Carcinoma, Hepatocellular
Conditions
Keywords
Regorafenib, BAY73-4506
Brief summary
The objective of this study was to evaluate efficacy and safety of regorafenib in patients with advanced liver cancer who had progressed after sorafenib treatment. Patients were treated with regorafenib or placebo using a 2:1 randomization scheme.
Interventions
DRUGRegorafenib (Stivarga, BAY73-4506)
Regorafenib, 40 mg tablets
DRUGPlacebo
Placebo tablets matching in appearance
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
* Histological or cytological confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases criteria in patients with a confirmed diagnosis of cirrhosis * Barcelona Clinic Liver Cancer stage Category B or C that cannot benefit from treatments of established efficacy with higher priority such as resection, local ablation, chemoembolization or systemic sorafenib. * Failure to prior treatment with sorafenib (defined as documented radiological progression according to the radiology charter). Randomization needs to be performed within 10 weeks after the last treatment with sorafenib. * Tolerability of prior treatment with sorafenib defined as not less than 20 days at a minimum daily dose of 400 mg QD within the last 28 days prior to withdrawal. * Liver function status Child-Pugh Class A. Child Pugh status should be calculated based on clinical findings and laboratory results during the screening period. Local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed \>/=4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intraarterial chemotherapy, without lipiodol or embolizing agents are not eligible. * Eastern Cooperative Oncology Group Performance Status of 0 or 1. * Adequate bone marrow, liver and renal function as assessed by the following laboratory tests conducted within 7 days before randomization. * Glomerular filtration rate \>/= 30 ml/min/1.73 m\^2 according to the Modification of diet in renal disease study equation. * At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1), and modified RECIST for HCC. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion. * Life expectancy of at least 3 months. * Women of childbearing potential and men must agree to use adequate contraception .
Exclusion criteria
: * Sorafenib treatment within 2 weeks of randomization. * Prior systemic treatment for HCC, except sorafenib. * Permanent discontinuation of prior sorafenib therapy due to sorafenib related toxicity. * Known history or symptomatic metastatic brain or meningeal tumors (head CT or MRI at screening to confirm the absence of central nervous system \[CNS\] disease if patient has symptoms suggestive or consistent with CNS disease). * Uncontrolled hypertension (systolic blood pressure \[BP\] \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management). * Uncontrolled ascites (defined as not easily controlled with diuretic or paracentesis treatment). * Ongoing infection \> Grade 2 according to NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) v. 4.0. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required. * Clinically significant bleeding NCI-CTCAE version 4.0 Grade 3 or higher within 30 days before randomization. * Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication. * Patients unable to swallow oral medications. * Interstitial lung disease with ongoing signs and symptoms at the time of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization (Day 1) of the first subject until 419 days later | Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months) | TTP was the time (days) from randomization to radiological or clinical disease progression assessed by independent radiological review. Median and 95% confidence interval were reported for the modified response evaluation criteria in solid tumors (mRECIST) and response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact. |
| Progression Free Survival (PFS) | From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) | Progression Free Survival (PFS) was defined as the time (days) from date of randomization to date of disease progression (radiological or clinical) or death due to any cause, if death occurs before progression was documented. Death in the absence of progression was a PFS event only if it occurred within the 12+1 weeks for subjects who discontinued treatment prior to cycle 8 and 24+2 weeks for subjects who discontinued treatment after to cycle 8 of the last evaluable tumor assessment; PFS were censored at the date of the last evaluable tumor assessment, if it occurred later. Median and 95% confidence interval 95% were reported for the mRECIST and RECIST 1.1 analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact. |
| Objective Tumor Response Rate (ORR) | From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months) | Objective tumor response rate (ORR) was defined as the percentage of subjects whose best tumor response CR or Partial Response (PR) observed during trial period assessed according to the mRECIST criteria and RECIST 1.1. CR= Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Subjects prematurely discontinuing without an assessment were to be considered non-responders for the analysis. |
| Disease Control Rate (DCR) | From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months) | Disease control rate (DCR) was defined as the percentage of subjects whose best response was CR (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), PR (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or stable disease (SD) (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST and RECIST 1.1 criteria. SD had to be maintained for at least 6 weeks from the first demonstration of that rating. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization (Day 1) of the first subject to end of follow upto 1710 days | Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause |
Countries
Argentina, Australia, Austria, Belgium, Brazil, China, Czechia, France, Germany, Hungary, Italy, Japan, Netherlands, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted between 14 May 2013 (first subject first visit), 29 February 2016 (primary completion date) and 05-July-2019 (Last Patient Last Visit =End of study).
