AFEQT: Colorectal Cancer Metastatic

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01670721
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 175
• Location: 1
• Arm: 1
• Duration (Months): 34
• Patients Per Site Per Month: 5.2

Study Details

Study Description

Brief Summary

Primary Objective:

To evaluate the safety of aflibercept in participants with mCRC treated with irinotecan/5-Fluorouracil (5-FU) combination (FOLFIRI) after failure of an oxaliplatin-based regimen (participants similar to those evaluated in the VELOUR trial [EFC10262, NCT00561470]) according to side effects prevention and management guidelines.

Secondary Objective:

To document the Health-Related Quality of Life (HRQL) of aflibercept in this participant population.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: AFLIBERCEPT; Drug: Irinotecan; Drug: Fluorouracil; Drug: Leucovorin	Phase 3

Detailed Description

Each participant was treated until disease progression (DP), unacceptable toxicity, death, Investigator's decision or participant's refusal for further treatment (whichever come first). Participants were followed-up during treatment and for at least 30 days after its last study treatment (either Aflibercept or FOLFIRI) administration, up to a maximum of 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 175 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Single Arm, Open Label Clinical Trial Evaluating Safety and Health Related Quality of Life of Aflibercept in Combination With Irinotecan/5-FU Chemotherapy (FOLFIRI) in Patients With Metastatic Colorectal Cancer (mCRC) Previously Treated With an Oxaliplatin-Containing Regimen
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin) Aflibercept 4 mg/kg intravenous (IV) infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.

Drug: AFLIBERCEPT; Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous; Other Names: AVE0005 ; Drug: Irinotecan; Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous; Drug: Fluorouracil; Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous; Drug: Leucovorin; Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) [Baseline upto 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure:723 days)]

   Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period. On-treatment period was defined as the time from the first dose of treatment to 30 days after the last dose of treatment (either Aflibercept or FOLFIRI). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.

Secondary Outcome Measures

1. Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)]

   EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.

2. Change From Baseline in HRQL European-Quality of Life-5 Dimension Instrument-3 Levels (EQ-5D-3L) Index Score [Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)]

   EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state.

3. Change From Baseline in HRQL EQ-5D-3L VAS Score [Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)]

   EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0 = worst imaginable health state and 100 = best imaginable health state. Baseline corresponded to last evaluable assessment before treatment administration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Histologically or cytologically proven adenocarcinoma of the colon or rectum.

• Metastatic disease.

• Age ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

• One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen. Participants must progressed during or following the last administration of the oxaliplatin based chemotherapy. Participants relapsing within 6 months of completion of oxaliplatin adjuvant chemotherapy were also eligible.

• Participants must be affiliated to a Social Security System.

Exclusion criteria:

Related to Methodology

• Prior therapy with irinotecan; Absolute neutrophil counts (ANC) <1.5 x 109/L; Platelet count <100 x 109/L; Hemoglobin <9.0 g/dL; Total bilirubin >1.5 x upper limit of normal (ULN); Transaminases >3 x ULN (unless liver metastasis are present, 5 x ULN in that case); Alkaline phosphatase >3 x ULN (unless liver metastasis are present, 5 x ULN in that case).

• Less than 4 weeks elapsed from prior radiotherapy or prior chemotherapy or major surgery to the time of inclusion or until the surgical wound was fully healed whichever came later (48 hours in case of minor surgical procedure or until wound full healing observed).

• Treatment with any investigational drug within 30 days prior to inclusion.

• AEs (with exception of alopecia, peripheral sensory neuropathy and those listed in specific exclusion criteria) from any prior anti cancer therapy of grade >1 National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.0 at the time of inclusion.

• History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease.

• Other prior malignancy. Basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or any other cancer from which the participant had been disease free for >5 years were allowed.

• Any of the following within 6 months prior to inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack.

• Any of the following within 3 months prior to inclusion: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event.

• Occurrence of deep vein thrombosis within 4 weeks, prior to inclusion.

• Known acquired immunodeficiency syndrome (AIDS)-related illnesses or known human deficiency virus (HIV) disease requiring antiretroviral treatment.

