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Trial record 87 of 196 for:    colon cancer | ( Map: Colorado, United States )

A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy

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: NCT01478594
Recruitment Status : Completed
First Posted : November 23, 2011
Results First Posted : April 3, 2015
Last Update Posted : July 8, 2015
Sponsor:
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Cancer
Interventions Drug: Tivozanib
Drug: Bevacizumab
Drug: mFOLFOX6
Enrollment 265
Recruitment Details Participants were at least 18 years of age with Stage IV metastatic colorectal cancer (mCRC) and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1).
Pre-assignment Details Participants were randomized in a 2:1 ratio (tivozanib to bevacizumab) and stratified by lactate dehydrogenase (LDH) status (< 1.5 x the upper limit of normal [ULN] or > 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or > 2).
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each 28-day cycle for 21 days followed by 7 days off treatment. Participants also received modified FOLFOX6 (mFOLFOX6) chemotherapy consisting of oxaliplatin, 85 mg/m^2, leucovorin 400 mg/m^2, and 5-fluorouracil 400 mg/m^2 bolus then 2400 mg/m^2 every 2 weeks on Days 1 and 15 of each cycle. Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Period Title: Overall Study
Started 177 88
Treated 177 87
Completed 112 [1] 60 [1]
Not Completed 65 28
Reason Not Completed
Randomized but Never Received Study Drug             0             1
Death             45             18
Lost to Follow-up             3             1
Withdrawal by Subject             9             3
Study Closed by Sponsor             8             5
[1]
Participants still on study as of 28 February 2014
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6 Total
Hide Arm/Group Description Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle. Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle. Total of all reporting groups
Overall Number of Baseline Participants 177 88 265
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 177 participants 88 participants 265 participants
61.9  (9.58) 62.6  (11.17) 62.2  (10.12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
Female
59
  33.3%
33
  37.5%
92
  34.7%
Male
118
  66.7%
55
  62.5%
173
  65.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
Hispanic or Latino
6
   3.4%
2
   2.3%
8
   3.0%
Not Hispanic or Latino
170
  96.0%
86
  97.7%
256
  96.6%
Unknown or Not Reported
1
   0.6%
0
   0.0%
1
   0.4%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
White 169 85 254
Black or African American 2 0 2
Asian 3 2 5
Native Hawaiian or other Pacific Islander 1 1 2
Other 2 0 2
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
United States 44 26 70
Hungary 24 8 32
Czech Republic 12 9 21
Canada 13 4 17
Finland 5 1 6
Spain 22 8 30
Belgium 10 9 19
Austria 8 3 11
Australia 15 9 24
Netherlands 1 1 2
United Kingdom 19 7 26
Italy 4 3 7
Eastern Cooperative Oncology Group (ECOG) performance status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
ECOG Performance Status 0 95 58 153
ECOG Performance Status 1 82 30 112
ECOG Performance Status 2 0 0 0
ECOG Performance Status 3 0 0 0
ECOG Performance Status 4 0 0 0
[1]
Measure Description: ECOG criteria: 0: Fully active. 1: Ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of all self-care. 3: Capable of limited self-care, confined to bed or chair more than 50% of waking hours. 4: Completely disabled, no self-care, totally confined to bed or chair. 5: Dead.
Lactate dehydrogenase (LDH) Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
< 1.5 Upper Limit of Normal 127 64 191
≥ 1.5 Upper Limit of Normal 50 24 74
[1]
Measure Description: The upper limit of normal (ULN) from the site was used.
Origin of Cancer  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
Rectal 53 24 77
Colon 124 64 188
Number of metastatic sites/organs  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
1 56 30 86
2 80 34 114
3 29 21 50
≥ 4 12 3 15
Kirsten rat sarcoma (KRAS) Mutation Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 177 participants 88 participants 265 participants
Wild-type 33 21 54
Mutant 23 16 39
Unknown 121 51 172
Time Since Initial Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 177 participants 88 participants 265 participants
9.41  (20.473) 10.88  (21.055) 9.90  (20.640)
Number of metastatic sites at screening  
Mean (Standard Deviation)
Unit of measure:  Metastatic sites
Number Analyzed 177 participants 88 participants 265 participants
2.0  (1.02) 2.0  (0.85) 2.0  (0.97)
1.Primary Outcome
Title Investigator-assessed Progression-Free Survival (PFS)
Hide Description

The time from the date of randomization until objective tumor progression or death due to any cause. Objective tumor progression was determined through radiological imaging and based on the requirements of the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1):

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.

