Study to Assess the Efficacy and Safety of Treatment With FOLFIRI-aflibercept Compared to Initial Treatment With FOLFIRI-aflibercept (for 6 Cycles) Followed by Maintenance With 5FU-aflibercept, in an Elderly Population With mCRC After Failure of an Oxaliplatin-based Regimen

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of treatment with FOLFIRI-aflibercept compared to initial treatment with FOLFIRI-aflibercept (for 6 cycles) followed by maintenance with 5FU-aflibercept, in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen

Official Title
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Randomised, Multicentre, Phase II Pilot Study to Assess the Efficacy and Safety of Treatment With FOLFIRI-aflibercept Compared to Initial Treatment With FOLFIRI-aflibercept (for 6 Cycles) Followed by Maintenance With 5FU-aflibercept, in an Elderly Population With Metastatic Colorectal Cancer (mCRC) After Failure of an Oxaliplatin-based Regimen

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Aflibercept
* Drug: Irinotecan
* Drug: folinic acid (dl racemic)
* Drug: 5Fluorouracil
* Drug: 5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent, and willing and able to comply with protocol requirements, Histologically proven adenocarcinoma of the colon and/or rectum, Existence of at least one measurable unidimensional lesion using CT or MRI based on the RECIST criteria, version 1.1 Patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed after a first line oxaliplatin-containing regimen for metastatic disease. Age ≥70 years World Health Organization (WHO) Performance status (PS) 0-2, Hematological status: neutrophils (ANC) ≥1.5x109 /L; platelets ≥100x109 /L; haemoglobin ≥9 g/dL Adequate renal function: Creatinine clearance ≥50 mL/min as calculated using the Cockcroft-Gault equation. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase (ALP) <5xULN Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour. Regular follow-up feasible. Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial. Exclusion Criteria: Uncontrolled hypercalcemia, Pre-existing permanent neuropathy (NCI grade >2) Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy, Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy), Treatment with any other investigational medicinal product within 28 days prior to study entry. Other serious and uncontrolled non-malignant disease, History or evidence upon physical examination of CNS metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy), Patients classified as fragile or delicate according to the following criteria: Dependence in one or more activities of daily living according to the Katz Index of Independence in Activities of Daily Living (ADL) scale Three or more comorbidities when assessing the presence of the following processes: congestive heart failure; heart valve disease; coronary artery disease; chronic (obstructive or restrictive) pulmonary disease; cerebrovascular disease; peripheral neuropathy, chronic kidney failure; hypertension; diabetes; concomitant cancers; collagen vascular disease; chronic liver disease; and disabling arthritis Presence of geriatric syndromes: moderate-severe dementia; delirium in stressful situations (urinary or respiratory tract infection, angina or drugs); moderate-severe depression that interferes with the patient's usual activity; frequent falls (three or more per month); inattentiveness (who could help you in the event of an emergency?); urinary incontinence in the absence of stress, infection, diuretics or prostatic hyperplasia; faecal incontinence in the absence of diarrhoea or laxatives; osteoporotic fractures of large bones or vertebral compression fractures Known Gilbert's syndrome Intolerance to atropine sulfate or loperamide Known dihydropyrimidine dehydrogenase deficiency Treatment with CYP3A4 inducers unless discontinued > 7 days prior to inclusion Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis. Other concomitant or previous malignancy, except: i/ adequately treated insitu carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years, Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days Patients with known allergy to any excipient to study drugs, History of myocardial infarction and/or stroke within 6 months prior to inclusion, NYHA class III and IV congestive heart failure Bowel obstruction. Less than 28 days elapsed from prior radiotherapy Patients with pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency Patients with severe infections

Ages Eligible for Study
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Minimum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>INDUCTION PHASE: 6 cycles of FOLFIRI + aflibercept MAINTENANCE PHASE: 5FU/LV + aflibercept | Drug: Aflibercept<br>* 4 mg/kg administered intravenous infusion on day 1<br>Drug: Irinotecan<br>* 180 mg/m2 intravenous infusion<br>Drug: folinic acid (dl racemic)<br>* 400 mg/m2 intravenous infusion<br>Drug: 5Fluorouracil<br>* 400 mg/m2 intravenous bolus<br>Drug: 5-FU<br>* 2400 mg/m2 continuous intravenous infusion over 46 hours<br>|
| Active Comparator: Group B<br>FOLFIRI + aflibercept | Drug: Aflibercept<br>* 4 mg/kg administered intravenous infusion on day 1<br>Drug: Irinotecan<br>* 180 mg/m2 intravenous infusion<br>Drug: folinic acid (dl racemic)<br>* 400 mg/m2 intravenous infusion<br>Drug: 5Fluorouracil<br>* 400 mg/m2 intravenous bolus<br>Drug: 5-FU<br>* 2400 mg/m2 continuous intravenous infusion over 46 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate based on the RECIST criteria |  | 48 months | 
| Disease control rate |  | 48 months | 
| Depth of response |  | 48 months | 
| Time to progression |  | 48 months | 
| Time to treatment failure |  | 48 months | 
| Overall survival |  | 48 months | 
| Incidence and severity of AEs CTCAE v4.03 criteria |  | 48 months | 
| Incidence of dose adjustments and compliance |  | 48 months | 
| VES-13 score (Vulnerable Elders Survey) as the utility measure for health deterioration |  | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FOLFIRI, aflibercept, 5-FU, oxaliplatin, elderly, metastatic colorectal cancer