Advanced Renal Cell Carcinoma
Conditions
Brief summary
Open-label, multi-center extension treatment protocol to allow access to tivozanib and sorafenib for subjects who have participated on the AV-951-09-301 protocol. Eligible subjects who were randomized to receive sorafenib on AV-951-09-301 and had documented progression of disease will receive a tivozanib dose of 1.5 mg/day. Eligible subjects who were randomized to tivozanib or sorafenib in AV-951-09-301, and displayed clinical benefit and acceptable tolerability to treatment, will continue to receive tivozanib or sorafenib at the same dose and schedule as in AV-951-09-301.
Detailed description
This is an extension treatment protocol to allow access to tivozanib or sorafenib for subjects enrolled on AV-951-09-301(parent protocol). Subjects who failed sorafenib on the parent protocol will be offered tivozanib. Subjects who were randomized to tivozanib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to tivozanib. Subjects who were randomized to sorafenib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to sorafenib. Subjects who continue receiving sorafenib on this protocol and progress will be allowed to cross-over to tivozanib.
Interventions
DRUGTivozanib
Tivozanib capsules, administered orally, on a dosing schedule of 3 weeks of treatment (beginning on Day 1) followed by 1 week off treatment. One cycle was defined as 4 weeks of treatment.
DRUGSorafenib
Sorafenib tablets, 400 mg twice daily, administered orally for 4 weeks (1 cycle = 4 weeks). One cycle was defined as 4 weeks of treatment. Cycles were repeated every 4 weeks.
Sponsors
AVEO Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject must have participated on Protocol AV-951-09-301, and must meet either of the following bulleted criteria: * Demonstrated disease progression per RECIST during treatment with sorafenib, OR * Demonstrated clinical benefit \[complete response (CR), partial response (PR), or stable disease (SD) per RECIST\] and acceptable tolerability after treatment with tivozanib or sorafenib on protocol AV-951-09-301. 2. Eastern Cooperative Oncology Group performance status ≤ 2 and life expectancy ≥ 3 months. 3. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment. 4. Ability to give written informed consent
Exclusion criteria
1. Newly identified central nervous system (CNS) malignancies or documented progression of CNS metastases; subjects will be allowed only if the CNS metastases have been adequately treated with radiotherapy or surgery. For subjects receiving steroid therapy for allowed steroid maintenance therapy. 2. Duration since last dose on Protocol AV-951-09-301: 1. For subjects continuing tivozanib or sorafenib (subjects who demonstrated clinical benefit and acceptable tolerability during treatment with tivozanib or sorafenib on protocol AV-951-09-301): more than 2 weeks since last dose of tivozanib or sorafenib. 2. For subjects initiating tivozanib (ie demonstrated disease progression during treatment with sorafenib): more than 4 weeks since last dose of sorafenib. Subjects demonstrating disease progression due to CNS metastasis will be allowed up to 8 weeks since last dose of sorafenib in order to complete treatment for CNS metastasis. 3. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug. 4. Any of the following hematologic abnormalities: * Hemoglobin \< 9.0 g/dL * Absolute neutrophil count \< 1500 per mm3 * Platelet count \< 75,000 per mm3 * Prothrombin time or Partial thromboplastin time \>1.5 × upper limit of normal (ULN) 5. Any of the following serum chemistry abnormalities: * Total bilirubin \> 1.5 × ULN (or \> 2.5 × ULN for subjects with Gilbert's syndrome) * Aspartate aminotransferase or alanine aminotransferase \> 2.5 × ULN (or \> 5 × ULN for subjects with liver metastasis) * Alkaline phosphatase \> 2.5 × ULN (or \> 5 × ULN for subjects with liver or bone metastasis) * Creatinine \> 2.0 × ULN * Proteinuria \> 3+ by urinalysis or urine dipstick 6. If female, pregnant or lactating. 7. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for at least 50 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 90 days after the last dose of study drug. All fertile male and female subjects,and their partners,must agree to use a highly effective method of contraception. Effective birth control includes (a) Intrauterine device plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study). 8. Uncontrolled hypertension: systolic blood pressure \> 150 mmHg or diastolic blood pressure \>100 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 24 hours apart. 9. Unhealed wounds (including active peptic ulcers). 10. Serious/active infection or infection requiring parenteral antibiotics. 11. Life-threatening illness or organ system dysfunction compromising safety evaluation. 12. Psychiatric disorder, altered mental status precluding informed consent or necessary testing. 13. Inability to comply with protocol requirements. 14. Treatment with another anti-cancer therapy or participation in another interventional protocol (excluding AV-951-09-301).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events | From enrollment assessed up to 3 years of treatment or until follow-up (up to 30 days end-of-trial visit after treatment discontinuation), whichever occurs earlier | Number of subjects with Treatment-Related Adverse Events (AEs) as assessed by Common Terminology Criteria for Adverse Events v3.0 |
