Donafenib Plus Sintilimab for Advanced HCC

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of donafenib combined with sintilimab in patients with advanced hepatocellullar carcinoma (HCC).

Detailed Description
-----------------
This is a Phase II study to evaluate the efficacy and safety of donafenib combined with sintilimab in patients with advanced HCC. 30 subjects with advanced HCC (Barcelona-Clinic- Liver-Cancer [BCLC] stage C, or China liver cancer staging [CNLC] IIIa/IIIb) will be enrolled in the study. Part 1 (Safety Run-in): 6 patients will receive donafenib 200mg P.O. BID and sintilimab 200mg I.V. for a 21-day cycle. Part 2: patients will receive donafenib at the recommended phase 2 dose determined from Part 1 and sintilimab 200mg I.V. Q3W. Donafenib will last until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. Sintilimab will last up to 24 months, or until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. Patients will be allowed to have donafenib or sintilimab as a sigle agent and will be still considered on study when the other drug cause intolerable toxicity.

Official Title
-----------------
Donafenib Combined With Sintilimab for Advanced HCC: a Single-arm, Single-center, Prospective Study

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

Intervention / Treatment
-----------------
* Drug: Donafenib+sintilimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Advanced HCC (BCLC stage C or CNLC IIIa/IIIb ) with diagnosis confirmed by histology/cytology or clinically Patients who have Tumor recurrence after surgical resection or ablation are allowed to be included Patients who previously received local treatment, such as transcatheter arterial chemoembolization, transcatheter arterial embolization and radiotherapy, are allowed to be included At least one measurable lesion Child-Pugh score ≤7 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ and hematologic function Life expectancy of at least 3 months Exclusion Criteria: Diffuse HCC Macrovascular invasion involving the main trunk or inferior vena cava Central nervous system metastasis History of malignancy other than HCC Esophageal and/or gastric varices bleeding within 3 months prior to initiation of study treatment Uncontrolled ascites History of hepatic encephalopathy Patients who received prior systemic therapy (chemotherapy, targeted therapy or immunotherapy) or hepatic arterial infusion chemotherapy (HAIC) for HCC History of organ and cell transplantation Active severe infection; use of antibiotics within 2 weeks prior to injection of sintilimab Autoimmune disease or immune deficiency Severe organ (heart, kidney) dysfunction

Ages Eligible for Study
-----------------
Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donafenib+sintilimab<br>Donafenib combined with sitilimab. | Drug: Donafenib+sintilimab<br>* Part 1 (Safety Run-in): donafenib 200mg P.O. BID and sintilimab 200mg I.V. for a 21-days cycle. Part 2: donafenib at the recommended phase 2 dose determined from Part 1 and sintilimab 200mg I.V. Q3W. Donafenib will last until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. Sintilimab will last up to 24 months, or until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. Patients will be allowed to have donafenib or sintilimab as a sigle agent and will be still considered on study when the other drug cause intolerable toxicity.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) assessed by investigators according to modified Response Evalutaion Criteria in Solid Tumors (mRECIST). | The time from initiation of treatment until the first occurrence of disease progression or death from any cause, whichever occurs first. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Number of patients with AE, treatment-related AE (TRAE), immune-related AE (irAE), AE of special interest (AESI), serious adverse event (SAE), assessed by NCI CTCAE v5.0. | 18 months | 
| PFS assessed by investigators according to Response Evalutaion Criteria in Solid Tumors (RECIST) v1.1 | The time from initiation of treatment until the first occurrence of disease progression or death from any cause, whichever occurs first. | 18 months | 
| Objective response rate (ORR) assessed by investigators according to mRECIST. | The percentage of patients who had a best overall tumor response rating of complete response (CR) or partial response (PR). | 18 months | 
| Disease control rate (DCR) assessed by investigators according to mRECIST. | The percentage of patients who had a tumor response rating of CR, PR, or stable disease (SD). | 18 months | 
| ORR assessed by investigators according to RECIST 1.1. | The percentage of patients who had a best overall tumor response rating of CR or PR. | 18 months | 
| DCR assessed by investigators according to RECIST 1.1. | The percentage of patients who had a tumor response rating of CR, PR, or SD. | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TKI, Hepatocellular Carcinoma, Donafenib, Sintilimab, PD-1 inhibitor