Trial Outcomes & Findings for A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma (NCT NCT01297244)

Last Updated: 2020-10-27

Results Overview

To Evaluate CD68, HIF (hypoxia induced factor) 1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

105 participants

Primary outcome timeframe

Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.

Results posted on

2020-10-27

Participant Flow

Subjects who met all the inclusion and none of the exclusion criteria were enrolled in 2 sites in the United States and Canada.

All screening assessments were performed within 21 days prior to the first dose of study drug. All subjects underwent inclusion exclusion criteria assessment and all eligible participants signed the informed consent before undergoing any study-related procedures.

Participant milestones

Participant milestones
Measure	Clear Cell RCC Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Non-Clear Cell RCC Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Overall Study STARTED	90	15
Overall Study COMPLETED	55	9
Overall Study NOT COMPLETED	35	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Clear Cell RCC Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Non-Clear Cell RCC Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Overall Study Progressive disease	22	3
Overall Study Adverse Event	9	1
Overall Study Death	1	1
Overall Study Clinical progression	1	1
Overall Study Withdrawal by Subject	2	0

Baseline Characteristics

A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Clear Cell RCC n=90 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Non-Clear Cell RCC n=15 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Total n=105 Participants Total of all reporting groups
Age, Continuous	60 years STANDARD_DEVIATION 9.99 • n=5 Participants	64.7 years STANDARD_DEVIATION 9.26 • n=7 Participants	60.7 years STANDARD_DEVIATION 9.98 • n=5 Participants
Sex: Female, Male Female	23 Participants n=5 Participants	1 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	67 Participants n=5 Participants	14 Participants n=7 Participants	81 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=5 Participants	0 Participants n=7 Participants	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	78 Participants n=5 Participants	15 Participants n=7 Participants	93 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) White	80 Participants n=5 Participants	13 Participants n=7 Participants	93 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.

Population: The primary efficacy analyses of correlations between biomarkers in blood and archived tissue and PFS and objective response were not completed due to voluntary study discontinuation. Therefore, data was not collected for this outcome measure.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.

To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Population: Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

Subjects were considered to be progression-free at 6 months if they did not have disease progression or death by Day 182 and if they had an evaluation of confirmed PR, unconfirmed PR, or SD on or after Day 144.

Outcome measures

Outcome measures
Measure	Tivozanib n=90 Participants 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. Tivozanib: 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.	Non-Clear Cell RCC n=15 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months	49 Participants	7 Participants

SECONDARY outcome

Timeframe: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Population: Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

Objective response rate (ORR) is defined as the proportion of evaluable subjects who had a best overall response of complete response (CR) or partial response (PR). Based on RECIST v1.1 for target lesions, CR is the disappearance of all target lesions, reduction in short axis of any pathological lymph nodes (whether target or non-target) to \< 10 mm and PR is at least a 30% decrease from baseline in the sum of diameters of target lesions.

Outcome measures

Outcome measures
Measure	Tivozanib n=90 Participants 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. Tivozanib: 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.	Non-Clear Cell RCC n=15 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Number of Subjects With Objective Response Rate (ORR)	24 Participants	2 Participants

SECONDARY outcome

Timeframe: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Population: Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

PFS is defined as the duration in days from the date of first dose of study drug to the date of first documentation of Progressive Disease (PD) or death (whichever came first), censored at the last tumor assessment documenting the absence of PD prior to the start of further anti-cancer therapy. Based on RECIST v1.1, progressive Disease (PD) is defined as an increase of at least 20%, and an absolute increase of at least 5 mm, in the sum of diameters of target lesions, taking as reference the smallest sum on study.

Outcome measures

Outcome measures
Measure	Tivozanib n=90 Participants 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. Tivozanib: 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.	Non-Clear Cell RCC n=15 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Kaplan-Meier Estimate of Progression-free Survival (PFS)	25.0 Weeks Interval 23.7 to NA=not estimable	23.6 Weeks Interval 16.4 to NA=not estimable

SECONDARY outcome

Timeframe: Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.

Population: ITT: All enrolled subjects who receive at least 1 dose of tivozanib. Although an additional subject had a serious adverse event of pneumonia in the Non-Clear Cell RCC that was documented as cause of death, this event is not included under "TEAE resulting in death" as it was not treatment emergent (onset was 30 days after the last dose).

Subjects were monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG.

Outcome measures

Outcome measures
Measure	Tivozanib n=90 Participants 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. Tivozanib: 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.	Non-Clear Cell RCC n=15 Participants Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Number of Subjects With Adverse Events Any TEAE	90 Participants	15 Participants
Number of Subjects With Adverse Events Study drug-related TEAE	87 Participants	15 Participants
Number of Subjects With Adverse Events Any TEAE of Grade 3 or higher	67 Participants	11 Participants
Number of Subjects With Adverse Events Study drug-related TEAE of Grade 3 or higher	61 Participants	10 Participants
Number of Subjects With Adverse Events TEAE resulting in death	1 Participants	0 Participants
Number of Subjects With Adverse Events Study drug-related TEAE resulting in death	0 Participants	0 Participants
Number of Subjects With Adverse Events Serious TEAE	16 Participants	2 Participants
Number of Subjects With Adverse Events Study drug-related serious TEAE	7 Participants	0 Participants
Number of Subjects With Adverse Events TEAE-discontinuation of study drug	10 Participants	1 Participants
Number of Subjects With Adverse Events Study drug-related TEAE-discontinuation-study drug	8 Participants	1 Participants
Number of Subjects With Adverse Events TEAE-reduction of study drug dose	10 Participants	1 Participants
Number of Subjects With Adverse Events Study drug-related TEAE-reduction of study drug	9 Participants	1 Participants
Number of Subjects With Adverse Events TEAE-interruption of study drug dosing	19 Participants	4 Participants
Number of Subjects With Adverse Events Study drug-related TEAE-interruption of study drug	14 Participants	3 Participants

Adverse Events

Clear Cell RCC

Serious events: 16 serious events

Other events: 90 other events

Deaths: 0 deaths

Non-Clear Cell RCC

Serious events: 2 serious events

Other events: 15 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	Clear Cell RCC n=90 participants at risk Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Non-Clear Cell RCC n=15 participants at risk Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Gastrointestinal disorders Pancreatitis	2.2% 2/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Gastrointestinal disorders Constipation	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
General disorders Asthenia	2.2% 2/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	6.7% 1/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
General disorders Non-cardiac chest pain	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Infections and infestations Herpes zoster	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Infections and infestations Cellulitis	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Infections and infestations Urosepsis	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Cardiac disorders Acute coronary syndrome	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Cardiac disorders Acute myocardial infarction	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Cardiac disorders Cardiac arrest	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Respiratory, thoracic and mediastinal disorders Dyspnea	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	6.7% 1/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Musculoskeletal and connective tissue disorders Flank pain	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Nervous system disorders Transient ischemic attack	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Renal and urinary disorders Renal failure acute	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Endocrine disorders Adrenal hemorrhage	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Injury, poisoning and procedural complications Gastroenteritis radiation	1.1% 1/90 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.	0.00% 0/15 • Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.