| Number of Cycles Subjects Received Treatment in Each Treatment Arm | From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902 | Number of cycles subjects received who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD |
| Total Dose Administered to Subjects in Each Treatment Arm (mg) | From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902 | The total dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD |
| Average Daily Dose Administered to Subjects in Each Treatment Arm | From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902 | The average daily dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD |
| Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm | From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902 | RDI is defined as 100% times the actual dose intensity divided by the intended dose intensity. The RDI of subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD |
| Number of Days Subjects Received Treatment in Each Treatment Arm | From enrollment to until all subjects discontinue (due to documented progressive disease [PD] or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902 | Number of days subjects received treatment who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DR) | From the first documentation of objective tumor response to the first documentation of objective tumor progression, assessed up to treatment discontinuation or to death due to any reason or maximum up to 3 years, whichever occurs earlier | DR was defined as the time from the first documentation of objective tumor response (confirmed CR or confirmed PR) according to RECIST (Version 1.0) to the first documentation of objective tumor progression or to death due to any reason. DR was calculated for the subgroup of subjects with a confirmed objective tumor response (PR or CR). CR is Disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Number of subjects with disease progression or death and censored endpoints were summarized and statistical analysis were performed for duration of response. |
| Progression-free Survival (PFS) | From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to the first documentation of objective tumor progression or death due to any reason or maximum up to 3 years, whichever occurred first | PFS was defined as the date of first dose of study drug to the first documentation of objective tumor progression or death due to any reason, whichever occurred first. For the crossover subjects and subjects with first-line experience on tivozanib treatment, the timeframe for PFS assessment started from the date of first dose of tivozanib in the AV-951-09-902 study. For subjects with first-line experience on sorafenib treatment, the timeframe for PFS assessment started from the date of first dose of sorafenib in the AV-951-09-902. Number of subjects with disease progression or death was summarized and statistical analysis were performed for PFS. |
| Overall Survival (OS) | From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to death due to any reason or maximum up to 3 years, whichever occurred first | OS was defined as the time from the first dose of study drug (tivozanib or sorafenib) date on this study to date of death due to any cause. Number of subjects died or alive was summarized and statistical analysis were performed for OS. |
| Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | From Day 1 to the end of treatment (EOT) Visit, approximately every 8 weeks | ORR is defined as the proportion of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST (Version 1.0), relative to the total population of dosed subjects. CR is disappearance of all target and non-target lesions and normalization of tumor marker levels. At least a 30% decrease in the sum of the loading dose (LD) of target lesions, taking as reference the baseline sum LD. To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 (NCT01030783), and demonstrated clinical benefit and acceptable tolerability to sorafenib. |
Countries
Bulgaria, Canada, Chile, Czechia, France, Hungary, India, Italy, Poland, Romania, Russia, Serbia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled at 55 sites in 14 countries. Study Period from 24 May 2010 (First Subject Dosed) to 04 July 2014 (Last Subject Last Visit).
