Sorafenib Plus Toripalimab for Unresectable HCC With Portal Vein Tumor Thrombus

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

Detailed Description
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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.

Official Title
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An Exploratory Study of Sorafenib Plus Toripalimab for Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

Conditions
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Unresectable Hepatocellular Cancer, Portal Vein Tumor Thrombus

Intervention / Treatment
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* Drug: sorafenib; toripalimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of unresectable hepatocellular carcinoma, or confirmed clinically in accordance with Chinese Association for the Study of Liver Diseases criteria (v2017) Radiographically measurable disease by RECIST version 1.1 in at least one site Radiographic evidence of portal vein cancer thrombus Survival expectation ≥3 months Eastern Cooperative Oncology Group: 0 or 1 Child-Pugh score A or B: score ≤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. 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+). Signed and dated written informed consent Exclusion Criteria: 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 Pregnant or lactating women, men and women of childbearing age who are unwilling or unable to take effective contraceptive measures History of other malignancy within the past 5 years Medium or more pleural and ascites with clinical symptoms 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 Central nervous system metastases Hepatic encephalopathy 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. Gastric or esophageal varices requiring treatment 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) 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. History of drug abuse or mental disorders History of organ or marrow transplants, or active autoimmune diseases requiring systemic treatment occurred within 2 years of the first administration Immunodeficiency disorders or HIV Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia and severe impairment of pulmonary function 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. 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.) Receiving vaccine within 30 days of the first administration Abdominal fistula, gastrointestinal perforation or abdominal abscess within 4 weeks of the first administration Receiving other experimental drugs or medical devices within 4 weeks of the first administration Any significant clinical and laboratory abnormalities that in the opinion of the investigator would affect safety assessment Failure to satisfy the investigator of fitness to participate for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: one-arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sorafenib plus toripalimab<br>Stage I：Subjects (n=3) in cohort A received oral sorafenib (400 mg qd), in combination with intravenous toripalimab (240 mg d1, q3w). Subjects (n=3) in cohort B received oral sorafenib (400 mg bid) and the administration of toripalimab is consistent with cohort A. If dose-limiting toxicity (DLT) does not occur within 42 days of the first administration, the dose is escalated. Stage II: According to the expansion dose based on stage I, subjects are enlarged to 39. | Drug: sorafenib; toripalimab<br>* Stage I: cohort A: sorafenib 400 mg qd+ toripalimab 240 mg d1; q3w cohort B: sorafenib 400 mg bid, toripalimab 240 mg d1; q3w Stage II: According to the expansion dose based on stage I, subjects are enlarged to 39.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression Free Survival rate | Proportion of patients with Progression Free Survival in 6-month | up to 6 months | 
| Incidence of Treatment-Emergent Adverse Event | Any adverse events related with treatment with Sorafenib Plus Toripalimab | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients | up to 6 months | 
| Disease Control Rate | Proportion of patients with stable disease, complete response and partial response | up to 6 months | 
| Progression Free Survival | A duration from the date of initial treatment with Sorafenib Plus Toripalimab to disease progression (defined by RECIST 1.1) or death of any cause. | up to 6 months | 
| Overall Survival | Duration from the date of initial treatment with Sorafenib Plus Toripalimab to the date of death due to any cause. | up to 1 year | 
| Duration of response | time from first documented complete or partial response to radiologically confirmed disease progression or death from any cause. | From the date of study enrollment to the time of death from any cause, assessed up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sorafenib, Toripalimab, Unresectable, Hepatocellular Cancer, Portal Vein Tumor Thrombus