Carcinoma, Hepatocellular
Conditions
Keywords
Sorafenib, TACE, DC bead, Combination
Brief summary
This study will look at whether our drug (sorafenib) in combination with chemotherapy delivered directly into your tumor using beads (DC Bead) will slow the progression of the disease. The beads used with the chemotherapy will slowly release the chemotherapy reducing the adverse effects that normally occur with chemotherapy.
Detailed description
Safety issues will be reported in Adverse Event section. In addition to the secondary outcome measures, Biomarkers and Patient Report Outcome will also be analyzed as other variables.
Interventions
DRUGSorafenib (Nexavar, BAY43-9006)
800 mg sorafenib (4 tablets) will be taken daily (400mg b.i.d. \[twice daily\], 2 tablets). Transarterial Chemoembolization (TACE) using DC Bead
DRUGPlacebo
4 tablets of placebo will be taken daily (2 tablets b.i.d). TACE using DC Bead
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
* Unresectable, multinodular asymptomatic tumor without vascular invasion or extrahepatic spread * Confirmed Diagnosis of HCC: * Cirrhotic subjects: Clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria * HCC can be defined in cirrhotic subjects by one imaging technique (Computed tomography \[CT\] scan, Magnetic resonance imaging \[MRI\], or second generation contrast ultrasound) showing a nodule larger than 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1-2 cm in diameter. * Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria. * Non-cirrhotic subjects: For subjects without cirrhosis, histological or cytological confirmation is mandatory * Documentation of original biopsy for diagnosis is acceptable * Child Pugh class A without ascites * Adequate bone marrow, liver and renal function as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to randomization:
Exclusion criteria
* Patients on a liver transplantation list or with advanced liver disease as defined below: * Child Pugh B and C * Active gastrointestinal bleeding * Encephalopathy * Ascites * Lesions having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation can not be selected as the target lesions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) - Independent Radiological Review (Primary Analysis) | From randomization of the first participant until 28 months later (cut-off date) | TTP is defined as the time (days) from randomization to radiological confirmed disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization of the first participant until 28 months later (cut-off date) | Overall Survival (OS) was defined as the time (days) from randomization to death due to any cause. Participants still alive at the time of analysis were censored at their last date of last contact. |
| Time to Untreatable Progression (TTUP) | From randomization of the first participant until 28 months later (cut-off date) | Time to untreatable progression (TTUP) was defined as the time (days) from randomization to untreatable progression. Participants without untreatable progression at the time of analysis were censored at their last date of tumor evaluation. |
| Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES) | From randomization of the first participant until 28 months later (cut-off date) | Time to vascular invasion/extrahepatic spread (TTVI/ES) was defined as the time (days) from randomization to vascular invasion/extrahepatic spread. Participants without vascular invasion/extrahepatic spread at the time of analysis were censored at their last date of tumor evaluation. |
| Tumor Response - Independent Radiological Review | From randomization of the first participant until 28 months later (cut-off date) | Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. |
| Tumor Response - Investigator Assessment | From randomization of the first participant until 28 months later (cut-off date) | Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. |
Countries
Australia, Austria, Belgium, Canada, China, France, Germany, Italy, Singapore, South Korea, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Participants were then also treated with Transarterial Chemoembolization (TACE) performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of sorafenib, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.) | 154 |
| Placebo + TACE Placebo was to be orally administered as 2 tablets bid (twice daily). Participants were then also treated with TACE performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of placebo, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.) | 153 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 43 | 27 |
| Overall Study | Clinical endpoint reached | 10 | 13 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | non-compliant with study drug | 3 | 1 |
| Overall Study | patient convenience | 2 | 0 |
| Overall Study | Physician Decision | 18 | 11 |
| Overall Study | Progression measurement proven | 7 | 15 |
| Overall Study | Protocol Violation | 5 | 9 |
| Overall Study | Second malignancy | 0 | 1 |
| Overall Study | Still treated with study medication | 0 | 1 |
| Overall Study | technical problems | 2 | 1 |
| Overall Study | Untreatable disease progression | 54 | 67 |
| Overall Study | Withdrawal by Subject | 10 | 6 |
Baseline characteristics
| Characteristic | Total | Sorafenib (Nexavar, BAY43-9006) + TACE | Placebo + TACE |
|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 11.9 | 62.5 Years STANDARD_DEVIATION 11.9 | 62.7 Years STANDARD_DEVIATION 11.9 |
| Age, Customized 65 - 74 years | 100 Participants | 52 Participants | 48 Participants |
| Age, Customized <65 years | 159 Participants | 77 Participants | 82 Participants |
| Age, Customized >=75 years | 48 Participants | 25 Participants | 23 Participants |
| Alfa-fetoprotein <400 ng/mL | 225 Participants | 113 Participants | 112 Participants |
| Alfa-fetoprotein >/=400 ng/mL | 82 Participants | 41 Participants | 41 Participants |
| Child pugh classification Class A | 305 Participants | 153 Participants | 152 Participants |
| Child pugh classification Class B | 1 Participants | 1 Participants | 0 Participants |
| Child pugh classification Missing | 1 Participants | 0 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status at enrollment Grade 0 | 306 Scores on a scale | 154 Scores on a scale | 152 Scores on a scale |
