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Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen (VELOUR)

This study has been completed.
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
National Surgical Adjuvant Breast and Bowel Project (NSABP)
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00561470
First received: November 20, 2007
Last updated: September 27, 2012
Last verified: March 2012
History of Changes
Results First Received: August 17, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Conditions: Colorectal Neoplasms
Neoplasm Metastasis
Interventions: Drug: Placebo
Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

  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
Between 19 November 2007 and 16 March 2010, 614 participants were randomized to the placebo arm and 612 participants were randomized to the aflibercept arm.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Participant Flow:   Overall Study
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
STARTED     614     612  
TREATED     609     607  
SAFETY POPULATION     605 [1]   611 [2]
ONGOING TREATMENT     11 [3]   14 [3]
COMPLETED     0 [4]   0 [4]
NOT COMPLETED     614     612  
Adverse Event                 74                 163  
Disease progression                 437                 305  
poor compliance to protocol                 4                 4  
Lost to Follow-up                 2                 0  
Physician Decision                 21                 20  
Consent Withdrawn                 2                 6  
Subject request                 43                 77  
Metastatic surgery                 10                 12  
Unauthorized procedure                 3                 1  
Randomized but not treated                 5                 5  
Missed visit window                 1                 4  
Planning surgery                 1                 1  
Ongoing Treatment                 11                 14  
[1] Treated participants excluding 4 who received at least 1 dose of Aflibercept
[2] Treated participants including 4 from Placebo/FOLFIRI who received at least 1 dose of Aflibercept
[3] Participants continuing treatment on the cutoff date of the final analysis
[4] Participants met treatment discontinuation criteria or were ongoing treatment on the cutoff date



  Baseline Characteristics
  Hide Baseline Characteristics

Reporting Groups
  Description
Placebo/Folfiri Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)
Aflibercept/Folfiri Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)
Total Total of all reporting groups

Baseline Measures
    Placebo/Folfiri     Aflibercept/Folfiri     Total  
Number of Participants  
[units: participants]
 		  614     612     1226  
Age  
[units: years]
Mean ± Standard Deviation 		  60.2  ± 10.8     59.5  ± 10.5     59.8  ± 10.7  
Age, Customized  
[units: participants]
 		     
<65 years     376     407     783  
>=65 but <75 years     199     172     371  
>=75 years     39     33     72  
Gender, Customized  
[units: participants]
 		     
Male     353     365     718  
Female     261     247     508  
Race/Ethnicity, Customized  
[units: participants]
 		     
Caucasian/White     523     548     1071  
Black     27     16     43  
Asian/Oriental     51     35     86  
Other     13     13     26  
Region of Enrollment  
[units: participants]
 		     
ARGENTINA     4     2     6  
AUSTRALIA     42     54     96  
AUSTRIA     3     4     7  
BELGIUM     37     45     82  
BRAZIL     21     27     48  
CHILE     31     33     64  
CZECH REPUBLIC     30     47     77  
DENMARK     9     6     15  
ESTONIA     7     3     10  
FRANCE     1     1     2  
GERMANY     23     12     35  
GREECE     9     10     19  
ITALY     26     23     49  
KOREA, REPUBLIC OF     39     26     65  
NETHERLANDS     20     14     34  
NEW ZEALAND     13     7     20  
NORWAY     14     19     33  
POLAND     24     32     56  
PUERTO RICO     4     2     6  
ROMANIA     16     16     32  
RUSSIAN FEDERATION     35     40     75  
SOUTH AFRICA     36     31     67  
SPAIN     27     28     55  
SWEDEN     10     4     14  
TURKEY     4     2     6  
UKRAINE     11     11     22  
UNITED KINGDOM     47     52     99  
UNITED STATES     71     61     132  
Eastern Cooperative Oncology Group (ECOG) performance status score [1]
[units: participants]
 		     
Participants with ECOG Score = 0     350     349     699  
Participants with ECOG Score = 1     250     250     500  
Participants with ECOG Score = 2     14     13     27  
Prior Bevacizumab [2]
[units: participants]
 		     
Yes     187     186     373  
No     427     426     853  
[1] The ECOG score assesses how the disease affects a participant's daily living abilities. It ranges from 0-5, with 0 being the best and 5 being the worst outcome. "0" reflects a fully active participant, able to carry on all pre-disease performance without restriction. "1" reflects a participant restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. "2" reflects an ambulatory participant, who is up and about more than 50% of waking hours, and capable of all self-care but unable to carry out any work activities.
[2] Number of participants randomized in the prior bevacizumab stratum as per the interactive voice response system (IVRS).



  Outcome Measures
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1.  Primary:   Overall Survival (OS)   [ Time Frame: From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years) ]

Measure Type Primary
Measure Title Overall Survival (OS)
Measure Description

Overall Survival was the time interval from the date of randomization to the date of death due to any cause. Once disease progression was documented, participants were followed every 2 months for survival status, until death or until the study cutoff date, whichever came first. The final data cutoff date for the analysis of OS was the date when 863 deaths had occurred (07 February 2011).

