Hepatocellular Carcinoma
Conditions
Brief summary
To prove that the efficacy and safety of 'Green Cross CELL\* Immuncell-LC group' is superior to 'non-treatment group(Control group)' in patient undergone curative resection(PEIT, RFA or operation) for hepatocellular carcinoma in Korea
Detailed description
Multicenter, randomized, open-labeled phase 3 clinical trial.
Interventions
BIOLOGICALImmuncell-LC
Activated T lymphocyte
Sponsors
GC Cell Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Prior to the test, patient is fully explained about the purpose/ contents and characteristics of the testing medication, and the patient him(her)self, the guardian or the legal representative signed on written consent. * The patient is more than 20 and less than 80 years old * The patient is diagnosed as hepatocellular carcinoma by pathological/ radiological test and he (she) is in the stage of I or II. (refer to the attached file 10). Hepatocellular carcinoma should be shown by radiological test; on dynamic CT, dynamic MRI or on angiography. * Child-Pugh Score should be less than 6 (refer to the attached file 7) * No matter how the patient has been treated before, his (her) tumor should be totally removed by curative resection (PEIT, RFA or operation) in 12 weeks. (based on the agreement date for written consent) The tumor's removal should be perfectly confirmed by pathological or radiological test with the mentioned method in 3) at least 4 weeks later. * ECOG Performance status (ECOG-PS) is less than 1 or equal to (refer to the exhibit 8) * Patient's remaining life-time should be expected at least more than 3 months. * Patient should meet below conditions by blood test, kidney and liver function test : Re-evaluation is possible during screening * Leukocyte count is bigger than (3 multiply 109/L) * Absolute Neutrophil Count (ANC) is bigger than or equal to 1,000/µL * Hemoglobin is bigger than or equal to 8.5 g/dL * Thrombocyte count is bigger than (5 multiply 1010/L) * BUN and serum Creatinine is less than or equal to 1.5 multiply normal upper-limit * No more disease abdominal extrahepatic transfer is confirmed by abdominal CT/ MRI
Exclusion criteria
* Hepatocellular carcinoma has been transferred by pathological/ radiological test (Stage III or Stage IV, refer to the exhibit 10) * The carcinoma has been invaded to main portal vein or major branch hepatic vein * Child-Pugh score is over 6 * Patient has serious problem with pulmonary function by sub- investigator's opinion * Patient who has disease history of immune deficiency (which can be worse by immunotherapy) or auto-immune disease (ex. arthritis rheumatism, Burger's disease, multiple sclerosis and adolescent-occurred insulin dependent diabetes) * Diagnosed as an immune deficiency patient * Patient who has disease history of malignant tumor within 5 years before this clinical trial. (except for skin cancer, local prostate cancer or carcinoma in situ of the uterine cervix * Patient who had anti-cancer medication before the clinical trial * Patient who has serious disease in other organs after tumor resection. * Patient has serious allergic-history by sub- investigator's opinion * Patient has serious mental disease by sub- investigator's opinion * Pregnant women, nursing mother or having intention of being pregnant during the clinical test * Patient who participated in other clinical trial within 4 weeks before this clinical trial * Patient who is incongruent to this clinical trial by sub- investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival(RFS) | Every 3months from the baseline for 24 months and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | RFS was measured from the date of randomization to the first recurrence or to death from any cause. |
| Recurrence Free Survival(RFS) Rate | Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | RFS rate was measured from the date of randomization to the first recurrence or to death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival(OS) | Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | Overall survival was measured from the date of randomization until death from any cause. |
| Cancer-specific Survivals | Every 3 months from baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | Cancer-specific survival was measured from the date of randomization until death resulting from HCC. |
| Overall Survival(OS) Rate | Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | Overall survival rate was measured from the date of randomization until death from any cause. |
| Cancer-specific Survival Rate | Every 3 months from baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit) | Cancer-specific survival rate was measured from the date of randomization until death resulting from HCC. |
Countries
South Korea
Participant flow
Recruitment details
This phase 3 clinical study was a multicenter, randomized, open-labeled trial. The study was conducted at 5 university affiliated hospitals in Korea. All eligible participants were assigned randomly, in a 1:1 ratio, to receive adjuvant adoptive immune therapy using a CIK cell agent or no adjuvant treatment.
