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

Sanofi1,226 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

1,226

Conditions

Colorectal Neoplasms

Interventions

PlaceboDRUG

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

Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)DRUG

4 mg/kg of Aflibercept was administered IV over 1 hour on Day 1, every 2 weeks.

FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)DRUG

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

FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)DRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

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

Outcomes

Primary Outcomes

Overall Survival (OS)

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)

Secondary Outcomes

Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)

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)

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

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)

Number of Participants With Adverse Events (AE)

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

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

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