OS was estimated using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model.
Time Frame From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years)  
Safety Issue No  

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.
Intent-to-treat population (ITT) – all participants who gave informed consent and were randomized.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Measured Values
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Number of Participants Analyzed  
[units: participants]
 		  614     612  
Number of Events (Death) Analyzed  
[units: Events (Death)]
 		  460     403  
Overall Survival (OS)  
[units: months]
Median ( Inter-Quartile Range ) 		  12.06  
  ( 6.83 to 21.03 )   		  13.50  
  ( 7.62 to 25.59 )  


Statistical Analysis 1 for Overall Survival (OS)
Groups [1] All groups
Method [2] Stratified Log-Rank test
P Value [3] 0.0032
Stratified Hazard Ratio [4] 0.817
95.34% Confidence Interval ( 0.713 to 0.937 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified Log-Rank test p-value. Stratified on ECOG Performance Status and prior Bevacizumab according to IVRS using the Cox Proportional Hazard Model. Significance threshold was set to 0.0466 using the O'Brien-Fleming alpha spending function.
[4] Other relevant estimation information:
  Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS using the Cox Proportional Hazard Model. Significance threshold was set to 0.0466 using the O'Brien-Fleming alpha spending function.



2.  Secondary:   Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)   [ Time Frame: From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months) ]

Measure Type Secondary
Measure Title Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)
Measure Description

PFS was the time interval from the date of randomization to the date of progression, or death from any cause if it occurs before tumor progression is documented. To evaluate disease progression, copies of all tumor imaging sets were systematically collected and assessed by the IRC.

PFS was analyzed using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model.

The analysis for PFS was performed as planned when 561 deaths (OS events) had occurred.
Time Frame From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months)  
Safety Issue No  

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.
Intent to Treat (ITT) population included all participants who gave informed consent and were randomized.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Measured Values
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Number of Participants Analyzed  
[units: participants]
 		  614     612  
Number of First PFS Events Analyzed  
[units: First PFS Events]
 		  454     393  
Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)  
[units: months]
Median ( Inter-Quartile Range ) 		  4.67  
  ( 2.60 to 9.10 )   		  6.90  
  ( 3.84 to 10.05 )  


Statistical Analysis 1 for Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)
Groups [1] All groups
Method [2] Stratified Log-Rank test
P Value [3] 0.00007
Stratified Hazard ratio [4] 0.758
99.99% Confidence Interval ( 0.578 to 0.995 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS
[4] Other relevant estimation information:
  Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS using the Cox Proportional Hazard Model.



3.  Secondary:   Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria   [ Time Frame: From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months) ]

Measure Type Secondary
Measure Title Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria
Measure Description

The overall ORR was the percentage of evaluable participants who achieved complete response [CR] or partial response [PR] according to RECIST criteria version 1.0.

  • CR reflected the disappearance of all tumor lesions (with no new tumors)
  • PR reflected a pre-defined reduction in tumor burden

Tumors were assessed by the IRC using Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and an observed response was confirmed by repeated imaging after 4 – 6 weeks.
Time Frame From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months)  
Safety Issue No  

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.
The evaluable patient population (EPP) for tumor response included all randomized participants with measurable disease at study entry, as per IRC evaluation, and with at least one valid post-baseline tumor evaluation.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Measured Values
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Number of Participants Analyzed  
[units: participants]
 		  530     531  
Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria  
[units: percentage of participants]
Number ( 95% Confidence Interval ) 		  11.1  
  ( 8.5 to 13.8 )   		  19.8  
  ( 16.4 to 23.2 )  


Statistical Analysis 1 for Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria
Groups [1] All groups
Method [2] Stratified Cochran-Mantel-Haenszel
P Value [3] 0.0001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  Stratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no) according to IVRS.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



4.  Secondary:   Number of Participants With Adverse Events (AE)   [ Time Frame: From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized ]

Measure Type Secondary
Measure Title Number of Participants With Adverse Events (AE)
Measure Description

All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 30 days after the last administration of study treatment, were recorded, and followed until resolution or stabilization.

The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported.
Time Frame From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized  
Safety Issue Yes  

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.
The safety population was the subset of the ITT population that took at least one dose of study treatment. Analyses was based on the treatment actually received (any participant who received at least one dose of aflibercept, even when receiving the rest of study treatment with placebo, was counted in the aflibercept treatment arm).

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Measured Values
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Number of Participants Analyzed  
[units: participants]
 		  605     611  
Number of Participants With Adverse Events (AE)  
[units: participants]
 		   
Treatment-Emergent Adverse Event (TEAE)     592     606  
Serious TEAE     198     294  
TEAE leading to Death     29     37  
TEAE causing permanent treatment discontinuation     73     164  

No statistical analysis provided for Number of Participants With Adverse Events (AE)



5.  Secondary:   Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay   [ Time Frame: Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo ]

Measure Type Secondary
Measure Title Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay
Measure Description Serum samples for immunogenicity assessment were analyzed using a bridging immunoassay to detect ADA. Positive samples in the ADA assay were further analyzed in the NAb assay using a validated, non-quantitative ligand binding assay.
Time Frame Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo  
Safety Issue No  

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.
Immunogenicity population included all participants who were treated and tested for immunogenicity at least once post-baseline.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered Aflibercept and FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

Measured Values
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Number of Participants Analyzed  
[units: participants]
 		  526     521  
Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay  
[units: participants]
 		   
At least one positive sample in the ADA assay     18     8  
At least one positive sample in the NAb assay     2     1  

No statistical analysis provided for Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay




  Serious Adverse Events
  Show Serious Adverse Events


  Other Adverse Events
  Show Other Adverse Events


  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.


Limitations and Caveats
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
No text entered.  


Results Point of Contact:  
Name/Title: International Clinical Development Study Director
Organization: sanofi-aventis
e-mail: contact-us@sanofi.com


No publications provided


Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00561470     History of Changes
Other Study ID Numbers: EFC10262, EudraCT 2007-000820-42
Study First Received: November 20, 2007
Results First Received: August 17, 2012
Last Updated: September 27, 2012
Health Authority: United States: Food and Drug Administration
Spain: Spanish Agency of Medicines
Australia: Department of Health and Ageing Therapeutic Goods Administration