Participants by arm
| Arm | Count |
|---|---|
| Immunotherapy Group Patients who had undergone curative treatment(surgical resection, radiofrequency ablation\[RFA\], or percutaneous ethanol injection\[PEI\]) for HCC of pretreatment clinical stage I or II according to the American Joint Committee on Cancer staging system(6th edition) based on radiologic imaging studies were eligible for this study with adjuvant adoptive immune therapy using a CIK cell agent | 114 |
| Control Group Patients who had undergone curative treatment(surgical resection, radiofrequency ablation\[RFA\], or percutaneous ethanol injection\[PEI\]) for HCC of pretreatment clinical stage I or II according to the American Joint Committee on Cancer staging system(6th edition) based on radiologic imaging studies were eligible for this study with no adjuvant treatment | 112 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 3 |
Baseline characteristics
| Characteristic | Control Group | Total | Immunotherapy Group |
|---|---|---|---|
| Age, Customized Age | 56.4 years STANDARD_DEVIATION 10.6 | 55.9 years STANDARD_DEVIATION 9.4 | 55.4 years STANDARD_DEVIATION 8.2 |
| Alanine aminotransferase level | 33.0 IU/L | 33.0 IU/L | 33.0 IU/L |
| Albumin level | 4.1 g/dL | 4.1 g/dL | 4.1 g/dL |
| Alkaline phosphatase level | 82.0 IU/L | 82.3 IU/L | 82.5 IU/L |
| Alpha fetoprotein level | 5.4 ng/mL | 5.3 ng/mL | 5.2 ng/mL |
| Aspartate aminotransferase level | 34.0 IU/L | 33.5 IU/L | 33.0 IU/L |
| Cause of liver disease Co-infection (Cirrhosis) | 70 participants | 146 participants | 76 participants |
| Cause of liver disease Co-infection (Others) | 10 participants | 17 participants | 7 participants |
| Cause of liver disease HBV and HCV | 2 participants | 4 participants | 2 participants |
| Cause of liver disease HBV infection only | 90 participants | 186 participants | 96 participants |
| Cause of liver disease HCV infection only | 10 participants | 19 participants | 9 participants |
| Creatinine level | 0.9 mg/dL | 0.9 mg/dL | 0.9 mg/dL |
| ECOG performance status 0 | 81 participants | 162 participants | 81 participants |
| ECOG performance status 1 | 31 participants | 64 participants | 33 participants |
| HCC stage Stage I | 94 participants | 192 participants | 98 participants |
| HCC stage Stage II | 18 participants | 34 participants | 16 participants |
| Number of HCC <3 | 110 participants | 222 participants | 112 participants |
| Number of HCC >3 or =3 | 2 participants | 4 participants | 2 participants |
| PIVKA-II | 18.0 mAU/mL | 18.5 mAU/mL | 19.0 mAU/mL |
| Platelet | 141.0 x 10^3/mm^3 | 128.6 x 10^3/mm^3 | 116.5 x 10^3/mm^3 |
| Prothrombin time | 13.9 seconds | 13.8 seconds | 13.7 seconds |
| Region of Enrollment Korea, Republic of | 112 participants | 226 participants | 114 participants |
| Sex: Female, Male Female | 21 Participants | 40 Participants | 19 Participants |
| Sex: Female, Male Male | 91 Participants | 186 Participants | 95 Participants |
| Size of HCC | 2.3 centimeter | 2.0 centimeter | 1.8 centimeter |
| Total bilirubin level | 0.8 mg/dL | 0.8 mg/dL | 0.8 mg/dL |
| Treatment modality Percutaneous ethanol injection | 4 participants | 17 participants | 13 participants |
| Treatment modality Radiofrequency ablation | 70 participants | 139 participants | 69 participants |
| Treatment modality Surgical resection | 38 participants | 70 participants | 32 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 71 / 115 | 47 / 115 |
| serious Total, serious adverse events | 9 / 115 | 4 / 115 |
Outcome results
Primary
Recurrence Free Survival(RFS)
RFS was measured from the date of randomization to the first recurrence or to death from any cause.
