Effect and Safety of Huaier Granules Combined With Targeted Drugs and Anti-PD-(L)1 Antibody Compared With Targeted Drugs Combined With Anti-PD-(L)1 Antibody in First Line Treatment of Unresectable Hepatocellular Carcinoma(uHCC)

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, controlled study. The purpose of this study is to evaluate the efficacy, safety and the impact on the quality of life of Huaier Granules combined with targeted drugs and anti-PD-(L)1 antibody compared with targeted drugs combined with anti-PD-(L)1 antibody in first line treatment of unresectable hepatocellular carcinoma.

Detailed Description
-----------------
China is a country with a high incidence of liver cancer. The latest forecast data of the International Agency for Research on Cancer (IARC) shows that the number of newly diagnosed liver cancer in China in 2020 is close to half of the total in the world. Hepatocellular carcinoma (HCC) is the main type of liver cancer, accounting for more than 85%-90%. About 60% of HCC patients are of advanced stage when first visit, and lose the opportunity to receive radical treatment. Currently, targeted drugs are recommended by the guidelines for first-line treatment of advanced HCC. Several studies have shown that the use of immune checkpoint inhibitors (mainly PD-(L)1 inhibitors) combined with targeted drugs can increase the survival benefits of patients with advanced HCC. However, the overall ORR of first-line treatment is less than 50%, and some patients have experienced high-grade adverse events. Huaier granules is an extract from a medicinal fungus. Previous studies have shown that Huaier granules can inhibit the proliferation, angiogenesis, metastasis and invasion of cancer cells, and can reverse the resistance of targeted drugs. Huaier granules is one of the most commonly used Chinese patent medicines in the treatment of HCC, and is recommended by CSCO guidelines（liver cancer）. Several previous studies have shown that Huaier granules can improve the efficacy and reduce the incidence of adverse events in all stages of HCC treatment. In this study, about 10 research centers will participate. The study will enroll 600 participants. The experimental group will enroll 200 participants who will be treated with Huaier granules combined with targeted drug and anti- PD-(L)1 antibody, the three specific treatment regimens were Huaier granules combined with Atezolizumab and Bevacizumab, Huaier granules combined with Camrelizumab and Apatinib, Huaier granules combined with Sintilimab and Bevacizumab. The control group will enroll 400 participants who will be treated with targeted drug combined with anti-PD-(L)1 antibody, the three specific treatment regimens were Atezolizumab combined with Bevacizumab, Camrelizumab combined with Apatinib, Sintilimab combined with Bevacizumab. In this study, participants will be followed up for 12 months.

Official Title
-----------------
Effect and Safety of Huaier Granules Combined With Targeted Drugs and Anti-PD-(L)1 Antibody Compared With Targeted Drugs Combined With Anti-PD-(L)1 Antibody in First Line Treatment of Unresectable Hepatocellular Carcinoma: a Prospective, Multi-center Study

