Hepatocellular Carcinoma
Conditions
Keywords
cabozantinib, XL184, liver cancer, hepatocellular carcinoma, tyrosine kinase inhibitor, MET kinase, vascular endothelial growth factor receptor 2 (VEGFR2)
Brief summary
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.
Interventions
DRUGPlacebo tablets
Sponsors
Exelixis
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
Select Inclusion Criteria: 1. Histological or cytological diagnosis of HCC. 2. The subject has disease that is not amenable to a curative treatment approach. 3. Received prior sorafenib. 4. Progression following at least 1 prior systemic treatment for HCC. 5. Recovery to from toxicities related to any prior treatments. 6. ECOG performance status of 0 or 1. 7. Adequate hematologic and renal function, based upon meeting protocol defined laboratory criteria within 7 days before randomization. 8. Child-Pugh Score of A. 9. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection. 10. Sexually active fertile subjects(male and female)must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment. 11. Female subjects of childbearing potential must not be pregnant at screening. Select
Exclusion criteria
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma. 2. Receipt of more than 2 prior systemic therapies for advanced HCC. 3. Any type of anticancer agent (including investigational) within 2 weeks before randomization. 4. Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment within 6 weeks of randomization. 5. Prior cabozantinib treatment. 6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization. 7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants. 8. Serious illness other than cancer that would preclude safe participation in the study. 9. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding. 10. Moderate or severe ascites. 11. Pregnant or lactating females. 12. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 45 months | The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction (ie, at approximately 466 deaths). The data cutoff date for this event-driven analysis in the Intent to Treat (ITT) population was 01 June 2017. Median OS was calculated using the Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 45 months | Duration of PFS is defined as the time of randomization to the earlier of the following events, progressive disease as determined by Investigator (per RECIST 1.0, which is defined by a ≥ 20% increase in the sum of the longest diameter of target lesions from baseline) or death due to any cause. A Kaplan- Meier analysis was performed to estimate the median duration. |
| Objective Response Rate (ORR) | ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Countries
Australia, Belgium, Canada, France, Germany, Hong Kong, Ireland, Italy, Netherlands, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 26 September 2013, Data cut-off date: 01 June 2017
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib (XL184) Cabozantinib (XL184) 60 mg tablet once daily
Cabozantinib tablets | 470 |
| Placebo Oral cabozantinib-matched placebo tablet once daily
Placebo tablets | 237 |
| Total | 707 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 98 | 11 |
| Overall Study | Clinical Deterioration | 72 | 38 |
| Overall Study | Lack of Efficacy | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | No Study Treatment Given | 3 | 0 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Progressive Disease | 206 | 152 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Cabozantinib (XL184) |
|---|---|---|---|
| Age, Continuous | 64.0 years | 64.0 years | 64.0 years |
| Age, Customized Age, Customized 65 to < 75 years old | 75 Participants | 233 Participants | 158 Participants |
| Age, Customized Age, Customized < 65 years old | 124 Participants | 364 Participants | 240 Participants |
| Age, Customized Age, Customized 75 to < 85 years old | 35 Participants | 102 Participants | 67 Participants |
| Age, Customized Age, Customized ≥ 85 years old | 3 Participants | 8 Participants | 5 Participants |
| Alcohol use Current | 30 Participants | 95 Participants | 65 Participants |
| Alcohol use Former | 124 Participants | 347 Participants | 223 Participants |
| Alcohol use Missing | 2 Participants | 8 Participants | 6 Participants |
| Alcohol use Never | 81 Participants | 257 Participants | 176 Participants |
| Body Mass Index (BMI) | 24.9 kg / m^2 | 24.5 kg / m^2 | 24.1 kg / m^2 |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 | 131 Participants | 376 Participants | 245 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 | 106 Participants | 330 Participants | 224 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 30 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 215 Participants | 632 Participants | 417 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 45 Participants | 35 Participants |
| Etiology of disease (stratification factor per IxRS), HBV (with or without known HCV) | 90 Participants | 272 Participants | 182 Participants |
| Etiology of disease (stratification factor per IxRS), HCV (without known HBV) | 51 Participants | 151 Participants | 100 Participants |
| Etiology of disease (stratification factor per IxRS), Other (neither HBV nor HCV) | 96 Participants | 284 Participants | 188 Participants |
| Geographic Region Asia | 59 Participants | 175 Participants | 116 Participants |
| Geographic Region Australia / New Zealand | 11 Participants | 26 Participants | 15 Participants |
| Geographic Region Europe | 108 Participants | 339 Participants | 231 Participants |
| Geographic Region North America (USA / Canada) | 59 Participants | 167 Participants | 108 Participants |
| Geographic region (stratification factor per IxRS) Asia | 59 Participants | 175 Participants | 116 Participants |
| Geographic region (stratification factor per IxRS) Other Regions | 178 Participants | 532 Participants | 354 Participants |
| Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS) No | 51 Participants | 153 Participants | 102 Participants |
| Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS) Yes | 186 Participants | 554 Participants | 368 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 82 Participants | 241 Participants | 159 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 19 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 49 Participants | 36 Participants |
| Race (NIH/OMB) White | 130 Participants | 394 Participants | 264 Participants |
| Sex: Female, Male Female | 35 Participants | 126 Participants | 91 Participants |
| Sex: Female, Male Male | 202 Participants | 581 Participants | 379 Participants |
| Smoking history Current | 42 Participants | 120 Participants | 78 Participants |
| Smoking history Former | 122 Participants | 351 Participants | 229 Participants |
| Smoking history Missing | 2 Participants | 5 Participants | 3 Participants |
| Smoking history Never | 71 Participants | 231 Participants | 160 Participants |
| Weight | 71.5 kg | 70.25 kg | 69 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 314 / 467 | 167 / 237 |
| other Total, other adverse events | 445 / 467 | 173 / 237 |
| serious Total, serious adverse events | 232 / 467 | 87 / 237 |
Outcome results
Primary
Overall Survival (OS)
The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction (ie, at approximately 466 deaths). The data cutoff date for this event-driven analysis in the Intent to Treat (ITT) population was 01 June 2017. Median OS was calculated using the Kaplan-Meier estimates.
Time frame: Up to 45 months
Population: The ITT population was used and included 707 randomized subjects (470 cabozantinib, 237 placebo) in the second interim analysis with a cutoff date of 01 June 2017.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib (XL184) | Overall Survival (OS) | 10.2 months |
| Placebo | Overall Survival (OS) | 8.0 months |
p-value: 0.004995% CI: [0.63, 0.92]Log Rank
Secondary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months)
Population: The analysis of ORR was performed in the ITT population (all randomized: 470 cabozantinib, 237 placebo) based upon response determined by Investigator per RECIST 1.1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cabozantinib (XL184) | Objective Response Rate (ORR) | 18 Participants |
| Placebo | Objective Response Rate (ORR) | 1 Participants |
p-value: 0.0086Cochran-Mantel-Haenszel
Secondary
Progression-Free Survival (PFS)
Duration of PFS is defined as the time of randomization to the earlier of the following events, progressive disease as determined by Investigator (per RECIST 1.0, which is defined by a ≥ 20% increase in the sum of the longest diameter of target lesions from baseline) or death due to any cause. A Kaplan- Meier analysis was performed to estimate the median duration.
Time frame: Up to 45 months
Population: The prespecified primary analysis of PFS was based on the first 707 randomized subjects (470 cabozantinib, 237 placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib (XL184) | Progression-Free Survival (PFS) | 5.2 months |
| Placebo | Progression-Free Survival (PFS) | 1.9 months |
p-value: <0.000195% CI: [0.36, 0.52]Log Rank