Trial Outcomes & Findings for A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma (NCT NCT00502307)

NCT ID: NCT00502307

Last Updated: 2020-09-01

Results Overview

To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

272 participants

Primary outcome timeframe

28 weeks after study entry

Results posted on

2020-09-01

Participant Flow

Participants who met all the inclusion and none of the exclusion criteria were enrolled

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.

Participant milestones

Participant milestones
Measure	Open-label Period: Tivozanib (AV-951) Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.
Open Label Period (16 Weeks) STARTED	272	0	0
Open Label Period (16 Weeks) COMPLETED	196	0	0
Open Label Period (16 Weeks) NOT COMPLETED	76	0	0
Double-Blind Period (12 Weeks) STARTED	0	61	57
Double-Blind Period (12 Weeks) COMPLETED	0	35	48
Double-Blind Period (12 Weeks) NOT COMPLETED	0	26	9
Maintenance Period STARTED	148	0	0
Maintenance Period COMPLETED	0	0	0
Maintenance Period NOT COMPLETED	148	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Open-label Period: Tivozanib (AV-951) Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.
Open Label Period (16 Weeks) Progressive disease	50	0	0
Open Label Period (16 Weeks) Discontinued due to other reasons	26	0	0
Double-Blind Period (12 Weeks) Progressive disease	0	23	2
Double-Blind Period (12 Weeks) Discontinued due to other reasons	0	3	7
Maintenance Period Progressive disease	80	0	0
Maintenance Period Discontinued due to other reasons	68	0	0

Baseline Characteristics

A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Open-label Period:Tivozanib (AV-951) n=272 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off). After 16 weeks (4 cycles), disease status was assessed and compared to baseline. Tivozanib was to be discontinued following disease progression or unacceptable toxicity.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	272 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	56.3 years STANDARD_DEVIATION 9.5 • n=5 Participants
Sex: Female, Male Female	81 Participants n=5 Participants
Sex: Female, Male Male	191 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	271 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Body Mass Index	26.5 kg/m^2 STANDARD_DEVIATION 4.6 • n=5 Participants

PRIMARY outcome

Timeframe: 28 weeks after study entry

To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=272 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=61 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=57 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) All assessment were performed by the study Investigator and similarly for IRR.
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Serious adverse events	16 Participants	2 Participants	3 Participants	—
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Grade 3 or higher adverse events	86 Participants	8 Participants	10 Participants	—
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Adverse events	215 Participants	31 Participants	32 Participants	—
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Treatment-related adverse events	174 Participants	13 Participants	7 Participants	—
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Discontinuations due to adverse events	10 Participants	1 Participants	3 Participants	—
Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) Deaths	6 Participants	1 Participants	2 Participants	—

PRIMARY outcome

Timeframe: 16 weeks after study entry

The ORR is defined as the rate of (CR+PR). Objective response rates following the 16-week, open-label period (investigator assessment and IRR assessment) were estimated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and was assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=272 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=272 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) All assessment were performed by the study Investigator and similarly for IRR.
Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population) Complete response	1 Participants	0 Participants	—	—
Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population) Partial response	66 Participants	49 Participants	—	—

PRIMARY outcome

Timeframe: 28 weeks after study entry

Percentages of subjects remaining progression-free at 12 weeks post-randomization were compared across the 2 treatment arms in the ITT population. A Cochran-Mantel- Haenszel (CMH) test of general association was used, stratifying by country to evaluate the null hypothesis that treatment arm is not associated with subjects remaining progression-free. Non-completers were treated as failures. Progression is defined using RECIST v1.0, 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.

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=61 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=57 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=61 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) n=57 Participants All assessment were performed by the study Investigator and similarly for IRR.
Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo	35 Participants	16 Participants	30 Participants	12 Participants

SECONDARY outcome

Timeframe: 28 weeks from study entry

PFS after randomization in the ITT population was described using the Kaplan-Meier methodology. PFS was compared across treatment arms using the log-rank test.

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=61 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=57 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=61 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) n=57 Participants All assessment were performed by the study Investigator and similarly for IRR.
Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization ) Number of subjects with progression	23 Participants	33 Participants	22 Participants	24 Participants
Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization ) Number of censored subjects	38 Participants	24 Participants	39 Participants	33 Participants

SECONDARY outcome

Timeframe: 12 months from study entry

Number of subjects with Overall PFS (from start of treatment) was estimated using the Kaplan-Meier methodology. Subjects randomized to receive placebo were censored at randomization. Withdrawals are also censored. An alternative analysis was conducted in which PFS for subjects randomized to receive tivozanib was weighted more heavily to compensate for the information loss from randomization of other subjects to receive placebo. Additional analyses in which withdrawal was considered a PFS event were also conducted.

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=61 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=57 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=61 Participants Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) n=57 Participants All assessment were performed by the study Investigator and similarly for IRR.
Overall Progression-free Survival (From Start of Treatment) Number of subjects with progression	47 Participants	33 Participants	36 Participants	24 Participants
Overall Progression-free Survival (From Start of Treatment) Number of censored subjects	14 Participants	24 Participants	25 Participants	33 Participants

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose

Population: The PK population had 21 subjects. However, there were subjects with missing data for both Cycle 1 Day 1 and Cycle 1 Day 21. Hence, the number of participants analyzed varies i.e, 20 for Cycle 1 Day 1 and 16 for Cycle 1 Day 21.

Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1.

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=21 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) All assessment were performed by the study Investigator and similarly for IRR.
Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects Cycle 1 Day 1	7.122 hours Standard Deviation 8.511	—	—	—
Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects Cycle 1 Day 21	3.64 hours Standard Deviation 5.61	—	—	—

SECONDARY outcome

Timeframe: Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=21 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) All assessment were performed by the study Investigator and similarly for IRR.
Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax) Cycle 1 Day 21	94.29 ng/mL Standard Deviation 37.80	—	—	—
Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax) Cycle 1 Day 1	15.51 ng/mL Standard Deviation 11.70	—	—	—

SECONDARY outcome

Timeframe: 28 weeks from study entry

Outcome measures

Outcome measures
Measure	Open-label Period: Tivozanib (AV-951) n=21 Participants Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Independent Radiology Reviewer (Placebo) All assessment were performed by the study Investigator and similarly for IRR.
Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)] Cycle 1 Day 1	258.2 h*ng/mL Standard Deviation 197.0	—	—	—
Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)] Cycle 1 Day 21	0 h*ng/mL Standard Deviation 0	—	—	—

Adverse Events

Open-label Period: Tivozanib (AV-951)

Serious events: 16 serious events

Other events: 215 other events

Deaths: 0 deaths

Double-blind Period: Tivozanib (AV-951)

Serious events: 2 serious events

Other events: 31 other events

Deaths: 0 deaths

Double-blind Period: Placebo

Serious events: 3 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

AVEO Pharmaceuticals, Inc.

Phone: 857-400-0101

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Open-label Period: Tivozanib (AV-951) n=272 participants at risk Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=61 participants at risk Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=57 participants at risk Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.74% 2/272 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.6% 1/61 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metatstatic renal cell carcinoma	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Nervous system disorders Paraplegia	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Infections and infestations Appendicitis	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Musculoskeletal and connective tissue disorders Pathological fracture	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Intestinal obstruction	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.74% 2/272 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Vascular disorders Hypertensive crisis	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Vascular disorders Hypotension	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Cardiac disorders Myocardial infarction	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Cardiac disorders Myocardial ischemia	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Injury, poisoning and procedural complications Joint dislocation	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Reproductive system and breast disorders Uterine prolapse	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.6% 1/61 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Infections and infestations Pneumonia	0.37% 1/272 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.

Measure	Open-label Period: Tivozanib (AV-951) n=272 participants at risk Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).	Double-blind Period: Tivozanib (AV-951) n=61 participants at risk Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.	Double-blind Period: Placebo n=57 participants at risk Subjects with \< 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner.
General disorders Asthenia	11.8% 32/272 • Number of events 49 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	9.8% 6/61 • Number of events 9 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	12.3% 7/57 • Number of events 7 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
General disorders Fatigue	10.7% 29/272 • Number of events 45 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.3% 2/61 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	7.0% 4/57 • Number of events 6 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
General disorders Pyrexia	5.1% 14/272 • Number of events 16 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.5% 2/57 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
General disorders Non-cardiac chest pain	3.7% 10/272 • Number of events 11 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.6% 1/61 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.5% 2/57 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Diarrhea	8.8% 24/272 • Number of events 40 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	6.6% 4/61 • Number of events 6 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Abdominal pain upper	2.6% 7/272 • Number of events 9 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Stomatitis	2.2% 6/272 • Number of events 13 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Musculoskeletal and connective tissue disorders Back pain	6.6% 18/272 • Number of events 25 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	4.9% 3/61 • Number of events 4 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Musculoskeletal and connective tissue disorders Bone pain	4.4% 12/272 • Number of events 17 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.5% 2/57 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Investigations Gamma-glutamyl transferase increased	5.5% 15/272 • Number of events 27 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	2.2% 6/272 • Number of events 16 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Skin and subcutaneous tissue disorders Rash generalized	3.3% 9/272 • Number of events 11 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Skin and subcutaneous tissue disorders Pruritus	2.2% 6/272 • Number of events 6 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Nervous system disorders Headache	4.0% 11/272 • Number of events 17 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Renal and urinary disorders Proteinuria	3.7% 10/272 • Number of events 11 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	4.9% 3/61 • Number of events 5 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Blood and lymphatic system disorders Anemia	2.2% 6/272 • Number of events 6 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Metabolism and nutrition disorders Anorexia	3.3% 9/272 • Number of events 12 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.3% 2/61 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Vascular disorders Combined Hypertension	41.9% 114/272 • Number of events 199 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Dysphonia	19.9% 54/272 • Number of events 76 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	4.9% 3/61 • Number of events 7 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Dyspnea	8.5% 23/272 • Number of events 33 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	9.8% 6/61 • Number of events 7 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	14.0% 8/57 • Number of events 8 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Respiratory, thoracic and mediastinal disorders Cough	5.9% 16/272 • Number of events 20 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.3% 2/61 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.8% 1/57 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Vomiting	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.3% 2/61 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.8% 1/57 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Abdominal pain	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.6% 1/61 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Gastrointestinal disorders Nausea	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/61 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.5% 2/57 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Infections and infestations Nasopharyngitis	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	3.3% 2/61 • Number of events 2 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	0.00% 0/57 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.00% 0/272 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	1.6% 1/61 • Number of events 1 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.	5.3% 3/57 • Number of events 3 • 1 year Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported.