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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)

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ClinicalTrials.gov Identifier: NCT00561470
Recruitment Status : Completed
First Posted : November 21, 2007
Results First Posted : September 28, 2012
Last Update Posted : September 28, 2012
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
NSABP Foundation Inc
Information provided by (Responsible Party):
Sanofi

Study Description
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Brief Summary:

The main objective of the study was to evaluate the effectiveness of aflibercept (versus placebo) in increasing the overall survival in participants with metastatic colorectal cancer treated with FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) and that have previously failed an oxaliplatin based treatment for metastatic disease.

The secondary objectives were to compare progression-free survival, to evaluate overall response rate, to evaluate the safety profile, to assess immunogenicity of intravenous (IV) aflibercept, and to assess pharmacokinetics of IV aflibercept in both treatment arms.


Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Neoplasm Metastasis Drug: Placebo Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) Phase 3

Detailed Description:

Participants were

  • randomized at baseline (treatment was initiated with 3 days of randomization)
  • administered treatment in cycles of 14-days till a study withdrawal criterion was met
  • followed up 30 days after discontinuation of treatment, and every 8 weeks until death or end of study.

The criteria for discontinuation of study treatment for a participant are:

  • participant (or legal representative) chose to withdraw from treatment

  • the investigator thought that continuation of the study would be detrimental to the participants well-being due to

    • disease progression
    • unacceptable AEs
    • intercurrent illnesses
    • non-compliance to the study protocol
  • participant was lost to follow-up
  • participant was unblinded for the investigational treatment
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1226 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multinational, Randomized, Double-blind Study, Comparing the Efficacy of Aflibercept Once Every 2 Weeks Versus Placebo in Patients With Metastatic Colorectal Cancer (MCRC) Treated With Irinotecan / 5-FU Combination (FOLFIRI) After Failure of an Oxaliplatin Based Regimen
Study Start Date : November 2007
Actual Primary Completion Date : February 2011
Actual Study Completion Date : June 2012

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo/FOLFIRI
Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met
 Drug: Placebo
4 mg/kg of sterile aqueous buffered vehicle (pH 6.0) was administered intra venously (IV) over 1 hour on Day 1, every 2 weeks

Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

The FOLFIRI regimen was initiated immediately after Placebo administration on Day 1

The FOLFIRI regimen included:

  • 180 mg/m² Irinotecan (Campto®, Camptosar®) IV infusion over 90 minutes and dl leucovorin 400 mg/m² (200 mg/m² for the l-isomer form) IV infusion over 2 hours, followed by:
  • 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by:
  • 5-FU 2400 mg/m² continuous IV infusion over 46-hours
Experimental: Aflibercept/FOLFIRI
Participants with Metastatic Colorectal Cancer administered Aflibercept followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met
 Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
4 mg/kg of Aflibercept was administered IV over 1 hour on Day 1, every 2 weeks.

Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

The FOLFIRI regimen was initiated immediately after Aflibercept administration on Day 1

The FOLFIRI regimen included:

  • 180 mg/m² Irinotecan (Campto®, Camptosar®) IV infusion over 90 minutes and dl leucovorin 400 mg/m² (200 mg/m² for the l-isomer form) IV infusion over 2 hours, followed by:
  • 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by:
  • 5-FU 2400 mg/m² continuous IV infusion over 46-hours


Outcome Measures
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Primary Outcome Measures :
  1. 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) ]

    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.



Secondary Outcome Measures :
  1. 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) ]

    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.


  2. 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) ]

    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.


  3. 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 ]

    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.


  4. 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 ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Participants who met the following main selection criteria were included in the study.

Inclusion Criteria:

  • Histologically or cytologically proven adenocarcinoma of the colon or rectum
  • Metastatic disease that is not amenable to potentially curative treatment
  • One and only one prior line of treatment for metastatic disease. This prior line should be an oxaliplatin based chemotherapy (participants who relapse within 6 months of completion of oxaliplatin based adjuvant chemotherapy are eligible)
  • Prior treatment with bevacizumab is permitted.

Exclusion Criteria:

  • Prior therapy with irinotecan
  • Eastern Cooperative Oncology Group performance status >2

The above information is not intended to contain all considerations relevant to participation in a clinical trial.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00561470


Locations
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Sponsors and Collaborators
Sanofi
Regeneron Pharmaceuticals
NSABP Foundation Inc
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00561470    
Other Study ID Numbers: EFC10262
EudraCT 2007-000820-42
First Posted: November 21, 2007    Key Record Dates
Results First Posted: September 28, 2012
Last Update Posted: September 28, 2012
Last Verified: March 2012
Keywords provided by Sanofi:
colorectal cancer
metastatic
anti-angiogenic
 irinotecan
5-FU
FOLFIRI
Additional relevant MeSH terms:
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Neoplasms
Colorectal Neoplasms
Neoplasm Metastasis
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Leucovorin
 Fluorouracil
Irinotecan
Aflibercept
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antidotes