Adoptive Autologous iNKT Cells for the Treatment of Progressed Hepatocellular Carcinoma Continuing on PD-1 Inhibitor Therapy

Study Overview
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Brief Summary
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The goal of this clinical trial is to explore the efficacy and safety of autologous iNKT cells in patients with progressed hepatocellular carcinoma (HCC) after treatment with PD-1 antibody. The main question it aims to answer are: the efficacy of autologous iNKT cells in patients with progressed HCC after treatment with PD-1 antibody. the safety of autologous iNKT cells in patients with progressed HCC after treatment with PD-1 antibody. Participants will be randomized 1:1 to receive Regorafenib + PD-1 + iNKT cells (RPI group) or the treatment of Regorafenib + PD-1 (RP group). Researchers will compare RPI group and RP group to see whether the iNKT cells can achieve a better therapeutic effect on HCC patients with PD-1 resistance.

Detailed Description
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Single center, randomized, open trial in Barcelona Clinic Liver Cancer（BCLC）C stage patients with progressed HCC after anti-angiogenic targeted drugs combined with PD-1 monoclonal antibody therapy to explore the efficacy and safety of autologous iNKT cells. This study includes screening period, treatment period and follow-up period (until the subjects withdrew their informed consent or received other anti-tumor therapy or participated in other clinical trials or the researchers judged that it is not in the best interests of patients to continue to participate in the study) after treatment. The patients will be randomized 1:1 using a random number table to receive Regorafenib + PD-1 + iNKT cells (RPI group) or the treatment of Regorafenib + PD-1 (RP group). iNKT Cells：Intravenous infusion. The cells will be infused every two weeks as a course of treatment for up to six courses. PD-1：Intravenous infusion, according to the drug instructions. Regorafenib：Oral administration, according to the drug instructions. All target and non-target lesions will be assessed by chest, abdomen, and pelvis CT or MRI at baseline and every 8 weeks until radiological progression (according to mRECIST/iRECIST). Safety and side-effect profiles will be assessed based on the nature, frequency, and severity of adverse events, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Official Title
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An Open Label, Randomized, Controlled, Clinical Trial of Adoptive Autologous Invariant Natural Killer T Cells for the Treatment of Progressed Hepatocellular Carcinoma Continuing on PD-1 Inhibitor Therapy

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: iNKT Cells
* Drug: PD-1
* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-75 years of age. Barcelona Clinic Liver Cancer（BCLC） C stage hepatocellular carcinoma (HCC) confirmed by CT, MRI, and/or histopathology. Progressed after receiving anti-angiogenic targeted drugs combined with PD-1 monoclonal antibody. Life expectancy of at least 12 weeks. Child-Pugh A/B. Voluntary signing of informed consent. Exclusion Criteria: History of severe hypertension or cardiac disease. known central nervous system (CNS) tumor or combined with other malignant disorders. Uncontrolled immune system or infectious disease. Known history of the human immunodeficiency virus (HIV) or syphilis infection. History of stem cell transplant or organ allograft. History of allergy to immunotherapy or related drugs. Bilirubin is twice times the upper limit of normal. Glomerular filtration rate （GFR）< 60ml/min. Serious complications include moderate or severe infective pleural and peritoneal effusion, pericardial effusion, upper gastrointestinal bleeding, hepatic encephalopathy. Pregnancy or lactation. History of severe allergy to any monoclonal antibody or anti-angiogenic targeted drug. Deemed not suitable for cellular immunotherapy by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: RPI group<br>Regorafenib + PD-1 + iNKT cells | Biological: iNKT Cells<br>* the iNKT cells will be intravenous infused every two weeks as a course of treatment for up to six courses , the reinfusion dose is determined according to the patient's body surface area, which was about 108 109cells/m2.<br>* Other names: Vα24+ T Cells;Drug: PD-1<br>* Intravenous infusion, according to the drug instructions.<br>Drug: Regorafenib<br>* Oral administration, according to the drug instructions.<br>|
| Other: RP group<br>Regorafenib + PD-1 | Drug: PD-1<br>* Intravenous infusion, according to the drug instructions.<br>Drug: Regorafenib<br>* Oral administration, according to the drug instructions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | The time from enrollment to disease progression according to the modified RECIST (mRECIST) guideline in trial immunotherapeutics, or death from any cause, whichever occurred first；the time from enrollment to confirmed disease progression (iCPD) according to the iRECIST | The time from enrollment to disease progression, or death from any cause, whichever occurred first, up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | including complete response (CR), partial response (PR), and disease stabilization (SD), evaluated by imaging according to iRECIST for target lesions and assessed by MRI/CT. | Evaluation was performed every 8 weeks after the start of the treatment, up to 24 months. | 
| Objective response rate (ORR) | complete response (CR) and partial response (PR) evaluated by imaging according to mRECIST/iRECIST for target lesions and assessed by MRI/CT. | Evaluation was performed every 8 weeks after the start of the treatment, up to 24 months. | 
| Overall survival (OS) | Time from the date of enrollment to the date of death from any cause. | Time from the date of enrollment to the date of death from any cause, up to 36 months. | 
| 1-year overall survival rate (1-year OS rate) | The proportion of subjects who were still alive from the date of enrollment to 1 year later | Time from the date of enrollment to 1 year later. | 
| Duration of Overall Response (DOR) | The time from the first tumor remission (CR or PR according to mRECIST/iRECIST) to the first recording of disease progression (PD according to mRECIST criteria or iCPD according to iRECIST) or death from any cause (whichever occurs first). | Time from the first tumor remission to the first recording of disease progression or death from any cause, up to 24 months.. | 
| Time to progression (TTP) | Time from the date of enrollment to the date of first disease progression (PD) according to mRECIST or iCPD according to iRECIST). | Time from the date of enrollment to the date of first disease progression, up to 24 months. | 
| Time to Quality of Life (QoL) Deterioration | EORTC QLQ-C30: European Organization for Research on Treatment of Cancer Quality of Life Questionnare-Core 30. The totally 30 items spread out over five functional scales (15 items), three symptom scales (7 items), a global health status/QoL scale (2 items), and six single items. 1-28 item ranges 1: not at all, 2: a little, 3: quite a lit, 4: very much; 29-30 item ranges 1-7 from very poor to excellent. Raw score (RS) is an average of all items in each area. Standardized score is in the range of 0-100 by formula SS=[1-(RS-1)/n] x100 (function) or SS=[（RS-1）/n]x100 (symptom or overall health) respectively. A high scale score represents a higher/healthy response level. Time to deterioration was defined as a decrease from baseline of 10 points or more on the EORTC QLQ-C30 maintained for two consecutive assessments. | Time from the date of enrollment, up to 24 months. |