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This study enrolls patients who have relapsed/advanced hepatocellular carcinoma (HCC, BCLC stage C). The HCC tumor relapsed or metastasized through the body after standard treatment or the patients cannot receive standard treatment under current conditions. This research study uses special immune system cells called iNKT cells, a new experimental treatment.
The purpose of this study is to find the biggest dose of iNKT cells that is safe and tolerance, to see how long they last in the body, to learn the immunoresponse in the body, to learn the side effects are and to see if the iNKT cells will help people with relapsed/advanced hepatocellular carcinoma (HCC).
PBMCs of enrolled patients were collected and then further separated by density gradient centrifugation. After washing three times, the cells were resuspended in serum-free medium with recombinant human IL-2 and α-GalCer. Restimulation with α-GalCer-pulsed autologous DCs was done on days 7. After 14 days of cultivation, the iNKT cells were harvested, washed thrice, and then resuspended in saline. The frequency of iNKT cells before and after cultured in vitro were determined by flow cytometry analysis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| iNKT cell loading dose:3x10^7/m2 | Experimental | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：3x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
|
| iNKT cell loading dose:6x10^7/m2 | Experimental | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：6x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
|
| iNKT cell loading dose:9x10^7/m2 | Experimental | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：9x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
|
| iNKT cell loading dose:1x10^10/m2 | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| iNKT cells | Biological | The patients received different doses of in vitro-expanded autologous iNKT cells through intravenous infusion. The dosage was escalated from 3x10^7 cells/m2 to 6x10^7 cells/m2 to 9x10^7 cells/m2. The maximum tolerated dose (MTD) was defined as the last dose level, and the dosage would be up to 1x10^10 cells/m2 if no MTD was observed after a 3+3 design. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Adverse Events | Defined as signs/symptoms, laboratory toxicities, and clinical events that are possibly, likely, or definitely related to study treatment Adverse events assessed according to NCI-CTCAE v4.0 criteria 2. | During the first 12 weeks, participants were assessed for adverse events every 2-4 weeks after infusion; after the first 12 weeks, participants were assessed for adverse events every 3 months, up to 20 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-Free Survival (PFS) | PFS is the time that passes from the date that patient enrolled in the clinical trial and the date on which HCC progresses or the date on which the patient dies. HCC progression was evaluated by imaging according to the irRC standard. Progression is defined as a ≥25% increase in the nadir of the sum of target lesions. | Through study completion, an average of 12 months. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jun Lu, Director | Beijing YouAn Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Youan Hospital,Capital Medical University | Beijing | Beijing Municipality | 100069 | China |
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A total of 10 patients were recruited in this study from April 2017 to May 2018. Patient 1-8 received cell transfusion in stages according to the plan of 10%，30%，60% of them were used per infusion every other day, and patient 9 and 10 infused all of the cells at one-time.
This study enrolled patients diagnosed of HCC in the stage of BCLC B or C. But they don't have severe dysfunction of liver, kidney, heart and lung. Expected survival is more than 12weeks.
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| ID | Title | Description |
|---|---|---|
| FG000 | iNKT Cell Loading Dose:3x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：3x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| FG001 | iNKT Cell Loading Dose:6x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：6x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| FG002 | iNKT Cell Loading Dose:9x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：9x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| FG003 | iNKT Cell Loading Dose:1x10^10/m2. | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：1x10^10/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
A total of 10 patients were enrolled in the experiment from April 2017 to May 2018.
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| ID | Title | Description |
|---|---|---|
| BG000 | iNKT Cell Loading Dose:3x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：3x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | All enrolled patients take a physical examination before the study begins. And they are clearly diagnosed of hepatocellular carcinoma and in the stage of Barcelona Clinic Liver Cancer (BCLC) stage B/C. But they don't have severe dysfunction of liver, kidney, heart and lung. The diagnosis of hepatocellular carcinoma (BCLC stage B/C) was confirmed by CT, MRI. Expected survival is more than 12weeks. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Adverse Events | Defined as signs/symptoms, laboratory toxicities, and clinical events that are possibly, likely, or definitely related to study treatment Adverse events assessed according to NCI-CTCAE v4.0 criteria 2. | Adverse events defined as the occurrence of toxicity events within 4 weeks after iNKT cells infusion. The severity of adverse events were divided into 5 levels. | Posted | Number | events | During the first 12 weeks, participants were assessed for adverse events every 2-4 weeks after infusion; after the first 12 weeks, participants were assessed for adverse events every 3 months, up to 20 months. |
|
During the first 12 weeks, participants were assessed for adverse events every 2-4 weeks after infusion; after the first 12 weeks, participants were assessed for adverse events every 3 months, up to 20 months.
The severity of adverse events were divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | iNKT Cell Loading Dose:3x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：3x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cirrhosis and upper gastrointestinal bleeding | Gastrointestinal disorders | CTCAE version 4.03 | Systematic Assessment | Not considered relatedto the iNKT cell therapy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chills | Immune system disorders | CTCAE version 4.03 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. LJUN | BeijingYouanH | 861366138148 | lujun98@ccmu.edu.cn |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 1, 2017 | Mar 23, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006528 | Carcinoma, Hepatocellular |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D007376 | Interleukin-2 |
| D005641 | Tegafur |
| C104201 | gimeracil |
| C489337 | potassium oxonate |
| ID | Term |
|---|---|
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
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Four planned loading dose of iNKT cells for 10 patients.
