Hepatocellular Carcinoma
Conditions
Keywords
Localised, unresectable, chemoembolization
Brief summary
This study will evaluate the role of everolimus in combination with local Transcatheter Arterial Chemoembolization (TACE) procedure in patients with localized unresectable Hepatocellular Carcinoma (HCC).
Interventions
DRUGeverolimus
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed hepatocellular carcinoma limited to liver and not suitable for resection, liver transplant, or radiofrequency ablation. * Intermediate stage (stage B) (according to recognized guidelines) and suitable for TACE therapy * At least one nodule between \> 2cm and ≤ 15cm in diameter with no vascular invasion or abdominal lymph node or distant metastases. * Must have 1 tumor which can be measured in 1 dimension according to specified criteria (RECIST and mRECIST) and has not previously been treated with any type of therapy. * ECOG performance status \< 2cm * Cirrhotic status of Child-Pugh class A or early B * HBV-DNA or HBsAg positive at screen or baseline: preventative treatment with anti-viral started 1-2 weeks prior to receiving study drug
Exclusion criteria
* Any local and/or investigational drugs within 28 days prior to randomization * Active bleeding during the last 28 days prior to screening including variceal bleeding * Prior therapy with mTOR inhibitors * Tumor burden of \> 60% liver involvement * Prior systemic or local therapy including TACE except for the first TACE at Day 0), surgery or liver transplantation * Failed first TACE at Day 0, Cycle 1 for any reason * Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory) * Alcohol intake of 80 grams per day * Undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from surgery * Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) Based on the Modified RECIST Criteria | 3, 6, 12, 18 and 24 months | Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on modified RECIST criteria. Progressive Disease: \>20% increase in sum of the longest diameters (SLD) of viable target lesion (arterial phase enhancement) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression Based on Original RECIST | 6, 12 months, end of study | Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on original RECIST criteria. Progressive Disease: \>20% increase in sum of the longest diameters (SLD) of target lesions with an absolute increase of ≥5 mm; new lesions. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed. |
| Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on Original RECIST | 6, 12 months, end of study | Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the Complete response: Disappearance of all target lesions or lymph nodes \<10 mm in the short axis Partial response: \>30% decrease in sum of the longest diameters (SLD) of target lesions Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed. |
| Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on the Modified RECIST | 6, 12 months, end of study | Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the modified RECIST. Complete response: Disappearance of arterial phase enhance-ment in all target lesions. Partial response: \>30% decrease in sum of the longest diameters (SLD) of viable target lesion (arterial phase enhance-ment)Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed. |
| Incidences of Cumulative New Nodular Recurrence, Portal Vein Invasion and Extra Hepatic Metastases | 30 months | Incidences of cumulative new nodular recurrence, portal vein invasion and extra hepatic metastases but incidence of portal vein invasion meant those patients without documented vascular invasion at screening/baseline. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed. |
| Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months | baseline, 30 months | Percentage of participants with a decrease in the sum of the of longest diameters (SLD) of target lesions from Baseline to 30 months |
| Overall Survival (OS) | 6, 12, 18, 24, 30 months | Overall survival was defined as the time from date of randomization to date of death due to any cause. If death had not occurred at the date of the analysis cut-off then OS was censored at the date of the last contact. |
Countries
Hong Kong, Taiwan, Thailand
Participant flow
Recruitment details
Of the 65 patients who were screened they reflect the actual enrolment but 59 patients were randomized and were included in the FAS, the Safety Set and the PP Set. There were no exclusions. Post-Treatment evaluations included any patients that was treated and does not reflect the number completed in the Overall Study.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + TACE everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE) | 33 |
| Placebo + TACE Placebo by mouth + transcatheter arterial chemoembolization (TACE) | 26 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study -Treatment Period | Abnormal test procedure results | 0 | 1 |
| Overall Study -Treatment Period | Administrative Problems | 1 | 0 |
| Overall Study -Treatment Period | Adverse Event | 3 | 0 |
| Overall Study -Treatment Period | Death | 2 | 1 |
| Overall Study -Treatment Period | Disease Progression | 23 | 22 |
| Overall Study -Treatment Period | New Cancer Therapy | 1 | 0 |
| Overall Study -Treatment Period | Protocol Deviation | 0 | 2 |
| Overall Study -Treatment Period | Withdrawal by Subject | 3 | 0 |
| Post-Treatment Evaluations | Death | 1 | 0 |
| Post-Treatment Evaluations | Disease Progression | 22 | 20 |
| Post-Treatment Evaluations | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Everolimus + TACE | Placebo + TACE | Total |
|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 11.29 | 61.0 years STANDARD_DEVIATION 10.32 | 59.6 years STANDARD_DEVIATION 10.85 |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 29 Participants | 19 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 33 | 25 / 26 |
| serious Total, serious adverse events | 10 / 33 | 7 / 26 |
Outcome results
Primary
Time to Progression (TTP) Based on the Modified RECIST Criteria
Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on modified RECIST criteria. Progressive Disease: \>20% increase in sum of the longest diameters (SLD) of viable target lesion (arterial phase enhancement)
Time frame: 3, 6, 12, 18 and 24 months
Population: Full Analysis Set (FAS) comprises all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + TACE | Time to Progression (TTP) Based on the Modified RECIST Criteria | 6.3 months |
| Placebo + TACE | Time to Progression (TTP) Based on the Modified RECIST Criteria | 6.4 months |
Secondary
Incidences of Cumulative New Nodular Recurrence, Portal Vein Invasion and Extra Hepatic Metastases
Incidences of cumulative new nodular recurrence, portal vein invasion and extra hepatic metastases but incidence of portal vein invasion meant those patients without documented vascular invasion at screening/baseline. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time frame: 30 months
Population: Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Secondary
Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on Original RECIST
Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the Complete response: Disappearance of all target lesions or lymph nodes \<10 mm in the short axis Partial response: \>30% decrease in sum of the longest diameters (SLD) of target lesions Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time frame: 6, 12 months, end of study
Population: Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Secondary
Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on the Modified RECIST
Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the modified RECIST. Complete response: Disappearance of arterial phase enhance-ment in all target lesions. Partial response: \>30% decrease in sum of the longest diameters (SLD) of viable target lesion (arterial phase enhance-ment)Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time frame: 6, 12 months, end of study
Population: Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Secondary
Overall Survival (OS)
Overall survival was defined as the time from date of randomization to date of death due to any cause. If death had not occurred at the date of the analysis cut-off then OS was censored at the date of the last contact.
Time frame: 6, 12, 18, 24, 30 months
Population: Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + TACE | Overall Survival (OS) | 29.9 months |
| Placebo + TACE | Overall Survival (OS) | 21.7 months |
Secondary
Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months
Percentage of participants with a decrease in the sum of the of longest diameters (SLD) of target lesions from Baseline to 30 months
Time frame: baseline, 30 months
Population: Full Analysis Set (FAS) comprises all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + TACE | Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months | 93.8 Percentage of participants |
| Placebo + TACE | Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months | 88.0 Percentage of participants |
Secondary
Time to Progression Based on Original RECIST
Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on original RECIST criteria. Progressive Disease: \>20% increase in sum of the longest diameters (SLD) of target lesions with an absolute increase of ≥5 mm; new lesions. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time frame: 6, 12 months, end of study
Population: Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.