Hepatocellular Carcinoma
Conditions
Brief summary
Hepatocellular carcinoma (HCC) is a common disease with high mortality. More than 80% patients receive a diagnosis when their tumors are too advanced for curative approaches and have a dismal prognosis. invariant Natural Killer T (iNKT) cell exhibit antitumor activity against malignant tumors through producing high levels of cytokines. iNKT cells are abundant in the liver, but their function is defective in liver cancer. After expansion and restored function in vitro, iNKT cells can home to liver, then they play key antitumor function. We have finished a phase I study of adoptive transfer of autologous iNKT cells for treating patients with unresectable HCC. Safety and feasibility of iNKT infusion was proved. The purpose of this study was to verify the effectiveness of iNKT cell infusion in patients with unresectable HCC who had previously failed transcatheter arterial embolization (TAE) / transcatheter arterial chemoembolization (TACE).
Detailed description
Patients with unresectable HCC will be enrolled and divided into two groups. Patients in trial group will be treated with combination of TAE/TACE and adoptive transfer of autologus iNKT cells. TAE/TACE will be performed at 0th and 4th week. iNKT cells will be infused at 1st, 3rd, 5th, 7th, 9th, 11th week after first TAE/TACE therapy. Patients in control group will be treated with TAE/TACE at 0th and 4th week. Overall survival (OS) time, progression-free survival (PFS) time, objective response rate(ORR), disease control rate(DCR) will be monitored. According to JSH guidelines, TAE/TACE failure is defined as an insufficient response after ≧2 consecutive TAE/TACE procedures that is evident on response evaluation computed tomography or magnetic resonance imaging after 1-3 months, these patients do not respond sufficiently to TAE/TACE.
Interventions
BIOLOGICALiNKT cells
5×10\^8-10\^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 9th, 11th week after first TAE/TACE therapy.
DRUGHuman recombinated Interleukin-2
IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days after iNKT cells infusion.
PROCEDURETAE/TACE
TAE/TACE will be conducted to all patients at 0th week and 4th week.
Sponsors
Beijing Shijitan Hospital, Capital Medical University
Beijing Ditan Hospital
Beijing YouAn Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-80 years. * Patients with hepatocellular carcinoma (BCLC, stageB/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\>3.0×10\^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 cell/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 |
|---|---|---|
| Progression-Free Survival(PFS) | From date of enrollment to disease progression according to mRECIST, or death from any cause, whichever occurred first，approximately 2 years. | PFS is the duration from the date of enrolled into clinical trial to the date of first documentation of tumor progression. Progression is defined using Modified RECIST (mRECIST),as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival(OS) | From date of randomization until the date of death from any cause, whichever came first, assessed up to 60 months. | OS is the duration from the date of enrollment to the date of death due to any causes. |
| Objective Response Rate(ORR) | Evaluation was performed at the 12th week after the start of the treatment. | ORR is the proportion of patients who had a response rate including complete remission (CR) and partial remission (PR) evaluated by imaging according to mRECIST for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of any intratumoral arterial enhancement in all target lesions；Partial Response (PR), At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Overall Response (OR) = CR + PR. |
| Disease Control Rate (DCR) | Evaluation was performed at the 12th week after the start of the treatment. | DCR is the proportion of patients who had a response rate including complete remission (CR), partial remission (PR) and disease stabilization (SD) evaluated by imaging according to mRECIST for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of any intratumoral arterial enhancement in all target lesions；Partial Response (PR), At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions;Stable disease(SD), Any cases that do not qualify for either partial response or progressive disease. Disease Control Rate (DCR) = CR + PR + SD. |
| Adverse Events(AEs) | The occurrence of AEs was observed for an average of 24 weeks after the completion of treatment (between 0-11 weeks of treatment) for up to a 60 week period in total. | The severities of AEs will be divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03. |
| Time to Quality of Life (QoL) Deterioration | Data will be collected at baseline and every 4 weeks until disease progression, then every 8 weeks for up to 60 weeks. | 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TAE/TACE+iNKT for Unresectable HCC TAE/TACE combined with autologous iNKT cells infusion will be applied for patients in experimental group. TAE/TACE will be performed at 0th and 4th week. 5×10\^8-10\^9/m2 iNKT cells will be infused to patients 1st, 3rd, 5th, 7th, 9th, 11th week after first TAE/TACE therapy.
iNKT cells: 5×10\^8-10\^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 9th, 11th week after first TAE/TACE therapy.
Human recombinated Interleukin-2: IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days after iNKT cells infusion.
TAE/TACE: TAE/TACE will be conducted to all patients at 0th week and 4th week. | 27 |
| TAE/TACE for Unresectable HCC TAE/TACE will be conducted at 0th week and 4th week.
TAE/TACE: TAE/TACE will be conducted to all patients at 0th week and 4th week. | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | TAE/TACE+iNKT for Unresectable HCC | TAE/TACE for Unresectable HCC | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 6 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 21 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 27 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 27 Participants | 54 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 27 participants | 27 participants | 54 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 23 Participants | 24 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 27 | 4 / 27 |
| other Total, other adverse events | 14 / 27 | 15 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Progression-Free Survival(PFS)
PFS is the duration from the date of enrolled into clinical trial to the date of first documentation of tumor progression. Progression is defined using Modified RECIST (mRECIST),as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.