Pre-assignment details
Overall, 843 subjects were screened, of them 270 subjects were screening failures. 573 subjects were randomized and assigned to treatment; of them 6 subjects never received treatment. 436 Entered survival Follow-up and 4 End of survival follow-up data not available.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best supportive care (BSC). | 194 |
| Regorafenib 160 mg (BAY73-4506) Subjects received regorafenib 160 milligram (mg) (4 \* 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC. | 379 |
| Total | 573 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Data collection finished | 4 | 14 |
| Overall Study | Did not enter Survival Follow up | 49 | 83 |
| Overall Study | End of survival follow-up not available | 2 | 2 |
| Overall Study | Lost to Follow-up | 4 | 10 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 10 |
Baseline characteristics
| Characteristic | Regorafenib 160 mg (BAY73-4506) | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 12.4 | 61.6 years STANDARD_DEVIATION 12.1 | 61.1 years STANDARD_DEVIATION 11.6 |
| Alpha-fetoprotein (AFP) (IVRS) < 400 ng/mL | 212 Participants | 317 Participants | 105 Participants |
| Alpha-fetoprotein (AFP) (IVRS) >= 400 ng/mL | 167 Participants | 256 Participants | 89 Participants |
| Alpha-fetoprotein (AFP) (RAVE) greater than or equal to (>=) 400 ng/mL | 162 Participants | 249 Participants | 87 Participants |
| Alpha-fetoprotein (AFP) (RAVE) less than (<) 400 nanogram per milliliter (ng/mL) | 217 Participants | 324 Participants | 107 Participants |
| Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE) ECOG PS 0 | 247 Participants | 377 Participants | 130 Participants |
| Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE) ECOG PS 1 | 132 Participants | 196 Participants | 64 Participants |
| ECOG PS: Interactive voice response system (IVRS) ECOG PS 0 | 251 Participants | 380 Participants | 129 Participants |
| ECOG PS: Interactive voice response system (IVRS) ECOG PS 1 | 128 Participants | 193 Participants | 65 Participants |
| Extrahepatic disease (IVRS) Absence | 129 Participants | 191 Participants | 62 Participants |
| Extrahepatic disease (IVRS) Presence | 250 Participants | 382 Participants | 132 Participants |
| Extrahepatic disease (RAVE) Absence | 114 Participants | 161 Participants | 47 Participants |
| Extrahepatic disease (RAVE) Presence | 265 Participants | 412 Participants | 147 Participants |
| Macrovascular invasion (IVRS) Absence | 262 Participants | 397 Participants | 135 Participants |
| Macrovascular invasion (IVRS) Presence | 117 Participants | 176 Participants | 59 Participants |
| Macrovascular invasion (RAVE) Absence | 269 Participants | 409 Participants | 140 Participants |
| Macrovascular invasion (RAVE) Presence | 110 Participants | 164 Participants | 54 Participants |
| Sex: Female, Male Female | 46 Participants | 69 Participants | 23 Participants |
| Sex: Female, Male Male | 333 Participants | 504 Participants | 171 Participants |
| The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry Advanced stage | 325 Participants | 497 Participants | 172 Participants |
| The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry Early stage | 1 Participants | 1 Participants | 0 Participants |
| The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry Intermediate stage | 53 Participants | 75 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 176 / 193 | 324 / 374 |
| other Total, other adverse events | 162 / 193 | 366 / 374 |
| serious Total, serious adverse events | 92 / 193 | 194 / 374 |
Outcome results
Primary
Overall Survival (OS)
Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time frame: From randomization (Day 1) of the first subject until 419 days later
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Overall Survival (OS) | 237 days | 95% Confidence Interval 192 |
| Regorafenib 160 mg (BAY73-4506) | Overall Survival (OS) | 323 days | 95% Confidence Interval 276 |
Comparison: Hazard ratio for OS and 95% confidence interval was calculated for stratified IVRS by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.p-value: =0.00001795% CI: [0.498, 0.782]Log Rank
Comparison: Hazard ratio for OS and 95% confidence interval was calculated for stratified RAVE (Sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.p-value: =0.00014995% CI: [0.527, 0.828]Log Rank
Comparison: Hazard ratio for OS and 95% confidence interval was calculated for unstratified (sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.p-value: =0.00010795% CI: [0.546, 0.831]Log Rank
Secondary
Disease Control Rate (DCR)
Disease control rate (DCR) was defined as the percentage of subjects whose best response was CR (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), PR (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or stable disease (SD) (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST and RECIST 1.1 criteria. SD had to be maintained for at least 6 weeks from the first demonstration of that rating.
