TriangleNCT00561470 · CITED IN SOURCE DOCUMENTS
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
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2012-09-28
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.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Overall Survival (OS)
Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)
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
Number of Participants With Adverse Events (AE)
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
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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.
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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
- intervention Names
- Drug: Placebo
- Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
- label
- Placebo/FOLFIRI
- type
- PLACEBO_COMPARATOR
- description
- 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
- intervention Names
- Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
- Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
- label
- Aflibercept/FOLFIRI
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Placebo/FOLFIRI
- description
- 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
- name
- Placebo
- type
- DRUG
- arm Group Labels
- Aflibercept/FOLFIRI
- description
- 4 mg/kg of Aflibercept was administered IV over 1 hour on Day 1, every 2 weeks.
- name
- Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
- type
- DRUG
- arm Group Labels
- Placebo/FOLFIRI
- description
- 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
- name
- FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
- type
- DRUG
- arm Group Labels
- Aflibercept/FOLFIRI
- description
- 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
- name
- FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- TRIPLE
- who Masked
- PARTICIPANT
- CARE_PROVIDER
- INVESTIGATOR
- primary Purpose
- TREATMENT
Enrollment
- count
- 1226
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- 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.
- measure
- 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)
- secondary Outcomes
- 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.
- measure
- 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)
- 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.
- measure
- 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)
- 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.
- measure
- 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
- 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.
- measure
- 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
Full study description
- 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
Source references
- references
- citation
- Pu T, Peddle AM, Wirapati P, Tsantoulis P, Wu Q, Hong Y, Samuel L, Desai J, Riener M, Saridaki Z, Cunningham D, Tejpar S. Exploratory biomarker analysis of RAS/BRAF somatic mutations and gene expression signatures for predicting treatment effects of aflibercept in the velour trial. NPJ Precis Oncol. 2026 Jan 13;10(1):50. doi: 10.1038/s41698-025-01253-5.
- pmid
- 41530374
- type
- DERIVED
- citation
- Wazan LE, Widhibrata A, Liu GS. Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications. Angiogenesis. 2024 Nov;27(4):641-661. doi: 10.1007/s10456-024-09942-8. Epub 2024 Aug 29.
- pmid
- 39207600
- type
- DERIVED
- citation
- 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.
- pmid
- 34789774
- type
- DERIVED
- citation
- 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.
- pmid
- 32168980
- type
- DERIVED
- citation
- 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.
- pmid
- 28807738
- type
- DERIVED
- citation
- 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.
- pmid
- 28761750
- type
- DERIVED
- citation
- 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.
- pmid
- 26706237
- type
- DERIVED
- citation
- 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.
- pmid
- 24140268
- type
- DERIVED
- citation
- 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.
- pmid
- 22949147
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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Preserved source evidence · Not medical advice