Hepatocellular Carcinoma
Conditions
Brief summary
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).
Detailed description
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.
Interventions
BIOLOGICALiNKT cells
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.
DRUGIL-2
IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days.
DRUGTegafur
Tegafur will be given at a dose of 40\ 60 mg bis in die (BID) 2 weeks.
Sponsors
Beijing YouAn Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Four planned loading dose of iNKT cells for 10 patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-80 years. * Patients with hepatocellular carcinoma (BCLC, stage C) proved by histopathology or proved by CT or MRI imaging system, relapsed after previous therapy and no effective therapies known at this time. * Life expectancy of ≥ 12 weeks. * WBC\>3.5×10\^9/L, LYMPH\> 0.8×10\^9/L, Hb\>85g/L, PLT\>50×10\^9/L, Cre\<1.5×the upper limit of normal value. * iNKT\>10/mL in peripheral blood mononuclear cell (PBMC). * Able to understand and sign the informed consent.
Exclusion criteria
* Any uncontrolled systematic disease: hypertension, heart disease, and et al.; * Portal vein tumor thrombus, central nervous system tumor metastasis, or combined with other tumors; * Receiving radiochemotherapy, local therapy, or targeting drugs within 4 weeks prior to this treatment; * Unstable immune systematic diseases or infectious diseases; * Combined with AIDS or syphilis; * Patients with history of stem cell or organ transplantation; * Patients with allergic history to related drugs and immunotherapy; * Patients with complications associated with liver diseases: moderate or severe pleural effusion, pericardial effusion, ascites, or gastrointestinal hemorrhage; * Pregnant or lactating subjects; * Unsuitable subjects considered by clinicians.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Through study completion, an average of 12 months. | 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. |
| Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | 4 weeks, 8 weeks, 12 weeks and 24 weeks after cell infusion. | 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. |
| Overall Survival (OS) | Through study completion, up to 20 months. | 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. |
Countries
China
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 3 |
| 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. | 3 |
| 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. | 1 |
| Total | 10 |
Baseline characteristics
| Characteristic | iNKT Cell Loading Dose:3x10^7/m2 | iNKT Cell Loading Dose:6x10^7/m2 | iNKT Cell Loading Dose:9x10^7/m2 | iNKT Cell Loading Dose:1x10^10/m2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 10 Participants |
| Age, Continuous | 50 years | 51 years | 52 years | 53 years | 51.5 years |
| BCLC (Barcelona Clinic Liver Cancer ) stage BCLC stage B | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| BCLC (Barcelona Clinic Liver Cancer ) stage BCLC stage C | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 2 / 3 | 1 / 1 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 2 / 3 | 1 / 1 |
Outcome results
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.
Time frame: 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.
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Adverse Events | Grade 3 | 2 events |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Adverse Events | Grade 2 | 0 events |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Adverse Events | Grade 5 | 1 events |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Adverse Events | Grade 4 | 0 events |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Adverse Events | Grade 1 | 12 events |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Adverse Events | Grade 3 | 0 events |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Adverse Events | Grade 1 | 2 events |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Adverse Events | Grade 2 | 1 events |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Adverse Events | Grade 4 | 0 events |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Adverse Events | Grade 5 | 1 events |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Adverse Events | Grade 2 | 1 events |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Adverse Events | Grade 4 | 0 events |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Adverse Events | Grade 3 | 1 events |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Adverse Events | Grade 1 | 8 events |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Adverse Events | Grade 5 | 2 events |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Adverse Events | Grade 3 | 0 events |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Adverse Events | Grade 2 | 1 events |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Adverse Events | Grade 5 | 1 events |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Adverse Events | Grade 1 | 4 events |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Adverse Events | Grade 4 | 0 events |
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.
Time frame: 4 weeks, 8 weeks, 12 weeks and 24 weeks after cell infusion.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | SD | 3 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | SD | 2 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | PD | 1 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | SD | 2 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | PD | 1 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | SD | 2 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | PD | 1 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | SD | 3 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | PD | 2 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | SD | 1 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | SD | 3 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | SD | 3 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | SD | 1 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | SD | 1 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | PD | 2 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | SD | 1 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | PD | 2 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | PD | 2 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | SD | 3 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | SD | 1 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 8th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | PD | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 4th week after cell infusion | SD | 1 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | SD | 1 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | PD | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 24th week after | SD | 1 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Number of Participants With Stabilized (SD) or Progressive (PD) Disease. | At 12th week after cell infusion | PD | 0 Participants |
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.
Time frame: Through study completion, up to 20 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| iNKT Cell Loading Dose:3x10^7/m2 | Overall Survival (OS) | <6months | 1 participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Overall Survival (OS) | >12months | 2 participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Overall Survival (OS) | 6-12months | 0 participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Overall Survival (OS) | <6months | 0 participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Overall Survival (OS) | >12months | 2 participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Overall Survival (OS) | 6-12months | 1 participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Overall Survival (OS) | 6-12months | 0 participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Overall Survival (OS) | <6months | 2 participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Overall Survival (OS) | >12months | 1 participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Overall Survival (OS) | <6months | 0 participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Overall Survival (OS) | >12months | 0 participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Overall Survival (OS) | 6-12months | 1 participants |
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.
Time frame: Through study completion, an average of 12 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| iNKT Cell Loading Dose:3x10^7/m2 | Progression-Free Survival (PFS) | <6months | 1 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Progression-Free Survival (PFS) | >12months | 1 Participants |
| iNKT Cell Loading Dose:3x10^7/m2 | Progression-Free Survival (PFS) | 6-12months | 1 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Progression-Free Survival (PFS) | <6months | 1 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Progression-Free Survival (PFS) | >12months | 0 Participants |
| iNKT Cell Loading Dose:6x10^7/m2 | Progression-Free Survival (PFS) | 6-12months | 2 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Progression-Free Survival (PFS) | 6-12months | 1 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Progression-Free Survival (PFS) | <6months | 2 Participants |
| iNKT Cell Loading Dose:9x10^7/m2 | Progression-Free Survival (PFS) | >12months | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Progression-Free Survival (PFS) | <6months | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Progression-Free Survival (PFS) | >12months | 0 Participants |
| iNKT Cell Loading Dose:1x10^10/m2 | Progression-Free Survival (PFS) | 6-12months | 1 Participants |