Pre-assignment details
All participants underwent inclusion and exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures. All the study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Crossover to Tivozanib The subjects who failed sorafenib (had Response Evaluation Criteria in Solid Tumors \[RECIST\] - defined progressive disease) on the parent protocol AV-951-09-301 will be offered tivozanib hydrochloride on Protocol AV- 951-09-902. | 161 |
| First Line Tivozanib The subjects who were randomized to tivozanib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability in Protocol AV-951-09-301. | 88 |
| First Line Sorafenib The subjects who were randomized to sorafenib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability were to be offered long-term access to sorafenib. | 28 |
| Total | 277 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 2 | 0 |
| Overall Study | Death | 15 | 1 | 0 |
| Overall Study | Lack of Efficacy | 4 | 0 | 0 |
| Overall Study | Noncompliance | 1 | 1 | 0 |
| Overall Study | Other | 5 | 2 | 0 |
| Overall Study | Progressive disease | 90 | 30 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Significant Surgical Procedure | 0 | 1 | 0 |
| Overall Study | Treatment Interruption for > 2 Weeks | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 1 |
Baseline characteristics
| Characteristic | Sorafenib Crossover to Tivozanib | First Line Tivozanib | First Line Sorafenib | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 41 Participants | 30 Participants | 11 Participants | 82 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 58 Participants | 17 Participants | 195 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 0 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 154 Participants | 84 Participants | 28 Participants | 266 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 156 Participants | 87 Participants | 28 Participants | 271 Participants |
| Sex: Female, Male Female | 46 Participants | 33 Participants | 9 Participants | 88 Participants |
| Sex: Female, Male Male | 115 Participants | 55 Participants | 19 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 87 / 161 | 82 / 88 | 28 / 28 |
| serious Total, serious adverse events | 49 / 161 | 17 / 88 | 4 / 28 |
Outcome results
Primary
Average Daily Dose Administered to Subjects in Each Treatment Arm
The average daily dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD
Time frame: From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Average Daily Dose Administered to Subjects in Each Treatment Arm | 1.46 mg/day | Standard Deviation 0.121 |
| First Line Tivozanib. | Average Daily Dose Administered to Subjects in Each Treatment Arm | 1.40 mg/day | Standard Deviation 0.196 |
| First Line Sorafenib. | Average Daily Dose Administered to Subjects in Each Treatment Arm | 651.47 mg/day | Standard Deviation 225.41 |
Primary
Number of Cycles Subjects Received Treatment in Each Treatment Arm
Number of cycles subjects received who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD
Time frame: From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Number of Cycles Subjects Received Treatment in Each Treatment Arm | 10.6 Number of cycles started | Standard Deviation 8.36 |
| First Line Tivozanib. | Number of Cycles Subjects Received Treatment in Each Treatment Arm | 11.8 Number of cycles started | Standard Deviation 4.85 |
| First Line Sorafenib. | Number of Cycles Subjects Received Treatment in Each Treatment Arm | 13.2 Number of cycles started | Standard Deviation 3.83 |
Primary
Number of Days Subjects Received Treatment in Each Treatment Arm
Number of days subjects received treatment who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD
Time frame: From enrollment to until all subjects discontinue (due to documented progressive disease [PD] or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Number of Days Subjects Received Treatment in Each Treatment Arm | Duration of Treatment | 290 Days | Standard Deviation 234.37 |
| Sorafenib Crossover to Tivozanib | Number of Days Subjects Received Treatment in Each Treatment Arm | Total Days Receiving Drug | 222.36 Days | Standard Deviation 181.722 |
| First Line Tivozanib. | Number of Days Subjects Received Treatment in Each Treatment Arm | Duration of Treatment | 325.3 Days | Standard Deviation 137.79 |
| First Line Tivozanib. | Number of Days Subjects Received Treatment in Each Treatment Arm | Total Days Receiving Drug | 241.0 Days | Standard Deviation 105.928 |
| First Line Sorafenib. | Number of Days Subjects Received Treatment in Each Treatment Arm | Duration of Treatment | 369.4 Days | Standard Deviation 107.6 |
| First Line Sorafenib. | Number of Days Subjects Received Treatment in Each Treatment Arm | Total Days Receiving Drug | 368.14 Days | Standard Deviation 107.946 |
Primary
Number of Subjects With Adverse Events
Number of subjects with Treatment-Related Adverse Events (AEs) as assessed by Common Terminology Criteria for Adverse Events v3.0
Time frame: From enrollment assessed up to 3 years of treatment or until follow-up (up to 30 days end-of-trial visit after treatment discontinuation), whichever occurs earlier
Population: Number of subjects with adverse events