| Eastern Cooperative Oncology Group (ECOG) performance status at enrollment Missing | 1 Scores on a scale | 0 Scores on a scale | 1 Scores on a scale |
| Number of non-target lesions 0 | 145 Participants | 72 Participants | 73 Participants |
| Number of non-target lesions 1 | 79 Participants | 40 Participants | 39 Participants |
| Number of non-target lesions 10 | 2 Participants | 1 Participants | 1 Participants |
| Number of non-target lesions 14 | 1 Participants | 1 Participants | 0 Participants |
| Number of non-target lesions 2 | 42 Participants | 24 Participants | 18 Participants |
| Number of non-target lesions 3 | 17 Participants | 7 Participants | 10 Participants |
| Number of non-target lesions 4 | 9 Participants | 3 Participants | 6 Participants |
| Number of non-target lesions 5 | 6 Participants | 4 Participants | 2 Participants |
| Number of non-target lesions 6 | 1 Participants | 0 Participants | 1 Participants |
| Number of non-target lesions 7 | 3 Participants | 1 Participants | 2 Participants |
| Number of non-target lesions 8 | 2 Participants | 1 Participants | 1 Participants |
| Number of target lesions 1 | 61 Participants | 30 Participants | 31 Participants |
| Number of target lesions 2 | 107 Participants | 58 Participants | 49 Participants |
| Number of target lesions 3 | 66 Participants | 33 Participants | 33 Participants |
| Number of target lesions 4 | 30 Participants | 12 Participants | 18 Participants |
| Number of target lesions 5 | 43 Participants | 21 Participants | 22 Participants |
| Sex: Female, Male Female | 46 Participants | 19 Participants | 27 Participants |
| Sex: Female, Male Male | 261 Participants | 135 Participants | 126 Participants |
| Time of first study medication since first progression | 1.91 Months | 1.45 Months | 2.56 Months |
| Time of first study medication since initial diagnosis | 1.71 Months | 1.60 Months | 1.91 Months |
| Time of first study medication since most recent progression | 1.09 Months | 1.02 Months | 1.25 Months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 150 / 153 | 139 / 151 |
| serious Total, serious adverse events | 86 / 153 | 56 / 151 |
Outcome results
Primary
Time to Progression (TTP) - Independent Radiological Review (Primary Analysis)
TTP is defined as the time (days) from randomization to radiological confirmed disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Time to Progression (TTP) - Independent Radiological Review (Primary Analysis) | 169 Days |
| Placebo + TACE | Time to Progression (TTP) - Independent Radiological Review (Primary Analysis) | 166 Days |
p-value: 0.07295% CI: [0.588, 1.08]Log Rank
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the time (days) from randomization to death due to any cause. Participants still alive at the time of analysis were censored at their last date of last contact.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Overall Survival (OS) | NA Days |
| Placebo + TACE | Overall Survival (OS) | NA Days |
p-value: 0.29595% CI: [0.606, 1.33]Log Rank
Secondary
Time to Untreatable Progression (TTUP)
Time to untreatable progression (TTUP) was defined as the time (days) from randomization to untreatable progression. Participants without untreatable progression at the time of analysis were censored at their last date of tumor evaluation.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Time to Untreatable Progression (TTUP) | 95 Days |
| Placebo + TACE | Time to Untreatable Progression (TTUP) | 224 Days |
p-value: 0.99995% CI: [1.2, 2.096]Log Rank
Secondary
Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES)
Time to vascular invasion/extrahepatic spread (TTVI/ES) was defined as the time (days) from randomization to vascular invasion/extrahepatic spread. Participants without vascular invasion/extrahepatic spread at the time of analysis were censored at their last date of tumor evaluation.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES) | NA Days |
| Placebo + TACE | Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES) | NA Days |
p-value: 0.07695% CI: [0.321, 1.2]Log Rank
Secondary
Tumor Response - Independent Radiological Review
Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Response (CR+PR) | 55 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Complete Response (CR) | 20 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Partial Response (PR) | 35 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Stable Disease | 52 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Progressive Disease | 20 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Independent Radiological Review | Not assessable | 27 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Progressive Disease | 36 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Response (CR+PR) | 43 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Stable Disease | 56 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Complete Response (CR) | 17 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Not assessable | 18 Participants |
| Placebo + TACE | Tumor Response - Independent Radiological Review | Partial Response (PR) | 26 Participants |
Secondary
Tumor Response - Investigator Assessment
Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time frame: From randomization of the first participant until 28 months later (cut-off date)
Population: Intent-to-treat (ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Response (CR+PR) | 66 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Complete Response | 21 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Partial Response | 45 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Stable Disease | 50 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Progressive Disease | 16 Participants |
| Sorafenib (Nexavar, BAY43-9006) + TACE | Tumor Response - Investigator Assessment | Not Assessable | 22 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Progressive Disease | 30 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Response (CR+PR) | 53 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Stable Disease | 57 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Complete Response | 20 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Not Assessable | 13 Participants |
| Placebo + TACE | Tumor Response - Investigator Assessment | Partial Response | 33 Participants |