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Trial record 1 of 1 for:    4130-CL-0201
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A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01478594
First Posted: November 23, 2011
Last Update Posted: July 8, 2015
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.
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.
Results First Submitted: February 19, 2015  
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

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
Tivozanib + mFOLFOX6 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.
Bevacizumab + mFOLFOX6 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.

Participant Flow:   Overall Study
    Tivozanib + mFOLFOX6   Bevacizumab + mFOLFOX6
STARTED   177   88 
Treated   177   87 
COMPLETED   112 [1]   60 [1] 
NOT COMPLETED   65   28 
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



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Tivozanib + mFOLFOX6 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.
Bevacizumab + mFOLFOX6 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 Total of all reporting groups

Baseline Measures
   Tivozanib + mFOLFOX6   Bevacizumab + mFOLFOX6   Total 
Overall Participants Analyzed 
[Units: Participants]
 177   88   265 
Age 
[Units: Years]
Mean (Standard Deviation)
 61.9  (9.58)   62.6  (11.17)   62.2  (10.12) 
Gender 
[Units: Participants]
     
Female   59   33   92 
Male   118   55   173 
Ethnicity (NIH/OMB) 
[Units: Participants]
     
Hispanic or Latino   6   2   8 
Not Hispanic or Latino   170   86   256 
Unknown or Not Reported   1   0   1 
Race/Ethnicity, Customized 
[Units: 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 
[Units: 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] 
[Units: 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] 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] 
[Units: Participants]
     
< 1.5 Upper Limit of Normal   127   64   191 
≥ 1.5 Upper Limit of Normal   50   24   74 
[1] The upper limit of normal (ULN) from the site was used.
Origin of Cancer 
[Units: Participants]
     
Rectal   53   24   77 
Colon   124   64   188 
Number of metastatic sites/organs 
[Units: Participants]
     
 56   30   86 
 80   34   114 
 29   21   50 
≥ 4   12   3   15 
Kirsten rat sarcoma (KRAS) Mutation Status 
[Units: Participants]
     
Wild-type   33   21   54 
Mutant   23   16   39 
Unknown   121   51   172 
Time Since Initial Diagnosis 
[Units: Months]
Mean (Standard Deviation)
 9.41  (20.473)   10.88  (21.055)   9.90  (20.640) 
Number of metastatic sites at screening 
[Units: Metastatic sites]
Mean (Standard Deviation)
 2.0  (1.02)   2.0  (0.85)   2.0  (0.97) 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Investigator-assessed Progression-Free Survival (PFS)   [ 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. ]

2.  Secondary:   Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)   [ Time Frame: 3 years ]

3.  Secondary:   Overall Survival (OS)   [ 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. ]

4.  Secondary:   Objective Response Rate (ORR)   [ 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. ]

5.  Secondary:   Duration of Response (DoR)   [ 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. ]

6.  Secondary:   Time to Treatment Failure (TTF)   [ 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. ]

7.  Secondary:   Health Related Quality of Life (HRQoL)   [ Time Frame: 3 years ]

8.  Secondary:   Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)   [ 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. ]

9.  Secondary:   Progression-free Survival Events by Lactate Dehydrogenase (LDH) 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. ]

10.  Secondary:   Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) 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. ]

11.  Secondary:   Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) 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. ]

12.  Secondary:   Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio   [ 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. ]

13.  Secondary:   Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) 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. ]

14.  Secondary:   Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) 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. ]

15.  Secondary:   Progression-Free Survival Events by Serum Interleukin-8 (IL-8) 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. ]

16.  Secondary:   Progression-Free Survival Events by Serum Neuropilin 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. ]

17.  Secondary:   Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) 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. ]

18.  Secondary:   Progression-Free Survival Events by Tumor VEGF-C RNA 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. ]

19.  Secondary:   Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio   [ 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. ]

20.  Secondary:   Progression-Free Survival Events by Tumor VEGF-D RNA 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. ]

21.  Secondary:   Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA 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. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: AVEO
phone: 1.617.588.1960
e-mail: clinical@aveooncology.com



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