Renal Cell Carcinoma
Conditions
Keywords
renal cell cancer, kidney, vascular endothelial growth factor receptor 2 (VEGFR2), tyrosine kinase inhibitor, hepatocyte growth factor receptor protein (MET), von Hippel-Lindau gene
Brief summary
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with Everolimus (Afinitor) on progression-free survival (PFS) and overall survival (OS) in subjects with advanced renal cell cancer that has progressed after prior VEGFR tyrosine kinase inhibitor therapy.
Interventions
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Select Inclusion Criteria: 1. Documented histological or cytological diagnosis of renal cell cancer with a clear-cell component. 2. Measurable disease as determined by the investigator. 3. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib). 4. Recovery from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. 5. Adequate organ and marrow function. 6. 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. 7. Female subjects of childbearing potential must not be pregnant at screening. Select
Exclusion criteria
1. Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus), or cabozantinib. 2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization. 3. Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks before randomization. 4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. 5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization. 6. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors. 7. Chronic treatment with corticosteroids or other immunosuppressive agents. 8. Serious illness other than cancer. 9. Major surgery within 3 months before randomization. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery at least 10 days before randomization. 10. Pregnant or lactating females. 11. 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 |
|---|---|---|
| Progression-free Survival (PFS) | PFS is measured from the date of randomization until the date of first documented disease progression or date of death from any cause as determined by the Independent Radiology Committee (IRC) per RECIST 1.1, assessed for up to 17 months. | The primary analysis of PFS is the time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria) or death due to any cause, whichever occurred first. A Kaplan-Meier analysis was performed to estimate the median duration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | OS was measured from the time of randomization until 320 deaths, approximately 28 months | Overall Survival (OS) is defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS was calculated using Kaplan-Meier estimates. Interim analyses for OS occurred after 320 deaths (78% of the total OS events needed for final analysis). |
| Objective Response Rate (ORR) | ORR was assessed at 8 weeks post-randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 21 months) | Objective Response Rate (ORR) is the number of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. ORR was assessed by the Independent Radiology Committee (IRC) per RECIST 1.1 which was confirmed by a subsequent visit \>= 28 days later, and was analyzed in the Intent to Treat (ITT) population at the time of the primary analysis of Progression Free Survival (PFS). The data cutoff date was 22 May 2015. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Russia, Slovakia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 08 August 2013, Data cut off date: 22 May 2015
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib (XL184) Cabozantinib (XL184) 60 mg tablet once daily.
Cabozantinib tablets | 330 |
| Everolimus (Afinitor) Everolimus (Afinitor) 10 mg tablet once daily.
Everolimus (Afinitor) tablets | 328 |
| Total | 658 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study (ITT) | Adverse Event | 32 | 31 |
| Overall Study (ITT) | Clinical Deterioration | 29 | 50 |
| Overall Study (ITT) | Lack of Efficacy | 3 | 0 |
| Overall Study (ITT) | Physician Decision | 5 | 2 |
| Overall Study (ITT) | Progressive Disease | 122 | 158 |
| Overall Study (ITT) | Protocol Violation | 1 | 1 |
| Overall Study (ITT) | Reason Not Provided | 0 | 1 |
| Overall Study (ITT) | Sponsor Decision | 0 | 1 |
| Overall Study (ITT) | Withdrawal by Subject | 6 | 11 |
| Primary Intent to Treat (PITT) | Adverse Event | 21 | 20 |
| Primary Intent to Treat (PITT) | Clinical Deterioration | 18 | 29 |
| Primary Intent to Treat (PITT) | Lack of Efficacy | 2 | 0 |
| Primary Intent to Treat (PITT) | Other | 0 | 1 |
| Primary Intent to Treat (PITT) | Physician Decision | 4 | 2 |
| Primary Intent to Treat (PITT) | Progressive Disease | 82 | 92 |
| Primary Intent to Treat (PITT) | Protocol Violation | 1 | 1 |
| Primary Intent to Treat (PITT) | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Cabozantinib (XL184) | Everolimus (Afinitor) | Total |
|---|---|---|---|
| Age, Customized <65 | 196 participants | 198 participants | 394 participants |
| Age, Customized 65 to <75 | 107 participants | 94 participants | 201 participants |
| Age, Customized 75 to <85 | 26 participants | 36 participants | 62 participants |
| Age, Customized =>85 | 1 participants | 0 participants | 1 participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 19 Participants | 18 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 278 Participants | 273 Participants | 551 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 33 Participants | 37 Participants | 70 Participants |
| Geographic Region Asia Pacific | 39 Participants | 47 Participants | 86 Participants |
| Geographic Region Europe | 167 Participants | 153 Participants | 320 Participants |
| Geographic Region Latin America | 6 Participants | 6 Participants | 12 Participants |
