Trial Outcomes & Findings for A Study of Aflibercept in Combination With FOLFIRI in Patients With Second-Line Metastatic Colorectal Cancer in Japan (NCT NCT01882868)

NCT ID: NCT01882868

Last Updated: 2017-03-14

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 62 participants
• Primary outcome timeframe: Baseline and every 6 weeks until DP (maximum duration: 16.4 months)
• Results posted on: 2017-03-14

Participant Flow

The study was conducted at 19 sites in Japan. A total of 68 participants were screened between 30 July 2013 and 12 March 2014, out of which 62 were enrolled and treated.

Among 68 participants screened, 6 were screen failures due to elevated urine protein-creatinine ratio (UPCR) and inadequate liver function tests (LFTs).

Participant milestones

Measure	Aflibercept + FOLFIRI 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.
Overall Study STARTED	62
Overall Study COMPLETED	62
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Aflibercept + FOLFIRI n=60 Participants 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.
Age, Continuous	61.6 years STANDARD_DEVIATION 9.8 • n=5 Participants
Sex: Female, Male Female	26 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0	40 participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1	20 participants n=5 Participants
Prior Treatment with Bevacizumab Had Prior Treatment	50 participants n=5 Participants
Prior Treatment with Bevacizumab Did Not Have Prior Treatment	10 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and every 6 weeks until DP (maximum duration: 16.4 months)

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=60 Participants 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.

Percentage of Participants With Overall Response

8.3 percentage of participants Interval 1.3 to 15.3

SECONDARY outcome

Timeframe: Baseline and every 6 weeks until DP or death, due to any cause (maximum duration: 16.4 months)

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

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

Progression Free Survival (PFS)

5.42 months Interval 4.14 to 6.702

SECONDARY outcome

Timeframe: Baseline up to death or study cut--off (maximum duration: 24.7 months)

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

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

Overall Survival (OS)

15.59 months Interval 11.203 to 19.811

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

62 participants

SECONDARY outcome

Timeframe: Baseline, at any time post baseline and 90 days after the last dose of aflibercept

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=62 Participants 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 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 At baseline in the ADA assay (n=62)	1 participants
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 At any time post-baseline in the ADA assay (n=62)	0 participants
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 At any time post-baseline in the NAb assay (n=62)	0 participants
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 At 90 days after last dose in the ADA assay (n=50)	0 participants
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 At 90 days after last dose in NAb assay (n=50)	0 participants

SECONDARY outcome

Timeframe: 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

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

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

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

73.19 mcg/mL Standard Deviation 10.72

SECONDARY outcome

Timeframe: 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

Population: ITT population included all registered 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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

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

246.9 mcg*day/mL Standard Deviation 41.1

SECONDARY outcome

Timeframe: 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

Population: ITT population included all registered 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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

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

304.6 mcg*day/mL Standard Deviation 62.8

SECONDARY outcome

Timeframe: 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

Population: ITT population included all registered 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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

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

0.8053 liter/day Standard Deviation 0.1784

SECONDARY outcome

Timeframe: 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

Population: ITT population included all registered 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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=62 Participants 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.

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

6.197 liters Standard Deviation 1.106

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma Free-Aflibercept (n=10)	90.8 mcg/mL Standard Deviation 16.5
Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma VEGF-Bound Aflibercept (n=8)	2.83 mcg/mL Standard Deviation 0.836

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
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 Plasma Free-Aflibercept (n=10)	0.07 days Interval 0.04 to 0.09
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 Plasma VEGF-Bound Aflibercept (n=8)	13.97 days Interval 7.01 to 16.05

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
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 Free-Aflibercept (n=10)	321 mcg*day/mL Standard Deviation 58.9
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=8)	24.4 mcg*day/mL Standard Deviation 6.17

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
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 Plasma Free-Aflibercept (n=10)	312 mcg*day/mL Standard Deviation 51.8
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 Plasma VEGF-Bound Aflibercept (n=5)	23.3 mcg*day/mL Standard Deviation 2.45

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

355 mcg*day/mL Standard Deviation 61.5

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

0.716 liter/day Standard Deviation 0.204

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

3.53 liters Standard Deviation 1.11

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

4.47 days Standard Deviation 0.680

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

930 ng/mL Standard Deviation 461

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

122 liter/hour Standard Deviation 76.2

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma Irinotecan	2220 ng/mL Standard Deviation 528
Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma SN-38	32.2 ng/mL Standard Deviation 11.4

