Cocktail Therapy for Hepatitis B Related Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The effect of anti-tumor treatment is not satisfying in HBV-related hepatocellular carcinoma (HBV-HCC) for reasons that HBV-HCC carries highly heterogeneous antigens to facilitate cancer cells escaping from immune surveillance and constructs an immunosuppressive microenvironment. Correspondingly, multiple signals loaded dendritic cells vaccine can efficiently present T cells with antigens of HCC sensitize their antitumor properties meanwhile low dose cyclophosphamide (CY) can effectively improve the microenvironment of immunity. Therefore, we put forward a new scientific therapy called multiple signals loaded dendritic cells vaccine combined low dose of cyclophosphamide combining with radical surgery or TACE or targeted agents for patients with hepatocellular carcinoma to prolong their survival time.

Detailed Description
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Detailed Description Patients who have good compliance complying with the inclusion criteria will be enrolled into our research. The 600 patients will be randomly assigned to experimental group and control group with the ratio of 1:1, control group will receive radical surgery or TACE or targeted agent treatment solely; another group (experimental group) after enrollment will radical surgery or TACE or targeted agent treatment in the first course. Then 20ml blood is taken for multiple signals loaded dendritic cells (MSDCV) culture (cell culture takes 7 days). Low dose (250mg/m^2) CY treatment will be performed on patients two days before the MSDCV treatment. The MSDCV combined CY therapy will perform per 4 weeks, total 6 times. All patients are evaluated the safety and efficacy of treatment by monitoring their blood parameters, tumor indicators and imaging examinations at each visit.

Official Title
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Precision Study on Cocktail Therapy to Improve the Efficacy of Hepatitis B-related Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Biological: Multiple Signals loaded Dendritic Cells Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In accordance with AASLD guidelines for the diagnosis of hepatocellular carcinoma，histology or imaging confirmed as primary hepatocellular carcinoma Patients with history of hepatitis B infection Male and female adult subjects (18～70 years old) Patients haven't received radiation therapy or chemotherapy or immunotherapy Normal renal function Blood routine test: Hb>=9g/dL, white cell count>=1.5*10^9/L, platelet count>=50*10^9/L Liver function: bilirubin<=50umol/L, aspartate aminotransferase (AST) or alanine aminotransferase(ALT)<=5 times the upper limit of normal Child-Pugh score<=9 Human Chorionic Gonadotropin(HCG) test negative(-) if patients are women of reproductive ages Women of reproductive ages promise to contracept until therapy course has been finished for 3 months Patients who have signed up informed consents Exclusion Criteria: Extrahepatic metastasis of hepatocellular carcinoma oHistory of embolism, chemotherapy or radiation History of major surgery in last 4 weeks History of radiofrequency ablation in last 6 weeks Acute infections in last 2 weeks Child-Pugh scores>9 Patients with hepatic encephalopathy Patients with ascites needed drainage Patients have history of other cancer Patients have history of HIV Pregnant women Patients with severe diseases like cardiac dysfunction Patients with mental illness that influence signing informed consents HBV infection combined with other types of hepatitis Patients with autoimmune diseases Immunosuppressant drugs users Patients cannot follow our trial principle

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSDCV immune therapy combined with radical surgery therapy<br>Multiple Signals loaded Dendritic Cells Vaccine(MSDCV) immune therapy：one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, total 6 times; Hepatocellular Carcinoma Radical surgery therapy: one time at a good operation time before the first time of MSDCV immune therapy | Drug: Cyclophosphamide<br>* Intravenous drip，250mg/m^2 per time，two days before each times of MSDCV therapy，total 6 times, in order to improve the immunosuppressive microenvironment of tumor，reduce CD4+CD25+FOXP3+regulatory T cells (Tregs）<br>* Other names: Endoxan;Biological: Multiple Signals loaded Dendritic Cells Vaccine<br>* one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, intravenous driptotal 6 times;<br>* Other names: MSDCV;|
| No Intervention: Radical surgery therapy<br>Hepatocellular Carcinoma Radical surgery therapy: one time at a good operation time | |
| Experimental: MSDCV immune therapy combined with TACE therapy<br>Multiple Signals loaded Dendritic Cells Vaccine(MSDCV) immune therapy：one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, total 6 times; Transcatheter Hepatic Arterial Chemoembolization (TACE) therapy: the first time of TACE therapy must perform before the first time of MSDCV immune therapy， then perform when necessary according to subjects condition | Drug: Cyclophosphamide<br>* Intravenous drip，250mg/m^2 per time，two days before each times of MSDCV therapy，total 6 times, in order to improve the immunosuppressive microenvironment of tumor，reduce CD4+CD25+FOXP3+regulatory T cells (Tregs）<br>* Other names: Endoxan;Biological: Multiple Signals loaded Dendritic Cells Vaccine<br>* one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, intravenous driptotal 6 times;<br>* Other names: MSDCV;|
| No Intervention: TACE therapy<br>Transcatheter Hepatic Arterial Chemoembolization (TACE) therapy: perform when necessary according to Subjects condition | |
| Experimental: MSDCV immune therapy combined with targeted agents therapy<br>Multiple Signals loaded Dendritic Cells Vaccine(MSDCV) immune therapy：one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, total 6 times; Targeted agents therapy: Sorafenib or Lenvatinib. For Sorafenib: 0.4g twice daily; for Lenvatinib: 12mg/8mg per day according to subjects condition | Drug: Cyclophosphamide<br>* Intravenous drip，250mg/m^2 per time，two days before each times of MSDCV therapy，total 6 times, in order to improve the immunosuppressive microenvironment of tumor，reduce CD4+CD25+FOXP3+regulatory T cells (Tregs）<br>* Other names: Endoxan;Biological: Multiple Signals loaded Dendritic Cells Vaccine<br>* one time every 4 weeks during 0 weeks to 20 weeks, about 5*10^7 cells per time, intravenous driptotal 6 times;<br>* Other names: MSDCV;|
| No Intervention: Targeted agents therapy<br>Targeted agents therapy: Sorafenib or Lenvatinib. For Sorafenib: 0.4g twice daily; for Lenvatinib: 12mg/8mg per day according to subjects condition | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free-Survival (PFS), month | The time from randomization until first documented progression or death from any cause，whichever came first | 240 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum AFP(alpha fetoprotein）, ng/ml | Measured for each subjects at each visits | 240 weeks | 
| serum PIVKA-II(Protein Induced by Vitamin K Absence or Antagonist-II), μg/L | Measured for each subjects at each visits | 240 weeks | 
| Overall Survival (OS), month | The time from random assignment to death from any cause | 240 weeks | 
| tumor size, mm | Utilizing Liver CT or MR examination | 240 weeks | 
| Number of participants with treatment-related adverse events | Assessed by CTCAE v4.0 | 240 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatocellular carcinoma, hepatitis B, Dendritic cells vaccine, cell therapy