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:
Sanofi
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
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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
Hide Participant Flow
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 |
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| 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| Consent Withdrawn | 2 | 6 |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
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 | |
|---|---|---|---|
|
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] |
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| <65 years | 376 | 407 | 783 |
| >=65 but <75 years | 199 | 172 | 371 |
| >=75 years | 39 | 33 | 72 |
|
Gender, Customized
[units: participants] |
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| Male | 353 | 365 | 718 |
| Female | 261 | 247 | 508 |
|
Race/Ethnicity, Customized
[units: participants] |
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| Caucasian/White | 523 | 548 | 1071 |
| Black | 27 | 16 | 43 |
| Asian/Oriental | 51 | 35 | 86 |
| Other | 13 | 13 | 26 |
|
Region of Enrollment
[units: participants] |
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| 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] |
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| 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
| 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 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 | |
|---|---|---|
|
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 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.
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 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 | |
|---|---|---|
|
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
Show Serious Adverse Events
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. |