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

Intervention / Treatment
-----------------
* Drug: Huaier granule
* Drug: Atezolizumab + Bevacizumab
* Drug: Camrelizumab+Apatinib
* Drug: Sintilimab+Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years and older Diagnosed as unresectable hepatocellular carcinoma (did not meet the indications of transcatheter arterial chemoembolization or disease progression after transcatheter arterial chemoembolization) by histopathological and/or cytological examination, or meeting the clinical diagnostic criteria of primary liver cancer by The Guideline for Diagnosis and Treatment of Hepatocellular Carcinoma (2022 Edition). CNLC liver cancer stage III. Liver function status Child-Pugh Class A or B, 7 points. No prior systemic therapy for HCC. Plan to receive one of the following treatment regimen: Atezolizumab and Bevacizumab, Camrelizumab and Apatinib, Sintilimab and Bevacizumab. Agree to receive Huaier granule treatment after enrollment (only for experimental group). Patients with active HBV infection can be enrolled if meeting one of the following conditions: ① within 28 days before enrollment, the patient's HBV DNA is < 500 IU / ml, if they have received anti HBV treatment, they need to continue the original antiviral treatment; if not, they need to receive anti-HBV treatment throughout the medication (according to local treatment standards; e.g. entecavir); ② for those with HBV DNA > 500 IU / ml and without antiviral treatment, they shall receive anti-HBV treatment for at least 7 days before joining the study (according to local treatment standards; e.g. entecavir), and are willing to continue to receive anti-HBV treatment during the study. Before joining the study, the serum HBV-DNA virus shall be retested and decreased by more than 1 log value; ③ For those with HBV DNA > 500 IU / ml and who have received antiviral treatment, they shall receive anti-HBV treatment for at least 7 days before enrollment (according to local treatment standards; e.g. entecavir), and are willing to continue to receive anti-HBV treatment during the study. Before enrollment, the serum HBV-DNA virus level shall be retested and decreased; Patients with active HCV infection can be enrolled when disease were stable after treatment; At least one evaluable tumor lesion. Be conscious, have language expression ability or reading ability, can communicate normally, and cooperate to complete the questionnaire evaluation; Volunteer to join the study and sign the informed consent form. Exclusion Criteria: More than two active primary tumors at the same time. Portal vein tumor thrombus invaded the superior mesenteric vein. Patients received radiotherapy or transcatheter arterial chemoembolization in the past 4 weeks. Estimated survival time less than 3 months. Patients allergic to the components of Huaier granules, or avoid to use Huaier granules or use with caution (only for experimental group). Patients not able to take medication orally (only for experimental group). Pregnant or lactating women or women prepare for pregnancy. Coagulation dysfunction (INR > 2.0, PT> 16s) or diseases with high possibility of bleeding (including but not limited to esophageal and/or gastric variceal bleeding, active ulcer, uncontrolled hypertension). Participating in clinical trials of other drugs. Refused to cooperate with follow-up. Other reasons that the researcher considers unsuitable to participate in this study.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Huaier granules combined with targeted drug and anti- PD-(L)1 antibody. There are there specific regimens: Huaier granules combined with Atezolizumab and Bevacizumab, Huaier granules combined with Camrelizumab and Apatinib, Huaier granules combined with Sintilimab and Bevacizumab. | Drug: Huaier granule<br>* Treatment period: Huaier Granule, oral administration, 10g each time, 3 times a day. Continuous medication until the end of the study, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first; or after researcher's judgement, patient would no longer benefit from the treatment. After disease progression, whether to continue the medication or not should be determined by the researcher and patient together.<br>Drug: Atezolizumab + Bevacizumab<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>Drug: Camrelizumab+Apatinib<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>Drug: Sintilimab+Bevacizumab<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>|
| Active Comparator: Arm 2<br>Targeted drug combined with anti-PD-(L)1 antibody. There are there specific regimens: Atezolizumab combined with Bevacizumab, Camrelizumab combined with Apatinib, Sintilimab combined with Bevacizumab. | Drug: Atezolizumab + Bevacizumab<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>Drug: Camrelizumab+Apatinib<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>Drug: Sintilimab+Bevacizumab<br>* Targeted Drug and Anti-PD-(L)1 antibody: Continuous medication until disease progression, intolerable toxicity, withdrawal from the study for any reason or death, whichever occurs first. Refer to drug instructions for specific usage.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Objective response rate: proportion of subjects who achieved complete remission (CR) or partial remission (PR) by primary tumor imaging evaluation. | Start of treatment until 12-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression free survival: time from the date when the subject first received Huaier Granules combined with targeted drug and anti-PD-(L)1 antibody to the first observation of tumor progression or death from any cause. | Start of treatment until 12-month follow-up | 
| DCR | Disease control rate: proportion of subjects who achieved complete remission (CR) or partial remission (PR) or stable disease (SD) by primary tumor imaging evaluation. | Start of treatment until 12-month follow-up | 
| TTR | Time to response: time from the date when the subject first received Huaier Granules combined with targeted drug and anti-PD-(L)1 antibody to the first observation of tumor remission (CR or PR) | Start of treatment until 12-month follow-up | 
| DoR | Duration of response: time from the first observation of tumor remission (CR or PR) to the first observation of tumor progression or death from any cause after the subject was treated with Huaier Granule combined with targeted drug and anti-PD-(L)1 antibody. | Start of treatment until 12-month follow-up | 
| Quality of life score | Evaluated by the quality of life core scale [The European Organization for Reasearch and Treatment of Cancer Quality of Life Questionnare-Core 30(EORTC QLQ-C30 )(Chinese version)] developed by European cancer research and treatment organization. The scope of each domain is 0 to 100. Higher scores in the functional and general health areas indicate better functional status and quality of life, and higher scores in the symptomatic areas indicate more symptoms or problems (poorer quality of life). | Up to 12 months since the start of treatment | 
| Incidence and severity of adverse events (AE) |  | Start of treatment until 12-month follow-up | 
| Incidence and severity of serious adverse events (SAE) |  | Start of treatment until 12-month follow-up | 
| Incidence and severity of adverse reactions (ADR) |  | Start of treatment until 12-month follow-up | 
| Incidence and severity of serious adverse reactions (SADR) |  | Start of treatment until 12-month follow-up | 
| Incidence and severity of suspicious and unexpected serious adverse reactions (SUSAR) |  | Start of treatment until 12-month follow-up | 
| Incidence and severity of adverse events of special interest (AESI) | Adverse events of special interest: proteinuria, enteritis, autoimmune myocarditis. | Start of treatment until 12-month follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Huaier granules, HCC, targeted therapy, PD-(L)1