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Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC.
iNKT Cell Loading Dose：1x10^10/m2.
IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days.
Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks.
|
|
| IL-2 | Drug | IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. |
|
|
| Tegafur | Drug | Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
|
|
| Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | Disease stabilization (SD) or progressive diseasee (PD) were valuated by imaging according to the irRC standard. Complete response (CR): Disappearance of all lesions; Partial response (PR): ≥50% decrease from baseline; SD: Neither CR or PD is met; PD≥25% increase in the nadir of the sum of target lesions. | 4 weeks, 8 weeks, 12 weeks and 24 weeks after cell infusion. |
| Overall Survival (OS) | OS is the time that passes from the date that patient enrolled in the clinical trial and the date on which the patient dies, according to the irRC standard. | Through study completion, up to 20 months. |
| BG001 | iNKT Cell Loading Dose:6x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：6x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| BG002 | iNKT Cell Loading Dose:9x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：9x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| BG003 | iNKT Cell Loading Dose:1x10^10/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：1x10^10/m^2 Cells. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| BG004 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| BCLC (Barcelona Clinic Liver Cancer ) stage | All enrolled patients take a physical examination before the study begins. And they are clearly diagnosed of hepatocellular carcinoma and in the stage of Barcelona Clinic Liver Cancer (BCLC) stage B/C. The diagnosis of hepatocellular carcinoma (BCLC stage B/C) was confirmed by CT, MRI. | Count of Participants | Participants |
|
| OG001 | iNKT Cell Loading Dose:6x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：6x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| OG002 | iNKT Cell Loading Dose:9x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：9x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
| OG003 | iNKT Cell Loading Dose:1x10^10/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：1x10^10/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. |
|
|
| Secondary | Progression-Free Survival (PFS) | PFS is the time that passes from the date that patient enrolled in the clinical trial and the date on which HCC progresses or the date on which the patient dies. HCC progression was evaluated by imaging according to the irRC standard. Progression is defined as a ≥25% increase in the nadir of the sum of target lesions. | Posted | Count of Participants | Participants | Through study completion, an average of 12 months. |
|
|
|
| Secondary | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | Disease stabilization (SD) or progressive diseasee (PD) were valuated by imaging according to the irRC standard. Complete response (CR): Disappearance of all lesions; Partial response (PR): ≥50% decrease from baseline; SD: Neither CR or PD is met; PD≥25% increase in the nadir of the sum of target lesions. | Posted | Count of Participants | Participants | 4 weeks, 8 weeks, 12 weeks and 24 weeks after cell infusion. |
|
|
|
| Secondary | Overall Survival (OS) | OS is the time that passes from the date that patient enrolled in the clinical trial and the date on which the patient dies, according to the irRC standard. | Posted | Number | participants | Through study completion, up to 20 months. |
|
|
|
| 1 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | iNKT Cell Loading Dose:6x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：6x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. | 1 | 3 | 1 | 3 | 3 | 3 |
| EG002 | iNKT Cell Loading Dose:9x10^7/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：9x10^7/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. | 2 | 3 | 2 | 3 | 3 | 3 |
| EG003 | iNKT Cell Loading Dose:1x10^10/m2 | Autologous in vitro expanded iNKT cells in conjunction with IL-2 and along with lymphodepleting chemotherapy (Tegafur) will be administered to patients with advanced HCC. iNKT Cell Loading Dose：1x10^10/m2. IL-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days. Tegafur: Tegafur will be given at a dose of 40~60 mg bis in die (BID) 2 weeks. | 1 | 1 | 1 | 1 | 1 | 1 |
|
| Refractory bile duct infection and toxic megacolon | Gastrointestinal disorders | CTCAE version 4.03 | Systematic Assessment | Not considered relatedto the iNKT cell therapy. |
|
| Spontaneous rupture of the tumor | Gastrointestinal disorders | CTCAE version 4.03 | Systematic Assessment | Not considered relatedto the iNKT cell therapy. |
|
| Fever | Immune system disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Pain | Gastrointestinal disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Decreased platelet count | Blood and lymphatic system disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Decreased neutrophil count | Blood and lymphatic system disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Decreased white blood cell count | Blood and lymphatic system disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Increased blood bilirubin level | Hepatobiliary disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Increased alanine transaminase level | Hepatobiliary disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Increased aspartate transaminase level | Hepatobiliary disorders | CTCAE version 4.03 | Systematic Assessment |
|
| Subcutaneous induration | Skin and subcutaneous tissue disorders | CTCAE version 4.03 | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D008113 | Liver Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
| D000602 |
| Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| 6-12months |
|
| >12months |
|
| PD |
|
| At 8th week after cell infusion |
|
| At 12th week after cell infusion |
|
| At 24th week after |
|
| 6-12months |
|
| >12months |
|