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Treatment related AE - Study Drug Dose Reduction | 9 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | AE leading to study drug discontinuation (AEDC) | 19 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any treatment-Related AE With Outcome of death | 1 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | AE Leading to Study Drug Dose Reduction | 11 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any treatment-related SAE | 7 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any serious adverse event (SAE) | 49 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any Treatment-Related AE | 86 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any AE of Grade 3 or Higher | 77 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Treatment-related AE - study drug interruption | 13 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any Treatment-Related Any Treatment AE ≥ Grade 3 | 39 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | AE | 124 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | AE leading to study drug interruption | 27 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any treatment-related AEDC | 3 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Adverse Events | Any AE With Outcome of Death | 21 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any Treatment-Related Any Treatment AE ≥ Grade 3 | 35 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | AE | 85 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any AE of Grade 3 or Higher | 55 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any Treatment-Related AE | 76 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any AE With Outcome of Death | 3 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any treatment-Related AE With Outcome of death | 1 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any serious adverse event (SAE) | 17 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any treatment-related SAE | 7 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | AE leading to study drug discontinuation (AEDC) | 4 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Any treatment-related AEDC | 0 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | AE leading to study drug interruption | 26 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Treatment-related AE - study drug interruption | 17 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | AE Leading to Study Drug Dose Reduction | 11 Participants |
| First Line Tivozanib. | Number of Subjects With Adverse Events | Treatment related AE - Study Drug Dose Reduction | 11 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Treatment related AE - Study Drug Dose Reduction | 10 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any treatment-related AEDC | 0 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any Treatment-Related Any Treatment AE ≥ Grade 3 | 15 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | AE Leading to Study Drug Dose Reduction | 10 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | AE leading to study drug interruption | 12 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any Treatment-Related AE | 27 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | AE | 28 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any serious adverse event (SAE) | 4 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any treatment-Related AE With Outcome of death | 0 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Treatment-related AE - study drug interruption | 10 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any AE With Outcome of Death | 0 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any AE of Grade 3 or Higher | 19 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | AE leading to study drug discontinuation (AEDC) | 0 Participants |
| First Line Sorafenib. | Number of Subjects With Adverse Events | Any treatment-related SAE | 2 Participants |
Primary
Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm
RDI is defined as 100% times the actual dose intensity divided by the intended dose intensity. The RDI of subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD
Time frame: From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm | 95.21 percentage of dose | Standard Deviation 9.393 |
| First Line Tivozanib. | Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm | 91.12 percentage of dose | Standard Deviation 14.762 |
| First Line Sorafenib. | Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm | 80.60 percentage of dose | Standard Deviation 28.603 |
Primary
Total Dose Administered to Subjects in Each Treatment Arm (mg)
The total dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD
Time frame: From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Total Dose Administered to Subjects in Each Treatment Arm (mg) | 318.84 mg | Standard Deviation 256.241 |
| First Line Tivozanib. | Total Dose Administered to Subjects in Each Treatment Arm (mg) | 344.58 mg | Standard Deviation 152.131 |
| First Line Sorafenib. | Total Dose Administered to Subjects in Each Treatment Arm (mg) | 244014.29 mg | Standard Deviation 116816.715 |
Secondary
Duration of Response (DR)
DR was defined as the time from the first documentation of objective tumor response (confirmed CR or confirmed PR) according to RECIST (Version 1.0) to the first documentation of objective tumor progression or to death due to any reason. DR was calculated for the subgroup of subjects with a confirmed objective tumor response (PR or CR). CR is Disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Number of subjects with disease progression or death and censored endpoints were summarized and statistical analysis were performed for duration of response.
