times ULN, albumin ≥30g/L (albumin or branched chain amino acids supplementation is not allowed within 14 days), INR≤1.5 times the ULN, Urine protein≤1+).
9. Signed and dated written informed consent

Exclusion Criteria:

1. History of severe allergic reactions to chimeric, human or humanized antibodies, or fusion proteins. Hypersensitive to any component of the CHO cell-derived preparation or JS001 preparation
2. Pregnant or lactating women, men and women of childbearing age who are unwilling or unable to take effective contraceptive measures
3. History of other malignancy within the past 5 years
4. Medium or more pleural and ascites with clinical symptoms
5. Active hemorrhage or abnormal coagulation function (PT>16s, APTT>43s, INR>1.5 x ULN), or having a tendency to bleed or undergoing thrombolysis, anticoagulation or anti-platelet therapy
6. Central nervous system metastases
7. Hepatic encephalopathy
8. History of gastrointestinal bleeding or having a tendency to bleed within 6 months before enrollment, e.g. local active ulcer lesions; fecal occult blood (+ +) or above should not be included; if continuous fecal occult blood (+), gastroscopy should be performed.
9. Gastric or esophageal varices requiring treatment
10. Untreated active hepatitis B (i.e. subjects with hepatitis B undergoing antiviral therapy and HBV Load < 100IU/mL before the first administration of Toripalimab , is allowed to be enrolled; for subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-) , prophylactic anti-HBV therapy is not required, but virus activation should be closely monitored)
11. HCV and the anti-HCV treatment ended within 4 weeks of the first administration. Notably, subjects with untreated chronic HCV infection or untreated HCV are allowed.
12. History of drug abuse or mental disorders
13. History of organ or marrow transplants, or active autoimmune diseases requiring systemic treatment occurred within 2 years of the first administration
14. Immunodeficiency disorders or HIV
15. Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia and severe impairment of pulmonary function
16. Using immunosuppressive agents or systemic or absorbable local corticosteroids for immunosuppressive purposes (prednisone or its equivalent at dose> 10 mg/day) , and the above are used within 2 weeks before admission.
17. Major liver or other operations were performed within 4 weeks of the first administration, or minor operations were performed within 1 week before the first administration (simple excision, tooth extraction, etc.)
18. Receiving vaccine within 30 days of the first administration
19. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 4 weeks of the first administration
20. Receiving other experimental drugs or medical devices within 4 weeks of the first administration
21. Any significant clinical and laboratory abnormalities that in the opinion of the investigator would affect safety assessment
22. Failure to satisfy the investigator of fitness to participate for any other reason.