Time frame: From date of enrollment to disease progression according to mRECIST, or death from any cause, whichever occurred first，approximately 2 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Progression-Free Survival(PFS) | 5.7 months |
| TAE/TACE for Unresectable HCC | Progression-Free Survival(PFS) | 2.7 months |
p-value: <0.00195% CI: [0.16, 0.63]Log Rank
Secondary
Adverse Events(AEs)
The severities of AEs will be divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03.
Time frame: The occurrence of AEs was observed for an average of 24 weeks after the completion of treatment (between 0-11 weeks of treatment) for up to a 60 week period in total.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Blood bilirubin increased (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Injection site reaction(Any Grade) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Glutamyl transpeptidase increased (≧ Grade 3) | 1 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Aspartate aminotransferase increased (Any Grade) | 4 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Chill (Any Grade) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Chill (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Fatigue(Any Grade) | 3 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Fatigue(≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Fever (Any Grade) | 3 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Fever (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Injection site reaction (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Callosity(Any Grade) | 4 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Callosity(≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Activation time of partial prothrombin (Any Grade) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Activation time of partial prothrombin (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Alanine aminotransferase increased (Any Grade) | 1 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Alanine aminotransferase increased (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Aspartate aminotransferase increased (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Blood bilirubin increased (Any Grade) | 3 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Alkaline phosphatase increased (Any Grade) | 1 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Alkaline phosphatase increased (≧ Grade 3) | 0 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Glutamyl transpeptidase increased (Any Grade) | 6 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Cholesterol high(Any Grade) | 1 Participants |
| TAE/TACE+iNKT for Unresectable HCC | Adverse Events(AEs) | Cholesterol high(≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Glutamyl transpeptidase increased (≧ Grade 3) | 1 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Activation time of partial prothrombin (Any Grade) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Injection site reaction(Any Grade) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Alkaline phosphatase increased (Any Grade) | 2 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Alanine aminotransferase increased (≧ Grade 3) | 2 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Activation time of partial prothrombin (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Aspartate aminotransferase increased (Any Grade) | 5 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Cholesterol high(≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Chill (Any Grade) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Alanine aminotransferase increased (Any Grade) | 8 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Chill (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Alkaline phosphatase increased (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Fatigue(Any Grade) | 5 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Cholesterol high(Any Grade) | 1 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Fatigue(≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Aspartate aminotransferase increased (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Fever (Any Grade) | 5 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Glutamyl transpeptidase increased (Any Grade) | 6 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Blood bilirubin increased (Any Grade) | 6 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Injection site reaction (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Fever (≧ Grade 3) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Callosity(Any Grade) | 0 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Blood bilirubin increased (≧ Grade 3) | 2 Participants |
| TAE/TACE for Unresectable HCC | Adverse Events(AEs) | Callosity(≧ Grade 3) | 0 Participants |
Secondary
Disease Control Rate (DCR)
DCR is the proportion of patients who had a response rate including complete remission (CR), partial remission (PR) and disease stabilization (SD) evaluated by imaging according to mRECIST for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of any intratumoral arterial enhancement in all target lesions；Partial Response (PR), At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions;Stable disease(SD), Any cases that do not qualify for either partial response or progressive disease. Disease Control Rate (DCR) = CR + PR + SD.
Time frame: Evaluation was performed at the 12th week after the start of the treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Disease Control Rate (DCR) | 23 Participants |
| TAE/TACE for Unresectable HCC | Disease Control Rate (DCR) | 9 Participants |
p-value: <0.001Fisher Exact
Secondary
Objective Response Rate(ORR)
ORR is the proportion of patients who had a response rate including complete remission (CR) and partial remission (PR) evaluated by imaging according to mRECIST for target lesions and assessed by MRI/CT: Complete Response (CR), Disappearance of any intratumoral arterial enhancement in all target lesions；Partial Response (PR), At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Overall Response (OR) = CR + PR.
Time frame: Evaluation was performed at the 12th week after the start of the treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Objective Response Rate(ORR) | 14 Participants |
| TAE/TACE for Unresectable HCC | Objective Response Rate(ORR) | 3 Participants |
p-value: =0.003Fisher Exact
Secondary
Overall Survival(OS)
OS is the duration from the date of enrollment to the date of death due to any causes.
Time frame: From date of randomization until the date of death from any cause, whichever came first, assessed up to 60 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Overall Survival(OS) | 25.9 months |
| TAE/TACE for Unresectable HCC | Overall Survival(OS) | 17.3 months |
Secondary
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 frame: Data will be collected at baseline and every 4 weeks until disease progression, then every 8 weeks for up to 60 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAE/TACE+iNKT for Unresectable HCC | Time to Quality of Life (QoL) Deterioration | 9.2 months |
| TAE/TACE for Unresectable HCC | Time to Quality of Life (QoL) Deterioration | 3.0 months |
p-value: =0.00195% CI: [0.19, 0.71]Log Rank