Participants who did not progress or had not died at the time of the analysis were censored at the date of last tumor assessment where non-progression was documented.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set included all randomized participants.
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 177 88
Median (95% Confidence Interval)
Unit of Measure: months
9.4
(8.5 to 10.1)
10.7
(7.5 to 12.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
Comments An interim futility analysis was to be performed when approximately 83 PFS events (50% of the total PFS events) were observed. The Lans DeMets beta spending function with an O’Brien-Fleming boundary was used to derive the futility boundary. If the hazard ratio (HR) for PFS was greater than 1.0581, enrollment was to be stopped. With this futility stopping rule, the adjusted study power was 78.6%.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.706
Comments [Not Specified]
Method Log Rank
Comments Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.091
Confidence Interval (2-Sided) 95%
0.693 to 1.718
Estimation Comments HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.
2.Secondary Outcome
Title Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)
Hide Description The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was not performed due to study closure.
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
3.Secondary Outcome
Title Overall Survival (OS)
Hide Description Overall survival (OS) is defined as the time from the date of randomization until the documented date of death. Participants still alive at the time of analysis were censored on the last day the participant was known to be alive.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 177 88
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(12.8 to NA)
[1]
Could not be estimated due to the low number of events at the time of the interim analysis
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.754
Comments [Not Specified]
Method Log Rank
Comments Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.116
Confidence Interval (2-Sided) 95%
0.561 to 2.218
Estimation Comments HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.
4.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description

Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) confirmed a minimum of four weeks apart based on RECIST 1.1 criteria.

CR: Disappearance of all target and non-target lesions and no new lesions.

PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and no progression of non-target lesions and no new lesions, or, disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits and no new lesions.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 m tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 177 88
Measure Type: Number
Unit of Measure: percentage of participants
45.2 43.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.718
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
5.Secondary Outcome
Title Duration of Response (DoR)
Hide Description Duration of response (DoR) is defined as the time from the date of the first documented response of CR or PR (whichever is first recorded) to documented progression or death. If a participant did not progress or had not died at the time of analysis, the duration of response was censored at the date of last tumor assessment. Duration of response is only defined for participants whose best overall response was CR or PR.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with a best overall response of complete response (CR) or partial response (PR).
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 80 38
Median (95% Confidence Interval)
Unit of Measure: months
7.4
(5.6 to 11.3)
9.3
(7.3 to 10.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.437
Comments [Not Specified]
Method Log Rank
Comments Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.389
Confidence Interval (2-Sided) 95%
0.604 to 3.194
Estimation Comments HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.
6.Secondary Outcome
Title Time to Treatment Failure (TTF)
Hide Description Time to Treatment Failure (TTF) is defined as the time from randomization to last dose date of tivozanib/bevacizumab. If a participant discontinued treatment for any reason, the participant was considered as an event. Participants remaining on treatment at the time of analysis were censored at date of last dose.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 177 88
Median (95% Confidence Interval)
Unit of Measure: months
5.5
(4.9 to 7.1)
5.4
(3.7 to 6.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.967
Comments [Not Specified]
Method Log Rank
Comments Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.006
Confidence Interval (2-Sided) 95%
0.746 to 1.358
Estimation Comments HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.
7.Secondary Outcome
Title Health Related Quality of Life (HRQoL)
Hide Description Time to deterioration in HRQoL measured by Colorectal cancer (CRC) subscale of the Functional Assessment of cancer Therapy Colorectal (FACT-C) scale, change in score from baseline using the European Quality of Life – 5 Dimensions (EQ-5D) and Fact Colorectal Symptom Index (FCSI) were not evaluated due to study closure.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was not performed due to study closure.
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)
Hide Description

An abnormality identified during a medical test is defined as an AE if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study medication or was clinically significant in the investigator's opinion.

An AE was serious if it resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required or prolonged inpatient hospitalization or other medically important event.

AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute Common Terminology Criteria for Grading Adverse Events (NCI-CTCAE) Version 4.03 per the following: 1=mild; 2= moderate; 3= severe; 4= life threatening; 5=death.

Treatment-related AEs were defined as events where the relationship to study drug was marked as probably or possibly, or was missing.

