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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
NSABP Foundation Inc
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00561470
First received: November 20, 2007
Last updated: September 27, 2012
Last verified: March 2012
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Consent Withdrawn                2                6 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
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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
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 
Overall Participants Analyzed 
[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 
[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.
Prior Bevacizumab [1] 
[Units: Participants]
     
Yes   187   186   373 
No   427   426   853 
[1] 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 
Participants Analyzed 
[Units: Participants]
 614   612 
Units Analyzed (Events (Death)) 
[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 method 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 
Participants Analyzed 
[Units: Participants]
 614   612 
Units Analyzed (First PFS Events) 
[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 method 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 
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 method 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 
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 
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


  Other Adverse Events


  Limitations and Caveats
  Hide 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.


  More Information