Time frame: From the first documentation of objective tumor response to the first documentation of objective tumor progression, assessed up to treatment discontinuation or to death due to any reason or maximum up to 3 years, whichever occurs earlier
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Duration of Response (DR) | Subjects who had disease progression or died | 10 Participants |
| Sorafenib Crossover to Tivozanib | Duration of Response (DR) | Subjects with censored endpoints | 19 Participants |
| First Line Tivozanib. | Duration of Response (DR) | Subjects with censored endpoints | 38 Participants |
| First Line Tivozanib. | Duration of Response (DR) | Subjects who had disease progression or died | 11 Participants |
| First Line Sorafenib. | Duration of Response (DR) | Subjects who had disease progression or died | 0 Participants |
| First Line Sorafenib. | Duration of Response (DR) | Subjects with censored endpoints | 16 Participants |
95% CI: [4.4, 12.9]
Secondary
Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib
ORR is defined as the proportion of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST (Version 1.0), relative to the total population of dosed subjects. CR is disappearance of all target and non-target lesions and normalization of tumor marker levels. At least a 30% decrease in the sum of the loading dose (LD) of target lesions, taking as reference the baseline sum LD. To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 (NCT01030783), and demonstrated clinical benefit and acceptable tolerability to sorafenib.
Time frame: From Day 1 to the end of treatment (EOT) Visit, approximately every 8 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Confirmed Objective Response Rate | 29 Participants |
| Sorafenib Crossover to Tivozanib | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Unconfirmed Objective Response Rate | 43 Participants |
| First Line Tivozanib. | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Confirmed Objective Response Rate | 49 Participants |
| First Line Tivozanib. | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Unconfirmed Objective Response Rate | 55 Participants |
| First Line Sorafenib. | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Confirmed Objective Response Rate | 16 Participants |
| First Line Sorafenib. | Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib | Overall Unconfirmed Objective Response Rate | 16 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the first dose of study drug (tivozanib or sorafenib) date on this study to date of death due to any cause. Number of subjects died or alive was summarized and statistical analysis were performed for OS.
Time frame: From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to death due to any reason or maximum up to 3 years, whichever occurred first
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Overall Survival (OS) | Died | 78 Participants |
| Sorafenib Crossover to Tivozanib | Overall Survival (OS) | Alive | 83 Participants |
| First Line Tivozanib. | Overall Survival (OS) | Died | 10 Participants |
| First Line Tivozanib. | Overall Survival (OS) | Alive | 78 Participants |
| First Line Sorafenib. | Overall Survival (OS) | Died | 0 Participants |
| First Line Sorafenib. | Overall Survival (OS) | Alive | 28 Participants |
95% CI: [6, 12.1]
95% CI: [17, 27.6]
Secondary
Progression-free Survival (PFS)
PFS was defined as the date of first dose of study drug to the first documentation of objective tumor progression or death due to any reason, whichever occurred first. For the crossover subjects and subjects with first-line experience on tivozanib treatment, the timeframe for PFS assessment started from the date of first dose of tivozanib in the AV-951-09-902 study. For subjects with first-line experience on sorafenib treatment, the timeframe for PFS assessment started from the date of first dose of sorafenib in the AV-951-09-902. Number of subjects with disease progression or death was summarized and statistical analysis were performed for PFS.
Time frame: From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to the first documentation of objective tumor progression or death due to any reason or maximum up to 3 years, whichever occurred first
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Crossover to Tivozanib | Progression-free Survival (PFS) | Subjects who had disease progression or died | 108 Participants |
| Sorafenib Crossover to Tivozanib | Progression-free Survival (PFS) | Subjects with censored endpoints | 53 Participants |
| First Line Tivozanib. | Progression-free Survival (PFS) | Subjects who had disease progression or died | 35 Participants |
| First Line Tivozanib. | Progression-free Survival (PFS) | Subjects with censored endpoints | 53 Participants |
| First Line Sorafenib. | Progression-free Survival (PFS) | Subjects with censored endpoints | 27 Participants |
| First Line Sorafenib. | Progression-free Survival (PFS) | Subjects who had disease progression or died | 1 Participants |
95% CI: [1.9, 5.2]
95% CI: [7.3, 12.7]
95% CI: [3.5, 9.2]