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)

• 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: Sanofi
• Collaborators: Regeneron Pharmaceuticals; NSABP Foundation Inc
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: November 20, 2007
• First Posted Date: November 21, 2007
• Results First Submitted Date: August 17, 2012
• Results First Posted Date: September 28, 2012
• Last Update Posted Date: September 28, 2012
• Study Start Date: November 2007
• Actual Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 27, 2012)

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.

• Original Primary Outcome Measures (submitted: November 20, 2007): Overall Survival

Current Secondary Outcome Measures (submitted: September 27, 2012)

• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: November 20, 2007)

• Progression Free Survival
• Tumor Response Rate [ Time Frame: every 6 weeks up to disease progression ]
• Safety [ Time Frame: every 2 weeks while on treatment ]
• Immunogenicity [ Time Frame: up to 90 days post last dose of study drug ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Colorectal Neoplasms
• Neoplasm Metastasis

Intervention

• 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: 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 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
• 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

Study Arms

• 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
  Interventions:

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

  • Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
  • Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

Publications *

• Lu L, Dercle L, Zhao B, Schwartz LH. Deep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging. Nat Commun. 2021 Nov 17;12(1):6654. doi: 10.1038/s41467-021-26990-6.
• Chau I, Fakih M, Garcia-Alfonso P, Linke Z, Ruiz Casado A, Marques EP, Picard P, Celanovic M, Cartwright T. Safety and Effectiveness of Aflibercept + Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) for the Treatment of Patients with Metastatic Colorectal Cancer (mCRC) in Current Clinical Practice: OZONE Study. Cancers (Basel). 2020 Mar 11;12(3):657. doi: 10.3390/cancers12030657.
• Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. doi: 10.1016/j.jgo.2017.07.010. Epub 2017 Aug 12.
• Stanel SC, Sjoberg J, Salmonson T, Foggi P, Caleno M, Melchiorri D, Gravanis I, Tzogani K, Pignatti F. European Medicines Agency approval summary: Zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer. ESMO Open. 2017 May 2;2(2):e000190. doi: 10.1136/esmoopen-2017-000190. eCollection 2017.
• Van Cutsem E, Joulain F, Hoff PM, Mitchell E, Ruff P, Lakomy R, Prausova J, Moiseyenko VM, van Hazel G, Cunningham D, Arnold D, Schmoll HJ, Ten Tije AJ, McKendrick J, Kroning H, Humblet Y, Gravalos C, Le-Guennec S, Andria M, Dochy E, Vishwanath RL, Macarulla T, Tabernero J. Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy. Target Oncol. 2016 Jun;11(3):383-400. doi: 10.1007/s11523-015-0402-9.
• Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. doi: 10.1016/j.ejca.2013.09.013. Epub 2013 Oct 16.
• Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. doi: 10.1200/JCO.2012.42.8201. Epub 2012 Sep 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 14, 2012): 1226
• Original Estimated Enrollment (submitted: November 20, 2007): 1200
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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

Administrative Information

• NCT Number: NCT00561470
• Other Study ID Numbers: EFC10262; EudraCT 2007-000820-42
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi
• Original Responsible Party: Not Provided
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current

Collaborators

• Regeneron Pharmaceuticals
• NSABP Foundation Inc

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: March 2012