A Clinical Study in Patients With High-risk Recurrent Primary Hepatocellular Carcinoma Using Autologous TILs

Study Overview
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Brief Summary
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Early clinical trials on evaluating the tolerance, safety and efficacy of autologous TILs in high-risk recurrent primary hepatocellular carcinoma

Official Title
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Early Clinical Trials on Evaluating the Tolerance, Safety and Efficacy of Autologous TILs in High-risk Recurrent Primary Hepatocellular Carcinoma

Conditions
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Hepatic Carcinoma

Intervention / Treatment
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* Drug: Tumor infiltrating lymphocyte


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years, gender unlimited; Patients diagnosis of primary hepatocellular carcinoma by histopathology and/or cytology; At the initial enrollment evaluation, patients were expected to accept radical resection of liver cancer and meet at least one of the following high-risk recurrence factors after surgery: ①There are 3 or more tumor lesions in the liver; ②The diameter of a single tumor lesion is >8cm; ③Existence macrovascular tumor thrombus; ④>5 MVI or MVI occurred in the distant paracancer tissues; Before enrollment (after radical resection of liver cancer), imaging evaluation was performed to ensure that the tumor was completely removed (clear margin); Must have at least 1 resectable lesion (diameter ≥2 cm); ECOG score <2; Child-Pugh score ≤7; Hematology and organ function indicators should be met simultaneously: (1) White blood cell count ≥3.0E+9/ L, neutrophil count ≥1.5E+9/ L, platelet countPlatelet count ≥8.0E10/ L, hemoglobin ≥80g/L (2) Liver function: aspartate aminotransferase (AST)≤5 times normal value, alanine aminotransferase (ALT)≤5 times normal value, bilirubin ≤5 times normal value, serum albumin ≥28 g/L; (3) Renal function: creatinine (Cr)≤1.5 times normal limit, creatinine clearance ≥50 mL/min; An estimated life expectancy of ≥3 months; Participation in this clinical study voluntary, can cooperate with researchers to carry out research, and sign informed consent. Exclusion Criteria: Primary hepatocellular carcinoma (HCC) has recurred in the past, or has other types of liver cancer at the same time (such as intrahepatic cholangiocarcinoma, mixed type of liver cancer); Have a history of high fever or severe infection within 2 weeks prior to pretreatment, or are expected to undergo systemic anti-infective therapy or systemic steroid therapy during this trial; Hepatic encephalopathy occurred within 2 weeks before pretreatment; Previous or screening with autoimmune liver disease; Screening with moderate or higher peritoneal effusion; Clear neurological/psychiatric symptoms are known to be associated with brain metastases and/or assessed by MMSE; Anti-tumor therapy such as chemotherapeutic drugs, targeted drugs, radio frequency ablation or minimally invasive intervention was received within 4 weeks before pretreatment; Have received or are expected to participate in this study within 4 weeks before pretreatment to receive TIL required focus radiotherapy, or tumor evaluation focus (target focus or non-target focus) radiotherapy, or radical radiotherapy; Any toxic response resulting from previous anti-tumor treatment prior to pretreatment did not return to grade 1 or below (CTCAE5.0 version); Previous history of organ / stem cell transplantation or expected to be involved in this trial for organ / stem cell transplantation; Left ventricular ejection fraction (LVEF)<45% or New York Heart Association (NYHA)≥ grade 2; Known or private HIV infection or syphilis infection; The previous 3 years other system primary malignant tumor history (except skin basal cell carcinoma or cervical carcinoma in situ); A known allergy to two or more non-homogeneous foods/drugs, or a known history of allergies to pre-treated drugs, including cyclophosphamide, fludarbin, interleukin; Pregnant, lactating women or within one year of having a family plan; Participated in other clinical trials within 3 months prior to screening; Other circumstances that the researchers considered inappropriate to participate in the experiment.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High dose group<br>10^10 TIL | Drug: Tumor infiltrating lymphocyte<br>* Tumor infiltrating lymphocytes were isolated from tumor tissues from tumor biopsy or operation. These TILs were cultured in human IL-2 medium for 4 to 5 weeks. 10e9 to 10e10 TILs were yielded. The phenotype, function and sterile were detected before these TILs infused patients.<br>|
| Experimental: Low dose group<br>10^9 TIL | Drug: Tumor infiltrating lymphocyte<br>* Tumor infiltrating lymphocytes were isolated from tumor tissues from tumor biopsy or operation. These TILs were cultured in human IL-2 medium for 4 to 5 weeks. 10e9 to 10e10 TILs were yielded. The phenotype, function and sterile were detected before these TILs infused patients.<br>|
| Experimental: Extension set<br>The number of TIL is decided by dose escalation experiment. | Drug: Tumor infiltrating lymphocyte<br>* Tumor infiltrating lymphocytes were isolated from tumor tissues from tumor biopsy or operation. These TILs were cultured in human IL-2 medium for 4 to 5 weeks. 10e9 to 10e10 TILs were yielded. The phenotype, function and sterile were detected before these TILs infused patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | To evaluate the tolerability and safty of autologous TILs in high-risk recurrent primary hepatocellular carcinoma. | 24 months | 
| Progression-Free Survival | To evaluate the tolerability and safty of autologous TILs in high-risk recurrent primary hepatocellular carcinoma. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Overall Survival | To evaluate the efficacy of autologous TILs in high-risk recurrent primary hepatocellular carcinoma. | 24 months | 
| EQ-5D score | To evaluate the efficacy of autologous TILs in high-risk recurrent primary hepatocellular carcinoma. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TIL; HCC; clinical research