Time Frame From first dose through 30 days after last dose of either tivozanib or bevacizumab, until the data cut-off date of 28 February 2014. The median duration of treatment was 168.0 days in the tivozanib (tiv) arm and 162.0 days in the bevacizumab (bev) arm.
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Hide Analysis Population Description
The safety analysis set consisted of all randomized participants who received at least one dose of study drug (tivozanib or bevacizumab), analyzed according to the treatment actually received.
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description:
Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 177 87
Measure Type: Number
Unit of Measure: participants
Any adverse event 177 87
CTCAE Grade 3 or higher 156 76
Any tivozanib/bevacizumab-related adverse event 158 74
Any mFOLFOX6-related adverse event 169 84
Any tivozanib/bevacizumab and mFOLFOX6-related AE 138 59
Any tivozanib/bevacizumab-related AE ≥ Grade 3 104 31
Any mFOLFOX6-related AE ≥ Grade 3 126 61
Any tiv/bev and mFOLFOX6-related AE ≥ Grade 3 75 23
Any AE with an outcome of death 8 2
Any tivozanib/bevacizumab-related AE of death 3 2
Any mFOLFOX6-related AE outcome of death 3 2
Any tiv/bev & mFOLFOX6-related AE outcome of death 3 2
Any serious adverse event (SAE) 82 42
Any tivozanib/bevacizumab-related SAE 38 15
Any mFOLFOX6-related SAE 45 23
Any tivozanib/bevacizumab and mFOLFOX6-related SAE 30 11
AE leading to tiv/bev discontinuation 73 30
AE leading to tivozanib/bevacizumab interruption 138 63
9.Secondary Outcome
Title Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum lactate dehydrogenase status.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Tivozanib: LDH < 1.5 ULN Tivozanib: LDH ≥ 1.5 ULN Bevacizumab: LDH < 1.5 ULN Bevacizumab : LDH ≥ 1.5 ULN
Hide Arm/Group Description:
Participants with LDH status < 1.5 ULN received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with LDH status ≥ 1.5 ULN received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with LDH status < 1.5 ULN received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with LDH status ≥ 1.5 ULN received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 127 50 64 24
Measure Type: Number
Unit of Measure: participants
42 24 16 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: LDH < 1.5 ULN, Bevacizumab: LDH < 1.5 ULN
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.331
Confidence Interval (2-Sided) 95%
0.746 to 2.375
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: LDH ≥ 1.5 ULN, Bevacizumab : LDH ≥ 1.5 ULN
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.575
Confidence Interval (2-Sided) 95%
0.285 to 1.160
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
10.Secondary Outcome
Title Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum vascular endothelial growth factor-A (VEGF-A) level. VEGF-A protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Hide Analysis Population Description
Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: VEGF-A < Median Tivozanib: VEGF-A ≥ Median Bevacizumab: VEGF-A < Median Bevacizumab: VEGF-A ≥ Median
Hide Arm/Group Description:
Participants with VEGF-A levels < median received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A levels ≥ median received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 54 54 29 26
Measure Type: Number
Unit of Measure: participants
20 24 6 12
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-A < Median, Bevacizumab: VEGF-A < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.608
Confidence Interval (2-Sided) 95%
0.635 to 4.073
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-A ≥ Median, Bevacizumab: VEGF-A ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.755
Confidence Interval (2-Sided) 95%
0.375 to 1.521
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
11.Secondary Outcome
Title Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C level. VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Arm/Group Title Tivozanib: VEGF-C < Median Tivozanib: VEGF-C ≥ Median Bevacizumab: VEGF-C < Median Bevacizumab: VEGF-C ≥ Median
Hide Arm/Group Description:
Participants with VEGF-C levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 52 56 27 28
Measure Type: Number
Unit of Measure: participants
15 29 8 10
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C < Median, Bevacizumab: VEGF-C < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.877
Confidence Interval (2-Sided) 95%
0.366 to 2.100
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C ≥ Median, Bevacizumab: VEGF-C ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.275
Confidence Interval (2-Sided) 95%
0.614 to 2.646
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
12.Secondary Outcome
Title Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C/VEGF-A ratio. VEGF-A and VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the ratio is expressed relative to the observed median.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: VEGF-C/VEGF-A < Median Tivozanib: VEGF-C/VEGF-A ≥ Median Bevacizumab: VEGF-C/VEGF-A < Median Bevacizumab: VEGF-C/VEGF-A ≥ Median
Hide Arm/Group Description:
Participants with VEGF-C/VEGF-A ratio < median received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A ratio ≥ median received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A ratio < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A ratio ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 53 55 26 29
Measure Type: Number
Unit of Measure: participants
21 23 11 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C/VEGF-A < Median, Bevacizumab: VEGF-C/VEGF-A < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.721
Confidence Interval (2-Sided) 95%
0.345 to 1.507
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C/VEGF-A ≥ Median, Bevacizumab: VEGF-C/VEGF-A ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.597
Confidence Interval (2-Sided) 95%
0.672 to 3.795
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
13.Secondary Outcome
Title Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-2 level. sVEGFR-2 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: sVEGFR-2 < Median Tivozanib: sVEGFR-2 ≥ Median Bevacizumab: sVEGFR-2 < Median Bevacizumab: sVEGFR-2 ≥ Median
Hide Arm/Group Description:
Participants with sVEGFR-2 levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-2 levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-2 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-2 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 46 62 27 28
Measure Type: Number
Unit of Measure: participants
15 29 5 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: sVEGFR-2 < Median, Bevacizumab: sVEGFR-2 < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.627
Confidence Interval (2-Sided) 95%
0.580 to 4.564
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: sVEGFR-2 ≥ Median, Bevacizumab: sVEGFR-2 ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.779
Confidence Interval (2-Sided) 95%
0.397 to 1.531
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
14.Secondary Outcome
Title Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-3 level. sVEGFR-3 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: sVEGFR-3 < Median Tivozanib: sVEGFR-3 ≥ Median Bevacizumab: sVEGFR-3 < Median Bevacizumab: sVEGFR-3 ≥ Median
Hide Arm/Group Description:
Participants with sVEGFR-3 levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-3 levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-3 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with sVEGFR-3 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 50 58 30 25
Measure Type: Number
Unit of Measure: participants
14 30 4 14
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: sVEGFR-3 < Median, Bevacizumab: sVEGFR-3 < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.946
Confidence Interval (2-Sided) 95%
0.636 to 5.956
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: sVEGFR-3 ≥ Median, Bevacizumab: sVEGFR-3 ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.806
Confidence Interval (2-Sided) 95%
0.422 to 1.538
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
15.Secondary Outcome
Title Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum interleukin-8 level. IL-8 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: IL-8 < Median Tivozanib: IL-8 ≥ Median Bevacizumab: IL-8 < Median Bevacizumab: IL-8 ≥ Median
Hide Arm/Group Description:
Participants with IL-8 levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with IL-8 levels ≥ median received 1.5 m tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with IL-8 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with IL-8 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 53 55 27 28
Measure Type: Number
Unit of Measure: participants
14 30 7 11
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: IL-8 < Median, Bevacizumab: IL-8 < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.776
Confidence Interval (2-Sided) 95%
0.303 to 1.991
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: IL-8 ≥ Median, Bevacizumab: IL-8 ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.241
Confidence Interval (2-Sided) 95%
0.615 to 2.501
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
16.Secondary Outcome
Title Progression-Free Survival Events by Serum Neuropilin Level
Hide Description The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum neuropilin level. Neuropilin protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available serum protein samples
Arm/Group Title Tivozanib: Neuropilin < Median Tivozanib: Neuropilin ≥ Median Bevacizumab: Neuropilin < Median Bevacizumab: Neuropilin ≥ Median
Hide Arm/Group Description:
Participants with neuropilin levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with neuropilin levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with neuropilin levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and FOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with neuropilin levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 53 55 30 25
Measure Type: Number
Unit of Measure: participants
10 34 6 12
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: Neuropilin < Median, Bevacizumab: Neuropilin < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.950
Confidence Interval (2-Sided) 95%
0.343 to 2.630
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: Neuropilin ≥ Median, Bevacizumab: Neuropilin ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.983
Confidence Interval (2-Sided) 95%
0.503 to 1.918
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
17.Secondary Outcome
Title Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level
Hide Description