| Geographic Region North America | 118 Participants | 122 Participants | 240 Participants |
| Heng Prognostic Criteria 0 adverse factors (favorable risk) | 66 Participants | 62 Participants | 128 Participants |
| Heng Prognostic Criteria 1-2 adverse factors (intermediate risk) | 210 Participants | 214 Participants | 424 Participants |
| Heng Prognostic Criteria 3-6 adverse factors (poor risk) | 54 Participants | 52 Participants | 106 Participants |
| Karnofsky performance status (KPS) 100 (normal activity) | 99 Participants | 74 Participants | 173 Participants |
| Karnofsky performance status (KPS) 70 (unable to work, cares for self) | 29 Participants | 22 Participants | 51 Participants |
| Karnofsky performance status (KPS) 80 (normal w/effort, minor signs/symptoms) | 75 Participants | 90 Participants | 165 Participants |
| Karnofsky performance status (KPS) 90 (normal activity, minor signs and symptoms) | 127 Participants | 142 Participants | 269 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 26 Participants | 47 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 3 Participants | 9 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 | 34 Participants | 36 Participants | 70 Participants |
| Race (NIH/OMB) White | 269 Participants | 263 Participants | 532 Participants |
| Randomization Stratification Factors per CRF MSKCC risk factors = 0 | 150 Participants | 150 Participants | 300 Participants |
| Randomization Stratification Factors per CRF MSKCC risk factors = 1 | 139 Participants | 135 Participants | 274 Participants |
| Randomization Stratification Factors per CRF MSKCC risk factors = 2 or 3 | 41 Participants | 43 Participants | 84 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI = 1 | 235 Participants | 229 Participants | 464 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI = 1, MSKCC risk factors = 0 | 102 Participants | 100 Participants | 202 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI = 1, MSKCC risk factors = 1 | 107 Participants | 103 Participants | 210 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI = 1, MSKCC risk factors = 2 or 3 | 26 Participants | 26 Participants | 52 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI ≥ 2 | 95 Participants | 99 Participants | 194 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI ≥ 2, MSKCC risk factors =0 | 48 Participants | 50 Participants | 98 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI ≥ 2, MSKCC risk factors = 1 | 32 Participants | 32 Participants | 64 Participants |
| Randomization Stratification Factors per CRF Prior VEGFR-TKI ≥ 2, MSKCC risk factors = 2 or 3 | 15 Participants | 17 Participants | 32 Participants |
| Sex/Gender, Customized Female | 77 participants | 86 participants | 163 participants |
| Sex/Gender, Customized Male | 253 participants | 241 participants | 494 participants |
| Sex/Gender, Customized Missing | 0 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 328 / 331 | 270 / 322 |
| serious Total, serious adverse events | 131 / 331 | 139 / 322 |
Outcome results
Primary
Progression-free Survival (PFS)
The primary analysis of PFS is the time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria) or death due to any cause, whichever occurred first. A Kaplan-Meier analysis was performed to estimate the median duration.
Time frame: PFS is measured from the date of randomization until the date of first documented disease progression or date of death from any cause as determined by the Independent Radiology Committee (IRC) per RECIST 1.1, assessed for up to 17 months.
Population: The pre-specified primary analysis of PFS was based on the first 375 randomized subjects (187 cabozantinib and 188 everolimus).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) | Progression-free Survival (PFS) | 7.4 months |
| Everolimus (Afinitor) | Progression-free Survival (PFS) | 3.8 months |
p-value: <0.000195% CI: [0.45, 0.74]Log Rank
Secondary
Objective Response Rate (ORR)
Objective Response Rate (ORR) is the number of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. ORR was assessed by the Independent Radiology Committee (IRC) per RECIST 1.1 which was confirmed by a subsequent visit \>= 28 days later, and was analyzed in the Intent to Treat (ITT) population at the time of the primary analysis of Progression Free Survival (PFS). The data cutoff date was 22 May 2015.
Time frame: ORR was assessed at 8 weeks post-randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 21 months)
Population: The analysis of ORR was performed in the ITT population (all randomized: 330 cabozantinib, 328 everolimus) based upon response determined by Independent Radiology Committee (IRC) per RECIST 1.1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) | Objective Response Rate (ORR) | 17 percentage of participants |
| Everolimus (Afinitor) | Objective Response Rate (ORR) | 3 percentage of participants |
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
Overall Survival (OS) is defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS was calculated using Kaplan-Meier estimates. Interim analyses for OS occurred after 320 deaths (78% of the total OS events needed for final analysis).
Time frame: OS was measured from the time of randomization until 320 deaths, approximately 28 months
Population: The Intent to Treat (ITT) population was used and included 658 randomized subjects (330 cabozantinib, 328 everolimus) in the second interim analysis with a cutoff date of 31 December 2015.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) | Overall Survival (OS) | 21.4 months |
| Everolimus (Afinitor) | Overall Survival (OS) | 16.5 months |
p-value: 0.000395% CI: [0.53, 0.83]Log Rank