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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Aflibercept
* Drug: Levofolinate
* Drug: Irinotecan
* Drug: 5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically or cytologically proven adenocarcinoma of the colon or rectum. Metastatic disease that was not amenable to potentially curative treatment. Participants with measurable disease. One prior chemotherapeutic regimen (containing oxaliplatin) for metastatic disease. Participants who relapsed within 6 months of completion of oxaliplatin-based adjuvant chemotherapy were also eligible. Exclusion criteria: Prior therapy with irinotecan. Less than 28 days elapsed from prior radiotherapy, prior surgery, or prior chemotherapy to the time of registration. Unresolved toxicity (grade >1) from prior anticancer therapy. Eastern Cooperative Oncology Group (ECOG) performance status >1. Brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis. Other prior malignancy. Pregnant or breast-feeding women. Uncontrolled hypertension. Inadequate bone marrow function, liver function, or renal function. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflibercept + FOLFIRI<br>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. | Drug: Aflibercept<br>* Pharmaceutical form: Concentrated solution (100 mg/4 mL [25 mg/mL], 200 mg/8 mL [25 mg/mL]) for infusion; Route of administration: Intravenous<br>* Other names: AVE0005;Drug: Levofolinate<br>* Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous<br>Drug: Irinotecan<br>* Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous<br>Drug: 5-FU<br>* Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response | 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. | Baseline and every 6 weeks until DP (maximum duration: 16.4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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. | Baseline and every 6 weeks until DP or death, due to any cause (maximum duration: 16.4 months) | 
| Overall Survival (OS) | 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. | Baseline up to death or study cut--off (maximum duration: 24.7 months) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. | First dose (Day 1 of Cycle 1) of study treatment up to end of treatment visit (30 days after last dose of study treatment) (maximum duration: 77 weeks) | 
| 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 | 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. | Baseline, at any time post baseline and 90 days after the last dose of aflibercept | 
| Maximum Observed Plasma Concentration (Cmax) for Free Aflibercept: ITT Population | 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. | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | 
| Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free Aflibercept: ITT Population | 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. | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | 
| Area Under the Concentration Time Curve (AUC) for Free Aflibercept: ITT Population | 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. | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | 
| Total Body Clearance (CL) for Free Aflibercept: ITT Population | 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. | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | 
| Volume of Distribution at the Steady State (Vss) for Free Aflibercept: ITT Population | 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. | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | 
| Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| 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 | 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. | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| 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 | 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. | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| 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 | 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. | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| Area Under the Concentration Time Curve (AUC) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| Total Body Clearance (CL) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| Volume of Distribution at the Steady State (Vss) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| Terminal Elimination Half-life (t1/2z) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | 
| Steady State Drug Concentration (Css) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1 | 
| Clearance at Steady State (CLss) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1 | 
| Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| 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 | 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. | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| Active Metabolite SN-38 / Irinotecan Ratio on Area Under the Concentration Time Curve (Rmet): Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| Total Body Clearance (CL) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | 
| Volume of Distribution at the Steady State (Vss) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | 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. | Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 |