Time frame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Disease Control Rate (DCR) | mRECIST | 36.1 percentage of subjects |
| Placebo | Disease Control Rate (DCR) | RECIST 1.1 | 34.5 percentage of subjects |
| Regorafenib 160 mg (BAY73-4506) | Disease Control Rate (DCR) | mRECIST | 65.2 percentage of subjects |
| Regorafenib 160 mg (BAY73-4506) | Disease Control Rate (DCR) | RECIST 1.1 | 65.7 percentage of subjects |
Comparison: Comparison of treatments were calculated.p-value: <0.00000195% CI: [-37.52, -21.11]Cochran-Mantel-Haenszel
Comparison: Comparison of treatments were calculated.p-value: <0.00000195% CI: [-39.57, -23.22]Cochran-Mantel-Haenszel
Secondary
Objective Tumor Response Rate (ORR)
Objective tumor response rate (ORR) was defined as the percentage of subjects whose best tumor response CR or Partial Response (PR) observed during trial period assessed according to the mRECIST criteria and RECIST 1.1. CR= Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Subjects prematurely discontinuing without an assessment were to be considered non-responders for the analysis.
Time frame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Objective Tumor Response Rate (ORR) | mRECIST | 4.1 percentage of subjects |
| Placebo | Objective Tumor Response Rate (ORR) | RECIST 1.1 | 2.6 percentage of subjects |
| Regorafenib 160 mg (BAY73-4506) | Objective Tumor Response Rate (ORR) | mRECIST | 10.8 percentage of subjects |
| Regorafenib 160 mg (BAY73-4506) | Objective Tumor Response Rate (ORR) | RECIST 1.1 | 6.6 percentage of subjects |
Comparison: Comparison of treatments were calculated.p-value: =0.0036595% CI: [-11.13, -2.63]Cochran-Mantel-Haenszel
Comparison: Comparison of treatments were calculated.p-value: =0.01999195% CI: [-7.55, -0.75]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time (days) from date of randomization to date of disease progression (radiological or clinical) or death due to any cause, if death occurs before progression was documented. Death in the absence of progression was a PFS event only if it occurred within the 12+1 weeks for subjects who discontinued treatment prior to cycle 8 and 24+2 weeks for subjects who discontinued treatment after to cycle 8 of the last evaluable tumor assessment; PFS were censored at the date of the last evaluable tumor assessment, if it occurred later. Median and 95% confidence interval 95% were reported for the mRECIST and RECIST 1.1 analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time frame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks)
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Progression Free Survival (PFS) | mRECIST | 45 days | 95% Confidence Interval 44 |
| Placebo | Progression Free Survival (PFS) | RECIST 1.1 | 45 days | 95% Confidence Interval 44 |
| Regorafenib 160 mg (BAY73-4506) | Progression Free Survival (PFS) | mRECIST | 95 days | 95% Confidence Interval 86 |
| Regorafenib 160 mg (BAY73-4506) | Progression Free Survival (PFS) | RECIST 1.1 | 102 days | 95% Confidence Interval 87 |
Comparison: Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.p-value: <0.00000195% CI: [0.369, 0.555]Log Rank
Comparison: Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.p-value: <0.00000195% CI: [0.397, 0.58]Log Rank
Comparison: Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.p-value: <0.00000195% CI: [0.347, 0.522]Log Rank
Comparison: Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.p-value: <0.00000195% CI: [0.376, 0.548]Log Rank
Secondary
Time to Progression (TTP)
TTP was the time (days) from randomization to radiological or clinical disease progression assessed by independent radiological review. Median and 95% confidence interval were reported for the modified response evaluation criteria in solid tumors (mRECIST) and response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time frame: From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time to Progression (TTP) | mRECIST | 45 days | 95% Confidence Interval 44 |
| Placebo | Time to Progression (TTP) | RECIST 1.1 | 45 days | 95% Confidence Interval 44 |
| Regorafenib 160 mg (BAY73-4506) | Time to Progression (TTP) | mRECIST | 97 days | 95% Confidence Interval 87 |
| Regorafenib 160 mg (BAY73-4506) | Time to Progression (TTP) | RECIST 1.1 | 119 days | 95% Confidence Interval 87 |
Comparison: Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.p-value: <0.00000195% CI: [0.355, 0.542]Log Rank
Comparison: Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.p-value: <0.00000195% CI: [0.388, 0.572]Log Rank
Comparison: Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.p-value: <0.00000195% CI: [0.334, 0.509]Log Rank
Comparison: Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.p-value: <0.00000195% CI: [0.365, 0.539]Log Rank
Other Pre-specified
Overall Survival (OS)
Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause
Time frame: From randomization (Day 1) of the first subject to end of follow upto 1710 days
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Overall Survival (OS) | 241 days | 95% Confidence Interval 196 |
| Regorafenib 160 mg (BAY73-4506) | Overall Survival (OS) | 326 days | 95% Confidence Interval 278 |