• Any severe acute or chronic medical condition, which could impair the ability of the participant to participate to the study or to interfere with interpretation of study results.

• Pregnant or breast-feeding women. Positive pregnancy test for women of reproductive potential.

• Participants with reproductive potential (female and male) who did not agree to use a method of contraception during the study treatment period and for at least 6 months following completion of study treatment. The definition of effective method was left to the investigator's judgment.

Related to Aflibercept:

• Urine protein-creatinine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 500 mg/24-h.

• Serum creatinine >1.5 x ULN . If creatinine 1.0-1.5 x ULN, creatinine clearance, calculated according to Cockroft-Gault formula, <60 ml/min will exclude the participant.

• Uncontrolled hypertension (blood pressure >140/90 mmHg or systolic blood pressure >160 mmHg when diastolic blood pressure <90 mmHg, on at least 2 repeated determinations on separate days, or upon clinical judgement within 3 months prior to study inclusion.

• Participants on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range international normalized ratio (INR) (>3) within the 4 weeks prior to inclusion.

• Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. INR >1.5 without vitamine K antagonist therapy), non-healing wound.

Related to FOLFIRI

• Known dihydropyrimidine dehydrogenase deficiency.

• Predisposing colonic or small bowel disorders in which the symptoms were uncontrolled as indicated by baseline of >3 loose stools daily.

• Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small intestine resection with chronic diarrhea.

• History of anaphylaxis or known intolerance to atropine sulphate or loperamide or appropriate antiemetics to be administered in conjunction with FOLFIRI.

• Treatment with concomitant anticonvulsivant agents that are cytochrome P450 3A4 (CYP3A4) inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days.

• Participants with known Gilbert's syndrome.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Administrative office	Paris		France

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01670721
• Other Study ID Numbers: AFLIBL06266; 2012-000048-89; U1111-1128-9325
• First Posted: Aug 22, 2012
• Last Update Posted: Nov 28, 2016
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Irinotecan; Aflibercept

Study Results

Participant Flow

Recruitment Details	The study was conducted at 38 sites in France. A total of 182 participants were screened between 08 August 2012 and 30 June 2014, out of which 175 participants were enrolled and treated.
Pre-assignment Detail	Participants enrolled in the study to assess the safety of Aflibercept in participants treated with a combination of Aflibercept with FOLFIRI regimen (Irinotecan, Leucovorin and 5-Fluorouracil [5-FU]).

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg intravenous (IV) infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until disease progression (DP), unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Period Title: Overall Study
STARTED	175
COMPLETED	122
NOT COMPLETED	53

Baseline Characteristics

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Overall Participants	175
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.5 (11.0)
Sex: Female, Male (Count of Participants)
Female	77 44%
Male	98 56%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period. On-treatment period was defined as the time from the first dose of treatment to 30 days after the last dose of treatment (either Aflibercept or FOLFIRI). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.
Time Frame	Baseline upto 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure:723 days)

Outcome Measure Data

Analysis Population Description

Safety population defined as the participants who signed the informed consent form and received at least part of one dose of study treatment.

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Measure Participants	175
Any TEAE	100.00 57.1%
Any serious TEAE	40.6 23.2%
Any serious related TEAE	21.1 12.1%
Any TEAE leading to death	9.1 5.2%
Any TEAE (permanent treatment discontinuation)	23.4 13.4%
Any TEAE (premature treatment discontinuation)	16.0 9.1%

2. Secondary Outcome

Title	Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
Description	EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.
Time Frame	Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)

Outcome Measure Data

Analysis Population Description

EORTC QLQ-C30 analysis population: participants who signed informed consent form; had an evaluable QLQ-C30 questionnaire at baseline and at least one evaluable assessment post baseline and received at least part of one dose of study treatment(either Aflibercept or FOLFIRI).Here, n=number of participants with available data at specified time-points.

