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

Phase 3

Completed

• Conditions: Colorectal Neoplasms; Neoplasm Metastasis
• Interventions: Drug: Placebo; Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

• Registration Number: NCT00561470
• Lead Sponsor: Sanofi

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 Timeline

• Study Start: 2007-11
• Study First Submitted: 2007-11-20
• Study First Submitted QC: 2007-11-20
• Study First Posted: 2007-11-21
• Primary Completion: 2011-02
• Status Verified: 2012-03
• Disposition First Submitted: 2012-03-14
• Disposition First Submitted QC: 2012-03-14
• Disposition First Posted: 2012-03-16
• Study Completion: 2012-06
• Results First Submitted: 2012-08-17
• Results First Submitted QC: 2012-09-27
• Last Update Submitted: 2012-09-27
• Results First Posted: 2012-09-28
• Last Update Posted: 2012-09-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1226

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo/FOLFIRI	Placebo	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
Placebo/FOLFIRI	FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)	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
Aflibercept/FOLFIRI	Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	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
Aflibercept/FOLFIRI	FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)	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

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	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

Name	Time	Method
Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)	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	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)	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	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.

Trial Locations

Locations (221)

Sanofi-Aventis Investigational Site Number 840119; 🇺🇸 Birmingham, Alabama, United States

Sanofi-Aventis Investigational Site Number 840074; 🇺🇸 Muscle Shoals, Alabama, United States

Sanofi-Aventis Investigational Site Number 840093; 🇺🇸 Hot Springs, Arizona, United States

Sanofi-Aventis Investigational Site Number 840080; 🇺🇸 Anaheim, California, United States

Sanofi-Aventis Investigational Site Number 840076; 🇺🇸 Fountain Valley, California, United States

Sanofi-Aventis Investigational Site Number 840120; 🇺🇸 Fountain Valley, California, United States

Sanofi-Aventis Investigational Site Number 840073; 🇺🇸 Greenbrae, California, United States

Sanofi-Aventis Investigational Site Number 840101; 🇺🇸 Hayward, California, United States

Sanofi-Aventis Investigational Site Number 840046; 🇺🇸 La Jolla, California, United States

Sanofi-Aventis Investigational Site Number 840116; 🇺🇸 Loma Linda, California, United States

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