The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-A RNA level.

RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available tumor biopsy RNA samples
Arm/Group Title Tivozanib: VEGF-A RNA < Median Tivozanib: VEGF-A RNA ≥ Median Bevacizumab: VEGF-A RNA < Median Bevacizumab: VEGF-A RNA ≥ Median
Hide Arm/Group Description:
Participants with VEGF-A RNA levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A RNA levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-A RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 40 38 18 17
Measure Type: Number
Unit of Measure: participants
13 18 7 5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-A RNA < Median, Bevacizumab: VEGF-A RNA < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.226
Confidence Interval (2-Sided) 95%
0.468 to 3.214
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-A RNA ≥ Median, Bevacizumab: VEGF-A RNA ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.232
Confidence Interval (2-Sided) 95%
0.447 to 3.396
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
18.Secondary Outcome
Title Progression-Free Survival Events by Tumor VEGF-C RNA Level
Hide Description

The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C RNA level.

RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available tumor biopsy RNA samples
Arm/Group Title Tivozanib: VEGF-C RNA < Median Tivozanib: VEGF-C RNA ≥ Median Bevacizumab: VEGF-C RNA < Median Bevacizumab: VEGF-A RNA ≥ Median
Hide Arm/Group Description:
Participants with VEGF-C RNA levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C RNA levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 41 37 16 19
Measure Type: Number
Unit of Measure: participants
14 17 6 6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C RNA < Median, Bevacizumab: VEGF-C RNA < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.803
Confidence Interval (2-Sided) 95%
0.307 to 2.100
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C RNA ≥ Median, Bevacizumab: VEGF-A RNA ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.505
Confidence Interval (2-Sided) 95%
0.585 to 3.873
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
19.Secondary Outcome
Title Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio
Hide Description

The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C/VEGF-A RNA ratio.

RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available tumor biopsy RNA samples
Arm/Group Title Tivozanib: VEGF-C/VEGF-A RNA < Median Tivozanib: VEGF-C/VEGF-A RNA ≥ Median Bevacizumab: VEGF-C/VEGF-A RNA < Median Bevacizumab: VEGF-C/VEGF-A RNA ≥ Median
Hide Arm/Group Description:
Participants with VEGF-C/VEGF-A RNA ratio < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A RNA ratio ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A RNA ratio < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-C/VEGF-A RNA ratio ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 38 40 16 19
Measure Type: Number
Unit of Measure: participants
16 15 6 6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C/VEGF-A RNA < Median, Bevacizumab: VEGF-C/VEGF-A RNA < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.921
Confidence Interval (2-Sided) 95%
0.356 to 2.385
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-C/VEGF-A RNA ≥ Median, Bevacizumab: VEGF-C/VEGF-A RNA ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.220
Confidence Interval (2-Sided) 95%
0.462 to 3.220
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
20.Secondary Outcome
Title Progression-Free Survival Events by Tumor VEGF-D RNA Level
Hide Description

The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-D RNA level.

RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Full analysis set with available tumor biopsy RNA samples
Arm/Group Title Tivozanib: VEGF-D RNA < Median Tivozanib: VEGF-D RNA ≥ Median Bevacizumab: VEGF-D RNA < Median Bevacizumab: VEGF-D RNA ≥ Median
Hide Arm/Group Description:
Participants with VEGF-D RNA levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-D RNA levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-D RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with VEGF-D RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 42 36 14 21
Measure Type: Number
Unit of Measure: participants
16 15 5 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-D RNA < Median, Bevacizumab: VEGF-D RNA < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.915
Confidence Interval (2-Sided) 95%
0.334 to 2.512
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: VEGF-D RNA ≥ Median, Bevacizumab: VEGF-D RNA ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.384
Confidence Interval (2-Sided) 95%
0.554 to 3.455
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
21.Secondary Outcome
Title Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level
Hide Description

The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor PIGF RNA level.

RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.

