Trial Outcomes & Findings for A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma (NCT NCT01030783)

Last Updated: 2019-10-28

Results Overview

Progression-Free Survival (PFS) 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 1.0 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

517 participants

Primary outcome timeframe

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.

Results posted on

2019-10-28

Participant Flow

Participant milestones

Participant milestones
Measure	Tivozanib (AV-951) tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Overall Study STARTED	260	257
Overall Study COMPLETED	211	231
Overall Study NOT COMPLETED	49	26

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tivozanib (AV-951) n=260 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Total n=517 Participants Total of all reporting groups
Age, Continuous	59 Years n=5 Participants	59 Years n=7 Participants	59 Years n=5 Participants
Sex: Female, Male Female	75 Participants n=5 Participants	68 Participants n=7 Participants	143 Participants n=5 Participants
Sex: Female, Male Male	185 Participants n=5 Participants	189 Participants n=7 Participants	374 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Population: ITT Population

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=260 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Progression-free Survival (PFS) of Subjects With Advanced Renal Cell Cancer (RCC) Randomized to Treatment With Tivozanib or Sorafenib	11.9 Months Interval 9.3 to 14.7	9.1 Months Interval 7.3 to 9.5

SECONDARY outcome

Timeframe: Date of randomization to date of death

Population: ITT Population

Overall survival (OS) is defined as the time from the date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive. Subjects lacking data beyond randomization will have their survival times censored on the date of randomization.

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=260 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Overall Survival (OS) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	28.2 Months Interval 22.5 to 33.0	30.8 Months Interval 28.4 to 33.3

SECONDARY outcome

Timeframe: Every 8 weeks from date of randomization until disease progression

Population: ITT Population

Objective response rate (ORR) is defined as the percentage of subjects who have at least a 30% reduction in the sum of diameters per RECIST (Version 1.0).

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=260 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Objective Response Rate (ORR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	33.1 percentage of participants Interval 27.4 to 39.2	23.3 percentage of participants Interval 18.3 to 29.0

SECONDARY outcome

Timeframe: Assessed every 8 weeks from date of randomization until date of progression

Population: ITT Population

Duration of response (DR) is defined as the time from the first documentation of objective tumor response to the first documentation of tumor progression per RECIST 1.0 or to death due to any cause.

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=86 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=58 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Duration of Response (DR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	15.0 Months Interval 12.9 to The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event.	12.9 Months Interval 11.0 to The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event.

SECONDARY outcome

Timeframe: From start of treatment therapy to completion of treatment therapy, an average of 11 months

Population: Safety Population

Dose reductions and interruptions were allowed for subjects taking tivozanib or sorafenib. Any modification of study drug administration, and the reason for such action, was clearly noted on the subject's eCRF.

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=259 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Safety and Tolerability of Tivozanib and Sorafenib Reasons for Dose Interruptions - Adverse Event	50 Participants	92 Participants
Safety and Tolerability of Tivozanib and Sorafenib Reasons for Dose Reductions - Adverse Event	36 Participants	111 Participants

SECONDARY outcome

Timeframe: At Day 1 of each 28 day cycle throughout the course of the study, for an average of 11 months per subject

Population: ITT Population, excluding questionnaires that were not analyzable

The Disease Related Symptom Scale of the Functional Assessment of Cancer Therapy - Advanced Kidney Cancer Symptom Index (FKSI-DRS) measured kidney specific symptoms on a 0-36 scale, with lower scores corresponding to worse overall QOL and higher scores corresponding to better overall QOL. The Functional Assessment of Cancer Therapy-General (FACT-G) measured general wellbeing scored on a 0-108 scale, with lower scores corresponding to worse overall QOL and higher scores corresponding to better overall QOL. The European Quality of Life-5 Dimensions (EQ-5D) measured patient health related quality of life scored on a 0-1 scale, with 0 being worse health state and 1 being perfect health state. The European Quality of Life-5 Dimensions Visual Analog Scales (EQ-5D VAS) measured patient health related quality of life on a visual analog scale from 0 to 100, with 0 being the worst and 100 being the best. These scales were self-administered by patients at the start of the visit.

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=257 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=250 Participants Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib FACT-G Total Score	74.16 Score on a scale Standard Error 0.785	73.05 Score on a scale Standard Error 0.802
To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib FKSI-DRS Score	28.71 Score on a scale Standard Error 0.227	28.58 Score on a scale Standard Error 0.233
To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib EQ-5D Weighted Health State Index	0.67 Score on a scale Standard Error 0.014	0.66 Score on a scale Standard Error 0.014
To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib EQ-5D VAS	71.50 Score on a scale Standard Error 0.826	68.49 Score on a scale Standard Error 0.841

SECONDARY outcome

Timeframe: Cycle 1, Day 1 (prior to dosing), Cycle 1, Day 15 (prior to dosing), Cycle 2, Day 1 (prior to dosing), and Cycle 2, Day 22-28

Population: All patients who had taken at least 1 dose of tivozanib and who had at least one measurable concentration value.

