Colorectal Cancer Metastatic

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: AFLIBERCEPT
* Drug: Irinotecan
* Drug: Fluorouracil
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically or cytologically proven adenocarcinoma of the colon or rectum. Metastatic disease. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)<br>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<br>* Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous<br>* Other names: AVE0005;Drug: Irinotecan<br>* Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous<br>Drug: Fluorouracil<br>* Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous<br>Drug: Leucovorin<br>* Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | 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. | Baseline upto 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure:723 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | 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) | 
| Change From Baseline in HRQL European-Quality of Life-5 Dimension Instrument-3 Levels (EQ-5D-3L) Index Score | 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. | 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) | 
| Change From Baseline in HRQL EQ-5D-3L VAS Score | 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. | 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) |