Time Frame From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
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Hide Analysis Population Description
Full analysis set with available tumor biopsy RNA samples
Arm/Group Title Tivozanib: PIGF RNA < Median Tivozanib: PIGF RNA ≥ Median Bevacizumab: PIGF RNA < Median Bevacizumab: PIGF RNA ≥ Median
Hide Arm/Group Description:
Participants with PIGF RNA levels < median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with PIGF RNA levels ≥ median received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with PIGF RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Participants with PIGF RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Overall Number of Participants Analyzed 39 39 17 18
Measure Type: Number
Unit of Measure: participants
14 17 5 7
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Statistical Analysis Overview Comparison Group Selection Tivozanib: PIGF RNA < Median, Bevacizumab: PIGF RNA < Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.538
Confidence Interval (2-Sided) 95%
0.548 to 4.320
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tivozanib: PIGF RNA ≥ Median, Bevacizumab: PIGF RNA ≥ Median
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.744
Confidence Interval (2-Sided) 95%
0.299 to 1.850
Estimation Comments The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.
Time Frame From the first dose through 30 days after last dose of either tivozanib or bevacizumab, until the data cut-off date of 28 February 2014. The median duration of treatment was 168.0 days in the tivozanib arm and 162.0 days in the bevacizumab arm.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Hide Arm/Group Description Participants received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6) chemotherapy every 2 weeks on Days 1 and 15 of each cycle. Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
All-Cause Mortality
Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Affected / at Risk (%) Affected / at Risk (%)
Total   82/177 (46.33%)   42/87 (48.28%) 
Blood and lymphatic system disorders     
Febrile neutropenia  1  5/177 (2.82%)  2/87 (2.30%) 
Neutropenia  1  3/177 (1.69%)  1/87 (1.15%) 
Anaemia  1  2/177 (1.13%)  1/87 (1.15%) 
Agranulocytosis  1  1/177 (0.56%)  0/87 (0.00%) 
Thrombocytopenia  1  1/177 (0.56%)  0/87 (0.00%) 
Thrombotic thrombocytopenic purpura  1  0/177 (0.00%)  1/87 (1.15%) 
Cardiac disorders     
Cardiac failure  1  2/177 (1.13%)  0/87 (0.00%) 
Aortic valve disease  1  1/177 (0.56%)  0/87 (0.00%) 
Atrial fibrillation  1  1/177 (0.56%)  2/87 (2.30%) 
Cardiomyopathy  1  1/177 (0.56%)  0/87 (0.00%) 
Cardiopulmonary failure  1  1/177 (0.56%)  0/87 (0.00%) 
Intracardiac thrombus  1  1/177 (0.56%)  0/87 (0.00%) 
Sinus bradycardia  1  1/177 (0.56%)  0/87 (0.00%) 
Sinus tachycardia  1  1/177 (0.56%)  0/87 (0.00%) 
Tachycardia  1  1/177 (0.56%)  1/87 (1.15%) 
Endocrine disorders     
Hyperthyroidism  1  1/177 (0.56%)  0/87 (0.00%) 
Gastrointestinal disorders     
Diarrhoea  1  7/177 (3.95%)  5/87 (5.75%) 
Abdominal pain  1  5/177 (2.82%)  4/87 (4.60%) 
Vomiting  1  5/177 (2.82%)  0/87 (0.00%) 
Intestinal obstruction  1  4/177 (2.26%)  2/87 (2.30%) 
Nausea  1  3/177 (1.69%)  0/87 (0.00%) 
Ascites  1  2/177 (1.13%)  0/87 (0.00%) 
Stomatitis  1  2/177 (1.13%)  0/87 (0.00%) 
Abdominal distension  1  1/177 (0.56%)  1/87 (1.15%) 
Abdominal pain upper  1  1/177 (0.56%)  0/87 (0.00%) 
Anal ulcer  1  1/177 (0.56%)  0/87 (0.00%) 
Colitis  1  1/177 (0.56%)  0/87 (0.00%) 
Colonic obstruction  1  1/177 (0.56%)  1/87 (1.15%) 
Constipation  1  1/177 (0.56%)  1/87 (1.15%) 
Gastrointestinal haemorrhage  1  1/177 (0.56%)  0/87 (0.00%) 
Haemorrhoidal haemorrhage  1  1/177 (0.56%)  0/87 (0.00%) 
Ileus  1  1/177 (0.56%)  1/87 (1.15%) 