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Measure Participants	152
Baseline (n=148)	69.54 (18.97)
At Cycle 3 (n=130)	-7.56 (19.78)
At Cycle 5 (n=99)	-10.86 (19.76)
At Cycle 7 (n=72)	-8.22 (20.00)
At Cycle 9 (n=51)	-9.31 (19.34)
At Cycle 11 (n=45)	-14.81 (21.24)
At Cycle 13 (n=25)	-12.67 (24.31)
At Cycle 15 (n=24)	-12.50 (18.22)
At Cycle 17 (n=14)	-14.29 (15.82)
At Cycle 19 (n=12)	-15.28 (11.70)
At Cycle 21 (n=10)	-15.83 (19.82)
At Cycle 23 (n=6)	-9.72 (20.01)
At Cycle 25 (n=4)	-8.33 (6.80)
At Cycle 27 (n=4)	-12.50 (15.96)
At Cycle 29 (n=2)	-8.33 (11.79)
At Cycle 31 (n=2)	-16.67 (0.00)
At Cycle 33 (n=1)	0.00 (NA)
At Cycle 35 (n=1)	0.00 (NA)
At Cycle 37 (n=2)	-8.33 (11.79)
At Cycle 39 (n=2)	-8.33 (11.79)
At Cycle 41 (n=2)	-8.33 (11.79)
At Cycle 43 (n=2)	-12.50 (5.89)
At Cycle 45 (n=2)	-4.17 (17.68)
At Cycle 47 (n=1)	0.00 (NA)
At end of study treatment (n=73)	-11.19 (24.38)

3. Secondary Outcome

Title	Change From Baseline in HRQL European-Quality of Life-5 Dimension Instrument-3 Levels (EQ-5D-3L) Index Score
Description	EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state.
Time Frame	Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)

Outcome Measure Data

Analysis Population Description

EQ-5D analysis population: participants who signed informed consent form, had an evaluable EQ-5D questionnaire at baseline and at least one evaluable assessment post baseline and received at least part of one dose of study treatment (either Aflibercept or FOLFIRI).Here, n = number of participants with available data at specified time-points.

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Measure Participants	148
Baseline (n=148)	0.78 (0.21)
At Cycle 3 (n=127)	-0.04 (0.23)
At Cycle 5 (n=96)	-0.08 (0.25)
At Cycle 7 (n=72)	-0.05 (0.20)
At Cycle 9 (n=49)	-0.09 (0.23)
At Cycle 11 (n=43)	-0.06 (0.20)
At Cycle 13 (n=24)	-0.09 (0.14)
At Cycle 15 (n=25)	-0.10 (0.16)
At Cycle 17 (n=14)	-0.03 (0.10)
At Cycle 19 (n=12)	-0.10 (0.12)
At Cycle 21 (n=10)	-0.03 (0.18)
At Cycle 23 (n=6)	-0.08 (0.15)
At Cycle 25 (n=3)	0.04 (0.22)
At Cycle 27 (n=3)	-0.09 (0.20)
At Cycle 29 (n=2)	-0.18 (0.04)
At Cycle 31 (n=1)	0.00 (NA)
At Cycle 37 (n=1)	-0.15 (NA)
At Cycle 39 (n=1)	0.00 (NA)
At Cycle 41 (n=1)	0.00 (NA)
At Cycle 43 (n=1)	0.00 (NA)
At Cycle 45 (n=1)	0.00 (NA)
At end of study treatment (n=71)	-0.20 (0.31)

4. Secondary Outcome

Title	Change From Baseline in HRQL EQ-5D-3L VAS Score
Description	EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0 = worst imaginable health state and 100 = best imaginable health state. Baseline corresponded to last evaluable assessment before treatment administration.
Time Frame	Pre-dose at Baseline, Day 1 of every odd cycle; and at end of treatment (30 days after last study treatment) (maximum exposure: 99 weeks)

Outcome Measure Data

Analysis Population Description

EQ-5D analysis population: participants who signed informed consent form, had an evaluable EQ-5D questionnaire at baseline and at least one evaluable assessment post baseline and received at least part of one dose of study treatment (either Aflibercept or FOLFIRI).Here, n = number of participants with available data at specified time-points.

