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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01297244
Recruitment Status : Completed
First Posted : February 16, 2011
Results First Posted : October 27, 2020
Last Update Posted : October 27, 2020
Sponsor:
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Renal Cell Carcinoma
Intervention Drug: Tivozanib
Enrollment 105
Recruitment Details Subjects who met all the inclusion and none of the exclusion criteria were enrolled in 2 sites in the United States and Canada.
Pre-assignment Details 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.
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 90 15
Completed 55 9
Not Completed 35 6
Reason Not Completed
Progressive disease             22             3
Adverse Event             9             1
Death             1             1
Clinical progression             1             1
Withdrawal by Subject             2             0
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 90 15 105
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 90 participants 15 participants 105 participants
60  (9.99) 64.7  (9.26) 60.7  (9.98)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 15 participants 105 participants
Female
23
  25.6%
1
   6.7%
24
  22.9%
Male
67
  74.4%
14
  93.3%
81
  77.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 15 participants 105 participants
Hispanic or Latino
10
  11.1%
0
   0.0%
10
   9.5%
Not Hispanic or Latino
78
  86.7%
15
 100.0%
93
  88.6%
Unknown or Not Reported
2
   2.2%
0
   0.0%
2
   1.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 15 participants 105 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
2
   2.2%
1
   6.7%
3
   2.9%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
5
   5.6%
1
   6.7%
6
   5.7%
White
80
  88.9%
13
  86.7%
93
  88.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
3
   3.3%
0
   0.0%
3
   2.9%
1.Primary Outcome
Title Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Clinical Activity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib.
Hide Description 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.
Time Frame Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tivozanib
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
2.Primary Outcome
Title Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Treatment-related Toxicity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib.
Hide Description To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.
Time Frame Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tivozanib
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
3.Primary Outcome
Title Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months
Hide Description 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.
Time Frame Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 90 15
Measure Type: Count of Participants
Unit of Measure: Participants
49
  54.4%
7
  46.7%
4.Secondary Outcome
Title Number of Subjects With Objective Response Rate (ORR)
Hide Description 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.
Time Frame Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 90 15
Measure Type: Count of Participants
Unit of Measure: Participants
24
  26.7%
2
  13.3%
5.Secondary Outcome
Title Kaplan-Meier Estimate of Progression-free Survival (PFS)
Hide Description 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.
Time Frame Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 90 15
Median (95% Confidence Interval)
Unit of Measure: Weeks
25.0 [1] 
(23.7 to NA)
23.6 [1] 
(16.4 to NA)
[1]
NA=not estimable
6.Secondary Outcome
Title Number of Subjects With Adverse Events
Hide Description

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.

Time Frame Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 90 15
Measure Type: Count of Participants
Unit of Measure: Participants
Any TEAE
90
 100.0%
15
 100.0%
Study drug-related TEAE
87
  96.7%
15
 100.0%
Any TEAE of Grade 3 or higher
67
  74.4%
11
  73.3%
Study drug-related TEAE of Grade 3 or higher
61
  67.8%
10
  66.7%
TEAE resulting in death
1
   1.1%
0
   0.0%
Study drug-related TEAE resulting in death
0
   0.0%
0
   0.0%
Serious TEAE
16
  17.8%
2
  13.3%
Study drug-related serious TEAE
7
   7.8%
0
   0.0%
TEAE-discontinuation of study drug
10
  11.1%
1
   6.7%
Study drug-related TEAE-discontinuation-study drug
8
   8.9%
1
   6.7%
TEAE-reduction of study drug dose
10
  11.1%
1
   6.7%
Study drug-related TEAE-reduction of study drug
9
  10.0%
1
   6.7%
TEAE-interruption of study drug dosing
19
  21.1%
4
  26.7%
Study drug-related TEAE-interruption of study drug
14
  15.6%
3
  20.0%
Time Frame Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.
Adverse Event Reporting Description Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
 
