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Irinotecan

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Aflibercept

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Aflibercept 4 mg/kg intravenous (IV) infusion (1-2 hours) on Day 1 of Cycle 1 and every 2 weeks (q2w) thereafter, in combination with FOLFIRI regimen on Days 1-3 of Cycle 1 and q2w thereafter until disease progression (DP), unacceptable toxicity or participant's refusal. FOLFIRI regimen: IV infusions of levofolinate 200 mg/m\^2 (2 hours) and irinotecan 180 mg/m\^2 (90 minutes) simultaneously, followed by 5-FU 400 mg/m\^2 IV bolus injection followed by continuous IV infusion of 5-FU (46 hours) at 2400 mg/m\^2.

Pharmaceutical form: Concentrated solution (100 mg/4 mL \[25 mg/mL\], 200 mg/8 mL \[25 mg/mL\]) for infusion; Route of administration: Intravenous

Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous

Levofolinate

5-FU

Clinical Sciences & Operations

Primary Objective:

To assess efficacy aflibercept + 5-fluorouracil (5-FU)/levofolinate/irinotecan (FOLFIRI) by objective response rate (ORR).

Secondary Objective:

To assess the following:

* safety profile;
* progression free survival (PFS);
* overall survival (OS);
* pharmacokinetics (PK);
* immunogenicity.

Screening was up to 24 days. Treatment period was continued until DP, unacceptable toxicity, or participant's refusal. Follow up period was continued until death, participant's refusal, or end of study, whichever came first.

This trial was conducted in Japan, where the International Nonproprietary Name (INN) designation for the study molecule is "aflibercept" and this term is therefore used throughout the synopsis. In the US, the US proper name is "ziv-aflibercept".

A Study of Aflibercept in Combination With FOLFIRI in Patients With Second-Line Metastatic Colorectal Cancer in Japan

A Single-Arm Phase II Study in Japan to Assess the Efficacy and Safety of Aflibercept Administered Every Two Weeks in Combination With FOLFIRI in Patients With Metastatic Colorectal Cancer Who Progressed During or Following an Oxaliplatin-Based Regimen

Overall response in participants was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) assessed by an independent radiological review committee (IRRC) according to response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as disappearance of all target lesions; any lymph node (target or non-target) must have reduction in the short axis to \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Percentage of participants with overall response and the 95% confidence interval (CI) were provided. The 95% CI was calculated using normal approximation.

PFS was defined as the time interval from the date of first study drug administration to the date of first observation of DP or death due to any cause, whichever came first. If death or progression was not observed, the participant was censored at the date of participant's last valid progression-free tumor assessment prior to the study cut-off date. DP for PFS was assessed by the IRRC based on tumor imaging according to RECIST 1.1. Progression in disease was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study with absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated by Kaplan-Meier estimates.

OS was defined as the time interval from the date of first study drug administration to the date of death due to any cause. If death was not observed, the participant was censored at the last date the participant was known to be alive or the study cut-off date, whichever was first. OS was estimated by Kaplan-Meier estimates.

Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on--treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.

Blood samples of participants were analyzed by using a titer-based, bridging immunoassay developed and validated to detect aflibercept ADA in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative, competitive ligand binding assay to detect NAb.

Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed pharmacokinetic (PK) analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.

Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.

In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1.

In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1.

In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of 5-FU in combination with aflibercept and irinotecan in Cycle 1.

In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.

In 10 participants of ITT population, additional blood samples were obtained for detailed non - compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.

In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan in combination with aflibercept and 5-FU in Cycle 1.

Regeneron Pharmaceuticals

Sanofi

Reported AEs are TEAEs that is AEs that developed/worsened during the study treatment period (defined as the first study treatment administration to End-of-Treatment Visit \[30 days of last infusion\]).

Aflibercept 4 mg/kg IV infusion (1-2 hours) on Day 1 of Cycle 1 and q2w thereafter, in combination with FOLFIRI regimen on Days 1-3 of Cycle 1 and q2w thereafter until DP, unacceptable toxicity or participant's refusal. FOLFIRI regimen: IV infusions of levofolinate 200 mg/m\^2 (2 hours) and irinotecan 180 mg/m\^2 (90 minutes) simultaneously, followed by 5-FU 400 mg/m\^2 IV bolus injection followed by continuous IV infusion of 5-FU (46 hours) at 2400 mg/m\^2.

Aflibercept + FOLFIRI

Age, Continuous

Sex: Female, Male

ECOG PS is used to assess how the disease affects the daily living abilities of the participant. It ranges on the scale from 0-5 (0= normal activity; 1= symptoms but ambulatory; 2= in bed for less than (\<) 50 percent (%) of the time; 3= in bed for greater than (\>) 50% of the time; 4= 100% bedridden; 5= dead.

Eastern Cooperative Oncology Group Performance Status (ECOG PS)

Had Prior Treatment

Did Not Have Prior Treatment

Prior Treatment with Bevacizumab

Evaluable participant (EP) population: all registered participants with measurable disease at study entry \& with at least 1 valid post-baseline tumor evaluation. Participants who died due to DP or had documented radiological progressive disease before first post-baseline imaging evaluation were also included.

Trial Transparency Team

EP population: all registered participants with measurable disease at study entry \& with at least 1 valid post-baseline tumor evaluation. Participants who died due to DP or had documented radiological progressive disease before first post-baseline imaging evaluation were also included.

Percentage of Participants With Overall Response

The safety population (all treated \[AT\] population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment.

Progression Free Survival (PFS)

The safety population (AT population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment.

Overall Survival (OS)

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

At baseline in the ADA assay (n=62)

At any time post-baseline in the ADA assay (n=62)

At any time post-baseline in the NAb assay (n=62)

At 90 days after last dose in the ADA assay (n=50)

At 90 days after last dose in NAb assay (n=50)

The safety population (AT population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment. Here 'n' signifies number of participants with available data for specified category.

Aflibercept 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

Intent-to-Treat (ITT) population included all registered participants.

Maximum Observed Plasma Concentration (Cmax) for Free Aflibercept: ITT Population

ITT population included all registered participants.

Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free Aflibercept: ITT Population

Area Under the Concentration Time Curve (AUC) for Free Aflibercept: ITT Population

Total Body Clearance (CL) for Free Aflibercept: ITT Population

Volume of Distribution at the Steady State (Vss) for Free Aflibercept: ITT Population

Plasma Free-Aflibercept (n=10)

Plasma VEGF-Bound Aflibercept (n=8)

Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.

Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Time to Reach Maximum Plasma Concentration Observed (Tmax) for Free and VEGF-Bound Aflibercept in Cycle 1: Participants With Additional Blood Sampling for Detailed PK Analysis

Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Plasma VEGF-Bound Aflibercept (n=5)

Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.

Area Under the Concentration Time Curve (AUC) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Total Body Clearance (CL) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Volume of Distribution at the Steady State (Vss) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Terminal Elimination Half-life (t1/2z) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis

Steady State Drug Concentration (Css) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis

Clearance at Steady State (CLss) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis

Plasma Irinotecan

Plasma SN-38

Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis

Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis

Plasma Irinotecan (n=10)

Plasma SN-38 (n=4)

Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis

Plasma SN-38 (n=5)

Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis

Active Metabolite SN-38 / Irinotecan Ratio on Area Under the Concentration Time Curve (Rmet): Participants With Additional Blood Sampling for Detailed PK Analysis

Spots Global Cancer Trial Database for A Study of Aflibercept in Combination With FOLFIRI in Patients With Second-Line Metastatic Colorectal Cancer in Japan

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