Arm/Group Title	Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Measure Participants	148
Baseline (n=125)	69.48 (19.10)
At cycle 3 (n=94)	-6.23 (17.82)
At cycle 5 (n=76)	-7.62 (17.23)
At cycle 7 (n=57)	-7.79 (14.14)
At cycle 9 (n=38)	-7.55 (16.12)
At cycle 11 (n=36)	-8.67 (16.09)
At cycle 13 (n=22)	-8.95 (17.56)
At cycle 15 (n=22)	-12.41 (19.57)
At cycle 17 (n=13)	-10.31 (17.44)
At cycle 19 (n=10)	-15.70 (18.19)
At cycle 21 (n=8)	-15.13 (19.87)
At cycle 23 (n=5)	-8.80 (10.71)
At cycle 25 (n=2)	-13.00 (4.24)
At cycle 27 (n=3)	-15.67 (9.81)
At cycle 29 (n=2)	-17.50 (3.54)
At cycle 31 (n=1)	-15.00 (NA)
At cycle 37 (n=1)	-15.00 (NA)
At cycle 39 (n=1)	-15.00 (NA)
At cycle 41 (n=1)	-15.00 (NA)
At cycle 43 (n=1)	-15.00 (NA)
At cycle 45 (n=1)	-15.00 (NA)
At end of study treatment (n=55)	-13.05 (20.82)