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
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	16900 ng*h/mL Standard Deviation 5970
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 SN-38	344 ng*h/mL Standard Deviation 173

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
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 Irinotecan (n=10)	17700 ng*h/mL Standard Deviation 6400
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=4)	341 ng*h/mL Standard Deviation 72.4

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure	Aflibercept + FOLFIRI n=10 Participants 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.
Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma Irinotecan (n=10)	5.19 hours Standard Deviation 0.736
Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis Plasma SN-38 (n=5)	10.3 hours Standard Deviation 3.08

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

0.0313 ratio Standard Deviation 0.0133

SECONDARY outcome

Timeframe: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

18.3 liter/hour Standard Deviation 6.04

SECONDARY outcome

Timeframe: Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1

Population: 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.

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.

Outcome measures

Measure

Aflibercept + FOLFIRI n=10 Participants 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.

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

92.5 liter Standard Deviation 33.8

Adverse Events

Aflibercept + FOLFIRI

Serious events: 20 serious events

Other events: 62 other events

Deaths: 0 deaths

Serious adverse events

Measure	Aflibercept + FOLFIRI n=62 participants at risk 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.
Blood and lymphatic system disorders Febrile neutropenia	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Diarrhoea	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Ileus	6.5% 4/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Oesophagitis	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
General disorders Catheter site pain	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
General disorders Fatigue	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
General disorders Pyrexia	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Hepatobiliary disorders Cholecystitis	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Hepatobiliary disorders Cholecystitis acute	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Biliary tract infection	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Peritonitis	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Pharyngitis	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Skin infection	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Urinary tract infection	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Injury, poisoning and procedural complications Lumbar vertebral fracture	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Metabolism and nutrition disorders Decreased appetite	6.5% 4/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Metabolism and nutrition disorders Dehydration	4.8% 3/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Musculoskeletal and connective tissue disorders Muscular weakness	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Nervous system disorders Hepatic encephalopathy	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Reproductive system and breast disorders Female genital tract fistula	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	1.6% 1/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).

Other adverse events

Measure	Aflibercept + FOLFIRI n=62 participants at risk 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.
Blood and lymphatic system disorders Febrile neutropenia	6.5% 4/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Blood and lymphatic system disorders Neutropenia	74.2% 46/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Abdominal pain	14.5% 9/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Constipation	16.1% 10/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Diarrhoea	67.7% 42/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Nausea	58.1% 36/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Stomatitis	46.8% 29/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Gastrointestinal disorders Vomiting	27.4% 17/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
General disorders Fatigue	61.3% 38/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
General disorders Pyrexia	21.0% 13/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Nasopharyngitis	9.7% 6/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Infections and infestations Upper respiratory tract infection	6.5% 4/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Investigations Weight decreased	9.7% 6/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Metabolism and nutrition disorders Decreased appetite	74.2% 46/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Musculoskeletal and connective tissue disorders Back pain	8.1% 5/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Nervous system disorders Dysgeusia	8.1% 5/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Nervous system disorders Headache	11.3% 7/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Psychiatric disorders Insomnia	9.7% 6/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Renal and urinary disorders Proteinuria	30.6% 19/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Respiratory, thoracic and mediastinal disorders Cough	11.3% 7/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Respiratory, thoracic and mediastinal disorders Dysphonia	29.0% 18/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Respiratory, thoracic and mediastinal disorders Epistaxis	40.3% 25/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Respiratory, thoracic and mediastinal disorders Hiccups	11.3% 7/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Skin and subcutaneous tissue disorders Alopecia	48.4% 30/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	12.9% 8/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Skin and subcutaneous tissue disorders Rash	11.3% 7/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Skin and subcutaneous tissue disorders Skin hyperpigmentation	9.7% 6/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Vascular disorders Hot flush	6.5% 4/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).
Vascular disorders Hypertension	46.8% 29/62 • All AEs were collected from signature of the informed consent form up to the final visit (77 weeks) regardless of seriousness or relationship to investigational medicinal product. 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 \[30 days of last infusion\]).

Additional Information

Trial Transparency Team

Sanofi

Email: Contact-US@sanofi.com

Results disclosure agreements

• Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
• Publication restrictions are in place

Restriction type: OTHER