Carcinoma, Renal Cell
Conditions
Brief summary
This is a Phase 3, open-label, randomized, controlled, multi-national, multi-center, parallel-arm study comparing tivozanib to sorafenib in participants with refractory advanced renal cell carcinoma (RCC). Participants will be randomized (1:1) to treatment with tivozanib or sorafenib. Participants will be stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category (favorable; intermediate; poor) and prior therapy (two prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI); a prior checkpoint inhibitor \[programmed cell death -1 protein (PD-1) or PD-1 ligand (PD1-L) inhibitor\] plus a prior VEGFR TKI; a prior VEGFR TKI plus any other systemic agent). All participants will be evaluated for progression free survival, overall survival, objective response rate, and the duration of response as well as safety and tolerability. Pharmacokinetic (PK) analyses are also included in study.
Interventions
DRUGSorafenib
Sorafenib
Tivozanib hydrochloride
Sponsors
AVEO Pharmaceuticals, Inc.
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
* 18 years or older * Participants with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib. * Histologically or cytologically confirmed RCC with a clear cell component (participants with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, and unclassified RCC are excluded). * Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Life expectancy ≥ 3 months.
Exclusion criteria
* Prior treatment with sorafenib or tivozanib. * More than 3 prior regimens for metastatic RCC. * Known central nervous system (CNS) metastases other than stable, treated brain metastases. Participants with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). * Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders. * Significant serum chemistry abnormalities * Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure, uncontrolled hypertension, myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug, history of serious ventricular arrhythmia, cardiac arrhythmias requiring anti-arrhythmic medications. * Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug. * Currently active second primary malignancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first. Disease progression was assessed every 8 weeks (up to approximately 5 years) | The PFS, as assessed by a blinded independent radiological review (IRR), is defined as the time from randomization to first documentation of objective tumor progression (progressive disease) or death due to any reasons whichever comes first. Disease progression per RECIST 1.1 criteria is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Date of randomization to date of death (up to approximately 5 years) | The OS is defined as the time from the date of randomization to date of death due to any cause. |
| Objective Response Rate (ORR) | Every 8 weeks from date of randomization until disease progression (up to approximately 5 years) | The ORR is defined as the percentage of participants who have at least a 30% reduction in the sum of diameters per RECIST (Version 1.1). |
| Duration of Response (DOR) | Assessed every 8 weeks from date of randomization until date of progression (up to approximately 5 years) | The DOR is defined as the time from the first documentation of objective tumor response to the first documentation of tumor progression per RECIST 1.1 or to death due to any cause. |
Countries
Belgium, Canada, Czechia, Denmark, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 350 participants were randomised and 343 were treated.
Participants by arm
| Arm | Count |
|---|---|
| Tivozanib Hydrochloride Participants randomized to this arm received the study drug, tivozanib hydrochloride. | 175 |
| Sorafenib Participants randomized to this arm received the comparator drug, sorafenib. | 175 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized but not treated | 2 | 6 |
Baseline characteristics
| Characteristic | Tivozanib Hydrochloride | Sorafenib | Total |
|---|---|---|---|
| Age, Continuous | 62 Years | 63 Years | 63 Years |
| IMDC risk category Favourable | 34 Participants | 36 Participants | 70 Participants |
| IMDC risk category Intermediate | 109 Participants | 105 Participants | 214 Participants |
| IMDC risk category Poor | 32 Participants | 34 Participants | 66 Participants |
| Previous therapies Checkpoint inhibitor plus VEGFR TKI | 47 Participants | 44 Participants | 91 Participants |
| Previous therapies Two VEGFR TKIs | 79 Participants | 80 Participants | 159 Participants |
| Previous therapies VEGFR TKI plus other systemic agent | 49 Participants | 51 Participants | 100 Participants |
| Race/Ethnicity, Customized Race Non-white | 10 Participants | 8 Participants | 18 Participants |
| Race/Ethnicity, Customized Race White | 165 Participants | 167 Participants | 332 Participants |
| Sex: Female, Male Female | 49 Participants | 47 Participants | 96 Participants |
| Sex: Female, Male Male | 126 Participants | 128 Participants | 254 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 114 / 175 | 113 / 175 |
| other Total, other adverse events | 171 / 173 | 170 / 170 |
| serious Total, serious adverse events | 81 / 173 | 67 / 170 |
Outcome results
Primary
Progression-free Survival (PFS)
The PFS, as assessed by a blinded independent radiological review (IRR), is defined as the time from randomization to first documentation of objective tumor progression (progressive disease) or death due to any reasons whichever comes first. Disease progression per RECIST 1.1 criteria is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first. Disease progression was assessed every 8 weeks (up to approximately 5 years)
Population: Intent-to-treat (ITT) Population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib Hydrochloride | Progression-free Survival (PFS) | 5.59 Months |
| Sorafenib | Progression-free Survival (PFS) | 3.88 Months |
p-value: 0.016595% CI: [0.56, 0.94]Log Rank
Secondary
Duration of Response (DOR)
The DOR is defined as the time from the first documentation of objective tumor response to the first documentation of tumor progression per RECIST 1.1 or to death due to any cause.
Time frame: Assessed every 8 weeks from date of randomization until date of progression (up to approximately 5 years)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib Hydrochloride | Duration of Response (DOR) | NA Months |
| Sorafenib | Duration of Response (DOR) | 5.65 Months |
Secondary
Objective Response Rate (ORR)
The ORR is defined as the percentage of participants who have at least a 30% reduction in the sum of diameters per RECIST (Version 1.1).
Time frame: Every 8 weeks from date of randomization until disease progression (up to approximately 5 years)
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tivozanib Hydrochloride | Objective Response Rate (ORR) | 31 Participants |
| Sorafenib | Objective Response Rate (ORR) | 14 Participants |
Secondary
Overall Survival (OS)
The OS is defined as the time from the date of randomization to date of death due to any cause.
Time frame: Date of randomization to date of death (up to approximately 5 years)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib Hydrochloride | Overall Survival (OS) | 16.39 Months |
| Sorafenib | Overall Survival (OS) | 19.15 Months |
p-value: 0.817495% CI: [0.75, 1.25]Log Rank