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

History of Changes

Results First Received: August 17, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Care Provider, 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Consent Withdrawn	2	6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

Gender, Customized
[Units: Participants]

Male

353

365

718

Female

261

247

508

Race/Ethnicity, Customized
[Units: Participants]

Caucasian/White

523

548

1071

Black

Asian/Oriental

Other

Region of Enrollment
[Units: Participants]

ARGENTINA

AUSTRALIA

AUSTRIA

BELGIUM

BRAZIL

CHILE

CZECH REPUBLIC

DENMARK

ESTONIA

FRANCE

GERMANY

GREECE

ITALY

KOREA, REPUBLIC OF

NETHERLANDS

NEW ZEALAND

NORWAY

POLAND

PUERTO RICO

ROMANIA

RUSSIAN FEDERATION

SOUTH AFRICA

SPAIN

SWEDEN

TURKEY

UKRAINE

UNITED KINGDOM

UNITED STATES

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

500

Participants with ECOG Score = 2

^[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

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)

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
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Stratified Log-Rank test
P Value ^[4]	0.0032
Stratified Hazard Ratio ^[5]	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]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	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.
[5]	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)

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
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Stratified Log-Rank test
P Value ^[4]	0.00007
Stratified Hazard ratio ^[5]	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]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	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
[5]	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)

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
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Stratified Cochran-Mantel-Haenszel
P Value ^[4]	0.0001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	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.
[4]	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

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

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

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Other Adverse Events

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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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