Large intestinal obstruction  1  1/177 (0.56%)  0/87 (0.00%) 
Small intestinal obstruction  1  1/177 (0.56%)  1/87 (1.15%) 
Enteritis  1  0/177 (0.00%)  1/87 (1.15%) 
Intestinal perforation  1  0/177 (0.00%)  1/87 (1.15%) 
Large intestine perforation  1  0/177 (0.00%)  1/87 (1.15%) 
Peritonitis  1  0/177 (0.00%)  1/87 (1.15%) 
Pneumatosis intestinalis  1  0/177 (0.00%)  1/87 (1.15%) 
General disorders     
Pyrexia  1  4/177 (2.26%)  7/87 (8.05%) 
Disease progression  1  3/177 (1.69%)  0/87 (0.00%) 
Asthenia  1  2/177 (1.13%)  0/87 (0.00%) 
Fatigue  1  2/177 (1.13%)  1/87 (1.15%) 
Catheter site erythema  1  1/177 (0.56%)  0/87 (0.00%) 
Device malfunction  1  1/177 (0.56%)  0/87 (0.00%) 
General physical health deterioration  1  1/177 (0.56%)  1/87 (1.15%) 
Localised oedema  1  1/177 (0.56%)  0/87 (0.00%) 
Oedema  1  1/177 (0.56%)  0/87 (0.00%) 
Stent malfunction  1  1/177 (0.56%)  0/87 (0.00%) 
Chest pain  1  0/177 (0.00%)  1/87 (1.15%) 
Malaise  1  0/177 (0.00%)  1/87 (1.15%) 
Mucosal inflammation  1  0/177 (0.00%)  1/87 (1.15%) 
Hepatobiliary disorders     
Bile duct stenosis  1  1/177 (0.56%)  0/87 (0.00%) 
Cholecystitis  1  1/177 (0.56%)  0/87 (0.00%) 
Jaundice cholestatic  1  1/177 (0.56%)  0/87 (0.00%) 
Hepatic haemorrhage  1  0/177 (0.00%)  1/87 (1.15%) 
Immune system disorders     
Drug hypersensitivity  1  1/177 (0.56%)  1/87 (1.15%) 
Hypersensitivity  1  1/177 (0.56%)  0/87 (0.00%) 
Infections and infestations     
Sepsis  1  4/177 (2.26%)  4/87 (4.60%) 
Lower respiratory tract infection  1  3/177 (1.69%)  1/87 (1.15%) 
Device related infection  1  2/177 (1.13%)  3/87 (3.45%) 
Arthritis bacterial  1  1/177 (0.56%)  0/87 (0.00%) 
Bacteraemia  1  1/177 (0.56%)  0/87 (0.00%) 
Gastroenteritis viral  1  1/177 (0.56%)  0/87 (0.00%) 
Infection  1  1/177 (0.56%)  2/87 (2.30%) 
Influenza  1  1/177 (0.56%)  1/87 (1.15%) 
Neutropenic sepsis  1  1/177 (0.56%)  0/87 (0.00%) 
Parotitis  1  1/177 (0.56%)  0/87 (0.00%) 
Perihepatic abscess  1  1/177 (0.56%)  0/87 (0.00%) 
Peritonitis bacterial  1  1/177 (0.56%)  0/87 (0.00%) 
Pneumonia  1  1/177 (0.56%)  1/87 (1.15%) 
Skin infection  1  1/177 (0.56%)  0/87 (0.00%) 
Staphylococcal infection  1  1/177 (0.56%)  0/87 (0.00%) 
Subcutaneous abscess  1  1/177 (0.56%)  0/87 (0.00%) 
Upper respiratory tract infection  1  1/177 (0.56%)  0/87 (0.00%) 
Urosepsis  1  1/177 (0.56%)  0/87 (0.00%) 
Wound infection  1  1/177 (0.56%)  0/87 (0.00%) 
Cellulitis  1  0/177 (0.00%)  1/87 (1.15%) 
Diverticulitis  1  0/177 (0.00%)  1/87 (1.15%) 
Enterocolitis viral  1  0/177 (0.00%)  1/87 (1.15%) 
Tooth abscess  1  0/177 (0.00%)  1/87 (1.15%) 
Urinary tract infection  1  0/177 (0.00%)  1/87 (1.15%) 
Injury, poisoning and procedural complications     
Overdose  1  1/177 (0.56%)  0/87 (0.00%) 
Wound necrosis  1  1/177 (0.56%)  0/87 (0.00%) 
Alcohol poisoning  1  0/177 (0.00%)  1/87 (1.15%) 
Laceration  1  0/177 (0.00%)  1/87 (1.15%) 
Investigations     
Alanine aminotransferase increased  1  1/177 (0.56%)  0/87 (0.00%) 
Blood lactate dehydrogenase increased  1  1/177 (0.56%)  0/87 (0.00%) 
C-reactive protein increased  1  1/177 (0.56%)  0/87 (0.00%) 
Heart rate increased  1  1/177 (0.56%)  0/87 (0.00%) 
International normalised ratio increased  1  1/177 (0.56%)  0/87 (0.00%) 
Platelet count decreased  1  1/177 (0.56%)  0/87 (0.00%) 
Troponin increased  1  1/177 (0.56%)  0/87 (0.00%) 
White blood cell count decreased  1  1/177 (0.56%)  0/87 (0.00%) 
Metabolism and nutrition disorders     
Cachexia  1  1/177 (0.56%)  0/87 (0.00%) 
Decreased appetite  1  1/177 (0.56%)  1/87 (1.15%) 
Dehydration  1  1/177 (0.56%)  1/87 (1.15%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/177 (0.56%)  0/87 (0.00%) 
Intervertebral disc degeneration  1  1/177 (0.56%)  0/87 (0.00%) 
Mobility decreased  1  1/177 (0.56%)  0/87 (0.00%) 
Flank pain  1  0/177 (0.00%)  1/87 (1.15%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Angiomyolipoma  1  1/177 (0.56%)  0/87 (0.00%) 
Cancer pain  1  1/177 (0.56%)  0/87 (0.00%) 
Duodenal neoplasm  1  1/177 (0.56%)  0/87 (0.00%) 
Nervous system disorders     
Reversible posterior leukoencephalopathy syndrome  1  2/177 (1.13%)  0/87 (0.00%) 
Transient ischaemic attack  1  2/177 (1.13%)  0/87 (0.00%) 
Aphasia  1  1/177 (0.56%)  0/87 (0.00%) 
Cerebral haemorrhage  1  1/177 (0.56%)  0/87 (0.00%) 
Headache  1  1/177 (0.56%)  1/87 (1.15%) 
Monoparesis  1  1/177 (0.56%)  0/87 (0.00%) 
Neuropathy peripheral  1  1/177 (0.56%)  0/87 (0.00%) 
Syncope  1  1/177 (0.56%)  1/87 (1.15%) 
Amnesia  1  0/177 (0.00%)  1/87 (1.15%) 
Psychiatric disorders     
Confusional state  1  1/177 (0.56%)  1/87 (1.15%) 
Delirium  1  1/177 (0.56%)  1/87 (1.15%) 
Depression  1  1/177 (0.56%)  0/87 (0.00%) 
Renal and urinary disorders     
Hydronephrosis  1  1/177 (0.56%)  0/87 (0.00%) 
Renal failure  1  1/177 (0.56%)  1/87 (1.15%) 
Renal failure acute  1  0/177 (0.00%)  2/87 (2.30%) 
Reproductive system and breast disorders     
Vaginal fistula  1  1/177 (0.56%)  0/87 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism  1  7/177 (3.95%)  0/87 (0.00%) 
Dyspnoea  1  3/177 (1.69%)  0/87 (0.00%) 
Epistaxis  1  1/177 (0.56%)  0/87 (0.00%) 
Hypoxia  1  1/177 (0.56%)  0/87 (0.00%) 
Pneumonia aspiration  1  1/177 (0.56%)  0/87 (0.00%) 
Pulmonary haemorrhage  1  1/177 (0.56%)  0/87 (0.00%) 
Respiratory failure  1  1/177 (0.56%)  0/87 (0.00%) 
Pneumonitis  1  0/177 (0.00%)  1/87 (1.15%) 
Surgical and medical procedures     
Anorectal operation  1  1/177 (0.56%)  0/87 (0.00%) 
Chemotherapy  1  1/177 (0.56%)  0/87 (0.00%) 
Vascular disorders     
Hypertension  1  4/177 (2.26%)  0/87 (0.00%) 
Deep vein thrombosis  1  3/177 (1.69%)  1/87 (1.15%) 
Thrombosis  1  2/177 (1.13%)  0/87 (0.00%) 
Hypertensive emergency  1  1/177 (0.56%)  0/87 (0.00%) 
Subclavian vein thrombosis  1  1/177 (0.56%)  0/87 (0.00%) 
Venous thrombosis  1  1/177 (0.56%)  0/87 (0.00%) 
Embolism  1  0/177 (0.00%)  1/87 (1.15%) 
Hypertensive crisis  1  0/177 (0.00%)  1/87 (1.15%) 
Jugular vein thrombosis  1  0/177 (0.00%)  2/87 (2.30%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
Affected / at Risk (%) Affected / at Risk (%)
Total   175/177 (98.87%)   85/87 (97.70%) 
Blood and lymphatic system disorders     
Neutropenia  1  93/177 (52.54%)  36/87 (41.38%) 
Thrombocytopenia  1  54/177 (30.51%)  13/87 (14.94%) 
Anaemia  1  20/177 (11.30%)  9/87 (10.34%) 
Leukopenia  1  19/177 (10.73%)  9/87 (10.34%) 
Endocrine disorders     
Hypothyroidism  1  25/177 (14.12%)  1/87 (1.15%) 
Eye disorders     
Conjunctivitis  1  3/177 (1.69%)  5/87 (5.75%) 
Gastrointestinal disorders     
Diarrhoea  1  101/177 (57.06%)  49/87 (56.32%) 
Nausea  1  97/177 (54.80%)  47/87 (54.02%) 
Vomiting  1  59/177 (33.33%)  24/87 (27.59%) 
Constipation  1  50/177 (28.25%)  32/87 (36.78%) 
Abdominal pain  1  42/177 (23.73%)  16/87 (18.39%) 
Stomatitis  1  36/177 (20.34%)  14/87 (16.09%) 
Dyspepsia  1  23/177 (12.99%)  9/87 (10.34%) 
Abdominal pain upper  1  13/177 (7.34%)  8/87 (9.20%) 
Aphthous stomatitis  1  9/177 (5.08%)  1/87 (1.15%) 
Dry mouth  1  9/177 (5.08%)  2/87 (2.30%) 
Dysphagia  1  9/177 (5.08%)  3/87 (3.45%) 
Rectal haemorrhage  1  7/177 (3.95%)  5/87 (5.75%) 
Flatulence  1  6/177 (3.39%)  5/87 (5.75%) 
General disorders     
Fatigue  1  95/177 (53.67%)  45/87 (51.72%) 
Mucosal inflammation  1  40/177 (22.60%)  28/87 (32.18%) 
Asthenia  1  37/177 (20.90%)  17/87 (19.54%) 
Pyrexia  1  17/177 (9.60%)  13/87 (14.94%) 
Oedema peripheral  1  14/177 (7.91%)  6/87 (6.90%) 
Temperature intolerance  1  11/177 (6.21%)  9/87 (10.34%) 