Time frame: Every 3months from the baseline for 24 months and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immunotherapy Group | Recurrence Free Survival(RFS) | 44.0 months |
| Control Group | Recurrence Free Survival(RFS) | 30.0 months |
p-value: 0.0195% CI: [0.43, 0.94]Log Rank
Primary
Recurrence Free Survival(RFS) Rate
RFS rate was measured from the date of randomization to the first recurrence or to death from any cause.
Time frame: Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immunotherapy Group | Recurrence Free Survival(RFS) Rate | RFS rate 12 months | 79.9 percentage of participants |
| Immunotherapy Group | Recurrence Free Survival(RFS) Rate | RFS rate 24 months | 72.5 percentage of participants |
| Immunotherapy Group | Recurrence Free Survival(RFS) Rate | RFS rate 36 months | 60.9 percentage of participants |
| Immunotherapy Group | Recurrence Free Survival(RFS) Rate | RFS rate 48 months | 49.6 percentage of participants |
| Control Group | Recurrence Free Survival(RFS) Rate | RFS rate 48 months | 39.6 percentage of participants |
| Control Group | Recurrence Free Survival(RFS) Rate | RFS rate 12 months | 65.1 percentage of participants |
| Control Group | Recurrence Free Survival(RFS) Rate | RFS rate 36 months | 44.3 percentage of participants |
| Control Group | Recurrence Free Survival(RFS) Rate | RFS rate 24 months | 53.8 percentage of participants |
Secondary
Cancer-specific Survival Rate
Cancer-specific survival rate was measured from the date of randomization until death resulting from HCC.
Time frame: Every 3 months from baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immunotherapy Group | Cancer-specific Survival Rate | Cancer-specific survival rate 12 months | 100.0 percentage of participants |
| Immunotherapy Group | Cancer-specific Survival Rate | Cancer-specific survival rate 24 months | 100.0 percentage of participants |
| Immunotherapy Group | Cancer-specific Survival Rate | Cancer-specific survival rate 36 months | 98.8 percentage of participants |
| Immunotherapy Group | Cancer-specific Survival Rate | Cancer-specific survival rate 48 months | 97.2 percentage of participants |
| Control Group | Cancer-specific Survival Rate | Cancer-specific survival rate 48 months | 87.5 percentage of participants |
| Control Group | Cancer-specific Survival Rate | Cancer-specific survival rate 12 months | 98.0 percentage of participants |
| Control Group | Cancer-specific Survival Rate | Cancer-specific survival rate 36 months | 91.0 percentage of participants |
| Control Group | Cancer-specific Survival Rate | Cancer-specific survival rate 24 months | 94.9 percentage of participants |
Secondary
Cancer-specific Survivals
Cancer-specific survival was measured from the date of randomization until death resulting from HCC.
Time frame: Every 3 months from baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immunotherapy Group | Cancer-specific Survivals | NA months |
| Control Group | Cancer-specific Survivals | NA months |
p-value: 0.0295% CI: [0.04, 0.87]Log Rank
Secondary
Overall Survival(OS)
Overall survival was measured from the date of randomization until death from any cause.
Time frame: Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immunotherapy Group | Overall Survival(OS) | NA months |
| Control Group | Overall Survival(OS) | NA months |
p-value: 0.00895% CI: [0.06, 0.75]Log Rank
Secondary
Overall Survival(OS) Rate
Overall survival rate was measured from the date of randomization until death from any cause.
Time frame: Every 3months from the baseline for 24 months, and then every 3-6 months until the data cut-off date, up to LSLV(Last Subject Last Visit)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immunotherapy Group | Overall Survival(OS) Rate | OS rate 12 months | 100.0 percentage of participants |
| Immunotherapy Group | Overall Survival(OS) Rate | OS rate 36 months | 97.5 percentage of participants |
| Immunotherapy Group | Overall Survival(OS) Rate | OS rate 48 months | 95.9 percentage of participants |
| Immunotherapy Group | Overall Survival(OS) Rate | OS rate 24 months | 100.0 percentage of participants |
| Control Group | Overall Survival(OS) Rate | OS rate 48 months | 84.8 percentage of participants |
| Control Group | Overall Survival(OS) Rate | OS rate 12 months | 98.0 percentage of participants |
| Control Group | Overall Survival(OS) Rate | OS rate 24 months | 91.8 percentage of participants |
| Control Group | Overall Survival(OS) Rate | OS rate 36 months | 88.1 percentage of participants |