Arm/Group Title Clear Cell RCC Non-Clear Cell RCC
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Clear Cell RCC Non-Clear Cell RCC
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Clear Cell RCC Non-Clear Cell RCC
Affected / at Risk (%) Affected / at Risk (%)
Total   16/90 (17.78%)   2/15 (13.33%) 
Cardiac disorders     
Acute coronary syndrome * 1  1/90 (1.11%)  0/15 (0.00%) 
Acute myocardial infarction * 1  1/90 (1.11%)  0/15 (0.00%) 
Cardiac arrest * 1  1/90 (1.11%)  0/15 (0.00%) 
Endocrine disorders     
Adrenal hemorrhage * 1  1/90 (1.11%)  0/15 (0.00%) 
Gastrointestinal disorders     
Pancreatitis * 1  2/90 (2.22%)  0/15 (0.00%) 
Constipation * 1  1/90 (1.11%)  0/15 (0.00%) 
General disorders     
Asthenia * 1  2/90 (2.22%)  1/15 (6.67%) 
Non-cardiac chest pain * 1  1/90 (1.11%)  0/15 (0.00%) 
Infections and infestations     
Herpes zoster * 1  1/90 (1.11%)  0/15 (0.00%) 
Cellulitis * 1  1/90 (1.11%)  0/15 (0.00%) 
Urosepsis * 1  1/90 (1.11%)  0/15 (0.00%) 
Injury, poisoning and procedural complications     
Gastroenteritis radiation * 1  1/90 (1.11%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain * 1  1/90 (1.11%)  0/15 (0.00%) 
Flank pain * 1  1/90 (1.11%)  0/15 (0.00%) 
Nervous system disorders     
Transient ischemic attack * 1  1/90 (1.11%)  0/15 (0.00%) 
Renal and urinary disorders     
Renal failure acute * 1  1/90 (1.11%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnea * 1  1/90 (1.11%)  1/15 (6.67%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Clear Cell RCC Non-Clear Cell RCC
Affected / at Risk (%) Affected / at Risk (%)
Total   90/90 (100.00%)   15/15 (100.00%) 
Endocrine disorders     
Hypothyroidism * 1  17/90 (18.89%)  6/15 (40.00%) 
Eye disorders     
Vision blurred * 1  9/90 (10.00%)  0/15 (0.00%) 
Gastrointestinal disorders     
Abdominal pain * 1  12/90 (13.33%)  6/15 (40.00%) 
Abdominal pain upper * 1  9/90 (10.00%)  1/15 (6.67%) 
Constipation * 1  19/90 (21.11%)  1/15 (6.67%) 
Diarrhoea * 1  44/90 (48.89%)  8/15 (53.33%) 
Dry mouth * 1  5/90 (5.56%)  3/15 (20.00%) 
Dyspepsia * 1  20/90 (22.22%)  4/15 (26.67%) 
Flatulence * 1  8/90 (8.89%)  1/15 (6.67%) 
Gastrooesophageal reflux disease * 1  8/90 (8.89%)  2/15 (13.33%) 
Nausea * 1  40/90 (44.44%)  12/15 (80.00%) 
Pancreatitis * 1  6/90 (6.67%)  0/15 (0.00%) 
Stomatitis * 1  26/90 (28.89%)  5/15 (33.33%) 
Vomiting * 1  18/90 (20.00%)  5/15 (33.33%) 
General disorders     
Asthenia * 1  5/90 (5.56%)  3/15 (20.00%) 
Fatigue * 1  53/90 (58.89%)  8/15 (53.33%) 
Oedema peripheral * 1  8/90 (8.89%)  1/15 (6.67%) 
Pain * 1  6/90 (6.67%)  1/15 (6.67%) 
Infections and infestations     
Nasopharyngitis * 1  6/90 (6.67%)  0/15 (0.00%) 
Upper respiratory tract infection * 1  4/90 (4.44%)  2/15 (13.33%) 
Investigations     
Amylase increased * 1  8/90 (8.89%)  0/15 (0.00%) 
Blood creatinine increased * 1  5/90 (5.56%)  1/15 (6.67%) 
Lipase increased * 1  13/90 (14.44%)  5/15 (33.33%) 
Weight decreased * 1  10/90 (11.11%)  4/15 (26.67%) 
Metabolism and nutrition disorders     
Decreased appetite * 1  30/90 (33.33%)  4/15 (26.67%) 
Dehydration * 1  6/90 (6.67%)  1/15 (6.67%) 
Hyperkalaemia * 1  5/90 (5.56%)  3/15 (20.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  13/90 (14.44%)  5/15 (33.33%) 
Back pain * 1  25/90 (27.78%)  1/15 (6.67%) 
Flank pain * 1  8/90 (8.89%)  0/15 (0.00%) 
Muscle spasms * 1  7/90 (7.78%)  1/15 (6.67%) 
Musculoskeletal pain * 1  6/90 (6.67%)  2/15 (13.33%) 
Myalgia * 1  5/90 (5.56%)  2/15 (13.33%) 
Pain in extremity * 1  10/90 (11.11%)  2/15 (13.33%) 
Nervous system disorders     
Dizziness * 1  16/90 (17.78%)  2/15 (13.33%) 
Dysgeusia * 1  11/90 (12.22%)  2/15 (13.33%) 
Headache * 1  25/90 (27.78%)  4/15 (26.67%) 
Psychiatric disorders     
Anxiety * 1  10/90 (11.11%)  0/15 (0.00%) 
Depression * 1  6/90 (6.67%)  1/15 (6.67%) 
Insomnia * 1  10/90 (11.11%)  0/15 (0.00%) 
Renal and urinary disorders     
Proteinuria * 1  11/90 (12.22%)  4/15 (26.67%) 
Respiratory, thoracic and mediastinal disorders     
Cough * 1  11/90 (12.22%)  4/15 (26.67%) 
Dysphonia * 1  42/90 (46.67%)  9/15 (60.00%) 
Dyspnoea * 1  20/90 (22.22%)  3/15 (20.00%) 
Epistaxis * 1  5/90 (5.56%)  3/15 (20.00%) 
Oropharyngeal pain * 1  5/90 (5.56%)  1/15 (6.67%) 
Rhinorrhoea * 1  8/90 (8.89%)  2/15 (13.33%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform * 1  5/90 (5.56%)  1/15 (6.67%) 
Dry skin * 1  8/90 (8.89%)  2/15 (13.33%) 
Palmar-plantar erythrodysaesthesia syndrome * 1  19/90 (21.11%)  1/15 (6.67%) 
Pruritus * 1  5/90 (5.56%)  1/15 (6.67%) 
Rash * 1  6/90 (6.67%)  3/15 (20.00%) 
Vascular disorders     
Hypertension * 1  58/90 (64.44%)  9/15 (60.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.0)
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: AVEO Pharmaceuticals, Inc.
Phone: 857-400-0101
EMail: Clinical@aveooncology.com
Layout table for additonal information
Responsible Party: AVEO Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01297244    
Other Study ID Numbers: AV-951-10-202
First Submitted: February 14, 2011
First Posted: February 16, 2011
Results First Submitted: July 7, 2020
Results First Posted: October 27, 2020
Last Update Posted: October 27, 2020