Infusion related reaction  1  9/177 (5.08%)  3/87 (3.45%) 
Pain  1  5/177 (2.82%)  5/87 (5.75%) 
Chest pain  1  2/177 (1.13%)  5/87 (5.75%) 
Immune system disorders     
Hypersensitivity  1  3/177 (1.69%)  6/87 (6.90%) 
Infections and infestations     
Urinary tract infection  1  19/177 (10.73%)  11/87 (12.64%) 
Nasopharyngitis  1  8/177 (4.52%)  6/87 (6.90%) 
Upper respiratory tract infection  1  6/177 (3.39%)  5/87 (5.75%) 
Investigations     
Weight decreased  1  34/177 (19.21%)  7/87 (8.05%) 
Neutrophil count decreased  1  14/177 (7.91%)  8/87 (9.20%) 
Alanine aminotransferase increased  1  10/177 (5.65%)  3/87 (3.45%) 
Aspartate aminotransferase increased  1  10/177 (5.65%)  4/87 (4.60%) 
Platelet count decreased  1  10/177 (5.65%)  3/87 (3.45%) 
Blood thyroid stimulating hormone increased  1  9/177 (5.08%)  0/87 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  63/177 (35.59%)  24/87 (27.59%) 
Hypokalaemia  1  20/177 (11.30%)  13/87 (14.94%) 
Hypomagnesaemia  1  12/177 (6.78%)  2/87 (2.30%) 
Dehydration  1  10/177 (5.65%)  7/87 (8.05%) 
Hyperglycaemia  1  8/177 (4.52%)  5/87 (5.75%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  26/177 (14.69%)  12/87 (13.79%) 
Pain in extremity  1  11/177 (6.21%)  6/87 (6.90%) 
Arthralgia  1  10/177 (5.65%)  5/87 (5.75%) 
Myalgia  1  5/177 (2.82%)  5/87 (5.75%) 
Muscle spasms  1  3/177 (1.69%)  5/87 (5.75%) 
Neck pain  1  2/177 (1.13%)  6/87 (6.90%) 
Nervous system disorders     
Neuropathy peripheral  1  74/177 (41.81%)  34/87 (39.08%) 
Paraesthesia  1  46/177 (25.99%)  20/87 (22.99%) 
Headache  1  28/177 (15.82%)  12/87 (13.79%) 
Dysgeusia  1  26/177 (14.69%)  18/87 (20.69%) 
Peripheral sensory neuropathy  1  21/177 (11.86%)  13/87 (14.94%) 
Dizziness  1  17/177 (9.60%)  6/87 (6.90%) 
Dysaesthesia  1  12/177 (6.78%)  5/87 (5.75%) 
Lethargy  1  11/177 (6.21%)  3/87 (3.45%) 
Neurotoxicity  1  10/177 (5.65%)  3/87 (3.45%) 
Hypoaesthesia  1  5/177 (2.82%)  5/87 (5.75%) 
Amnesia  1  1/177 (0.56%)  5/87 (5.75%) 
Psychiatric disorders     
Insomnia  1  23/177 (12.99%)  15/87 (17.24%) 
Anxiety  1  8/177 (4.52%)  6/87 (6.90%) 
Renal and urinary disorders     
Proteinuria  1  19/177 (10.73%)  5/87 (5.75%) 
Respiratory, thoracic and mediastinal disorders     
Dysphonia  1  42/177 (23.73%)  13/87 (14.94%) 
Epistaxis  1  33/177 (18.64%)  25/87 (28.74%) 
Dyspnoea  1  26/177 (14.69%)  13/87 (14.94%) 
Cough  1  20/177 (11.30%)  12/87 (13.79%) 
Oropharyngeal pain  1  16/177 (9.04%)  6/87 (6.90%) 
Hiccups  1  10/177 (5.65%)  2/87 (2.30%) 
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysaesthesia syndrome  1  34/177 (19.21%)  7/87 (8.05%) 
Alopecia  1  18/177 (10.17%)  14/87 (16.09%) 
Rash  1  16/177 (9.04%)  4/87 (4.60%) 
Pruritus  1  7/177 (3.95%)  7/87 (8.05%) 
Hyperhidrosis  1  1/177 (0.56%)  5/87 (5.75%) 
Vascular disorders     
Hypertension  1  77/177 (43.50%)  25/87 (28.74%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data or after 18 months after database lock, whichever comes first. Sponsor must receive a site’s manuscript at least 30 days prior to publication for review and comment. Sponsor may delay the publication for up to 60 days to seek patent protection.
Results Point of Contact
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Name/Title: Medical Director
Organization: AVEO
Phone: 1.617.588.1960
EMail: clinical@aveooncology.com
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Responsible Party: AVEO Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01478594     History of Changes
Other Study ID Numbers: 4130-CL-0201
2011-003502-24 ( EudraCT Number )
First Submitted: November 21, 2011
First Posted: November 23, 2011
Results First Submitted: February 19, 2015
Results First Posted: April 3, 2015
Last Update Posted: July 8, 2015