Samples for tivozanib serum concentrations will be collected at the following time points: Cycle 1, Day 1 (prior to dosing), Cycle 1, Day 15 (prior to dosing), Cycle 2, Day 1 (prior to dosing), and Cycle 2, Day 22-28. The serum concentrations of tivozanib were tabulated for individual subjects and summarized by nominal time using standard descriptive statistics (concentrations presented in ng/mL).

Outcome measures

Outcome measures
Measure	Tivozanib (AV-951) n=254 Participants tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Pharmacokinetics (Serum Concentrations) of Tivozanib Cycle 1, Day 1	0 ng/mL Interval 0.0 to 0.0	—
Pharmacokinetics (Serum Concentrations) of Tivozanib Cycle 1, Day 15	69.05 ng/mL Interval 65.0 to 73.1	—
Pharmacokinetics (Serum Concentrations) of Tivozanib Cycle 2, Day 1	30.87 ng/mL Interval 28.0 to 33.7	—
Pharmacokinetics (Serum Concentrations) of Tivozanib Cycle 2, Day 22-28	54.37 ng/mL Interval 49.8 to 59.0	—

Adverse Events

Tivozanib (AV-951)

Serious events: 74 serious events

Other events: 238 other events

Deaths: 0 deaths

Sorafenib

Serious events: 56 serious events

Other events: 249 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

AVEO Pharmaceuticals, Inc.

Phone: 617-588-1960

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tivozanib (AV-951) n=259 participants at risk tivozanib (AV-951): Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Sorafenib n=257 participants at risk Sorafenib: Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Vascular disorders Hypertension	44.8% 116/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	35.4% 91/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Diarrhoea	24.3% 63/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	33.1% 85/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Nausea	13.1% 34/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	7.4% 19/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Stomatitis	11.6% 30/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	8.9% 23/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Vomiting	7.7% 20/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	4.7% 12/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Abdominal pain upper	6.9% 18/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	6.6% 17/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Abdominal pain	6.2% 16/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	3.9% 10/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Gastrointestinal disorders Constipation	4.6% 12/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	5.1% 13/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
General disorders Fatigue	20.5% 53/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	16.0% 41/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
General disorders Asthenia	17.0% 44/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	17.1% 44/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
General disorders Pyrexia	4.2% 11/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	5.1% 13/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Investigations Weight decreased	18.9% 49/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	21.0% 54/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Investigations Blood thyroid stimulating hormone increased	5.4% 14/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	2.3% 6/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Investigations Lipase increased	4.6% 12/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	9.3% 24/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Investigations Blood phosphorus decreased	1.9% 5/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	6.2% 16/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Respiratory, thoracic and mediastinal disorders Dysphonia	21.2% 55/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	4.7% 12/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.0% 31/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	8.6% 22/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Respiratory, thoracic and mediastinal disorders Cough	8.9% 23/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	7.0% 18/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Musculoskeletal and connective tissue disorders Back pain	14.7% 38/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	8.2% 21/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Musculoskeletal and connective tissue disorders Arthralgia	7.3% 19/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	4.3% 11/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Musculoskeletal and connective tissue disorders Pain in extremity	5.4% 14/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	2.3% 6/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	13.9% 36/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	54.1% 139/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Skin and subcutaneous tissue disorders Alopecia	2.3% 6/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	21.4% 55/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Skin and subcutaneous tissue disorders Rash erythematous	2.3% 6/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	6.2% 16/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Skin and subcutaneous tissue disorders Dry skin	1.9% 5/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	5.1% 13/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Skin and subcutaneous tissue disorders Rash papular	1.2% 3/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	6.2% 16/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Nervous system disorders Headache	8.9% 23/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	4.3% 11/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Metabolism and nutrition disorders Decreased appetite	10.8% 28/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	9.3% 24/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Renal and urinary disorders Proteinuria	9.3% 24/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	8.2% 21/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Blood and lymphatic system disorders Anaemia	5.8% 15/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	5.8% 15/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population
Endocrine disorders Hypothyroidism	5.4% 14/259 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population	1.9% 5/257 • From first dose to last dose plus 30 days, approximately 1 year on average Safety Population