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 723) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during 'on-treatment period' (from the first dose of treatment to 30 days after the last dose of treatment [either aflibercept or FOLFIRI]).
Arm/Group Title	Aflibercept + FOLFIRI(Irinotecan, 5-Fluorouracil & Leucovorin)
Arm/Group Description	Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment (maximum exposure: Week 99).
All Cause Mortality
	Aflibercept + FOLFIRI(Irinotecan, 5-Fluorouracil & Leucovorin)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Aflibercept + FOLFIRI(Irinotecan, 5-Fluorouracil & Leucovorin)
	Affected / at Risk (%)	# Events
Total	71/175 (40.6%)
Blood and lymphatic system disorders
ANAEMIA	1/175 (0.6%)
FEBRILE NEUTROPENIA	2/175 (1.1%)
PANCYTOPENIA	1/175 (0.6%)
Eye disorders
VITREOUS HAEMORRHAGE	1/175 (0.6%)
Gastrointestinal disorders
ABDOMINAL PAIN	3/175 (1.7%)
ANAL FISTULA	1/175 (0.6%)
DIARRHOEA	8/175 (4.6%)
GASTROINTESTINAL FISTULA	1/175 (0.6%)
GASTROINTESTINAL HAEMORRHAGE	1/175 (0.6%)
INTESTINAL OBSTRUCTION	3/175 (1.7%)
NAUSEA	2/175 (1.1%)
PANCREATITIS	1/175 (0.6%)
RECTAL HAEMORRHAGE	1/175 (0.6%)
RECTOURETHRAL FISTULA	1/175 (0.6%)
SMALL INTESTINAL PERFORATION	1/175 (0.6%)
STOMATITIS	1/175 (0.6%)
SUBILEUS	2/175 (1.1%)
TOOTH LOSS	1/175 (0.6%)
VOMITING	1/175 (0.6%)
General disorders
ASTHENIA	1/175 (0.6%)
DISEASE PROGRESSION	9/175 (5.1%)
FATIGUE	1/175 (0.6%)
GENERAL PHYSICAL HEALTH DETERIORATION	8/175 (4.6%)
INFLUENZA LIKE ILLNESS	1/175 (0.6%)
PYREXIA	3/175 (1.7%)
Hepatobiliary disorders
HEPATIC FAILURE	2/175 (1.1%)
Infections and infestations
ABDOMINAL WALL ABSCESS	1/175 (0.6%)
DEVICE RELATED INFECTION	1/175 (0.6%)
DEVICE RELATED SEPSIS	1/175 (0.6%)
ESCHERICHIA INFECTION	1/175 (0.6%)
INFECTION	2/175 (1.1%)
LUNG INFECTION	2/175 (1.1%)
PELVIC ABSCESS	1/175 (0.6%)
SEPSIS	1/175 (0.6%)
SEPTIC SHOCK	1/175 (0.6%)
TOOTH INFECTION	1/175 (0.6%)
Injury, poisoning and procedural complications
HEAD INJURY	1/175 (0.6%)
Investigations
BLOOD ALKALINE PHOSPHATASE INCREASED	1/175 (0.6%)
LAPAROSCOPY	1/175 (0.6%)
Metabolism and nutrition disorders
DECREASED APPETITE	2/175 (1.1%)
DEHYDRATION	1/175 (0.6%)
HYPERGLYCAEMIA	1/175 (0.6%)
HYPOKALAEMIA	1/175 (0.6%)
Musculoskeletal and connective tissue disorders
BONE PAIN	1/175 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
INFECTED NEOPLASM	1/175 (0.6%)
METASTASES TO CENTRAL NERVOUS SYSTEM	2/175 (1.1%)
METASTATIC PAIN	1/175 (0.6%)
Nervous system disorders
CEREBELLAR ISCHAEMIA	1/175 (0.6%)
CEREBROVASCULAR ACCIDENT	1/175 (0.6%)
DIZZINESS	1/175 (0.6%)
HEADACHE	1/175 (0.6%)
NEUROPATHY PERIPHERAL	1/175 (0.6%)
Psychiatric disorders
CONFUSIONAL STATE	1/175 (0.6%)
DEPRESSION	1/175 (0.6%)
Renal and urinary disorders
RENAL COLIC	1/175 (0.6%)
RENAL FAILURE	2/175 (1.1%)
URINARY RETENTION	1/175 (0.6%)
Reproductive system and breast disorders
PRIAPISM	1/175 (0.6%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/175 (0.6%)
EPISTAXIS	1/175 (0.6%)
PLEURAL EFFUSION	1/175 (0.6%)
PNEUMOTHORAX	2/175 (1.1%)
PULMONARY EMBOLISM	4/175 (2.3%)
PULMONARY OEDEMA	1/175 (0.6%)
Surgical and medical procedures
HEPATECTOMY	1/175 (0.6%)
INTRAPERITONEAL HYPERTHERMIC CHEMOTHERAPY	1/175 (0.6%)
Vascular disorders
PHLEBITIS	1/175 (0.6%)
THROMBOSIS	1/175 (0.6%)
VARICOSE ULCERATION	1/175 (0.6%)
Other (Not Including Serious) Adverse Events
	Aflibercept + FOLFIRI(Irinotecan, 5-Fluorouracil & Leucovorin)
	Affected / at Risk (%)	# Events
Total	172/175 (98.3%)
Blood and lymphatic system disorders
NEUTROPENIA	39/175 (22.3%)
Gastrointestinal disorders
ABDOMINAL PAIN	36/175 (20.6%)
ABDOMINAL PAIN UPPER	14/175 (8%)
CONSTIPATION	39/175 (22.3%)
DIARRHOEA	121/175 (69.1%)
GASTROOESOPHAGEAL REFLUX DISEASE	10/175 (5.7%)
NAUSEA	86/175 (49.1%)
PROCTALGIA	10/175 (5.7%)
RECTAL HAEMORRHAGE	11/175 (6.3%)
STOMATITIS	83/175 (47.4%)
VOMITING	47/175 (26.9%)
General disorders
ASTHENIA	98/175 (56%)
FATIGUE	33/175 (18.9%)
PYREXIA	14/175 (8%)
Investigations
WEIGHT DECREASED	68/175 (38.9%)
Metabolism and nutrition disorders
DECREASED APPETITE	59/175 (33.7%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	10/175 (5.7%)
BACK PAIN	18/175 (10.3%)
MYALGIA	11/175 (6.3%)
Nervous system disorders
DYSGEUSIA	13/175 (7.4%)
HEADACHE	32/175 (18.3%)
NEUROPATHY PERIPHERAL	19/175 (10.9%)
PARAESTHESIA	9/175 (5.1%)
Renal and urinary disorders
PROTEINURIA	25/175 (14.3%)
Respiratory, thoracic and mediastinal disorders
DYSPHONIA	22/175 (12.6%)
DYSPNOEA	17/175 (9.7%)
EPISTAXIS	43/175 (24.6%)
Skin and subcutaneous tissue disorders
ALOPECIA	36/175 (20.6%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	23/175 (13.1%)
Vascular disorders
HYPERTENSION	74/175 (42.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.