Phase II Trial to Assess FOLFIRI+Aflibercept Efficacy in Patients With Oxaliplatin-pretreated Metastatic Colorectal Cancer With or Without ACE Polymorphisms

Study Overview
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Brief Summary
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The purpose of this study is to assess FOLFIRI+aflibercept efficacy in patients with or without ACE polymorphisms in terms of Progression-free survival (PFS).

Official Title
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A Phase II Trial to Assess FOLFIRI+Aflibercept Efficacy in Patients With Oxaliplatin-pretreated Metastatic Colorectal Cancer With or Without ACE Polymorphisms

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFIRI+aflibercept


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, Metastatic disease confirmed. 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 an oxaliplatin-containing regimen. Age ≥18 years World Health Organization (WHO) Performance status (PS) 0-2, Hematological status: neutrophils (ANC) ≥1.5x109 /L; platelets ≥100x109 /L; haemoglobin ≥9g/dL Adequate renal function: serum creatinine level < 1.5 x ULN 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. For female patients of childbearing potential, negative serum pregnancy test Female patients must commit to using reliable and appropriate methods of contraception until at least three months after the end of study treatment (when applicable). 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 ncephalopathy, 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), 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 Pregnant or breastfeeding women, 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.

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: FOLFIRI+aflibercept<br> | Drug: FOLFIRI+aflibercept<br>* Aflibercept: 4 mg/kg administered intravenous infusion on day 1 FOLFIRI regimen immediately after aflibercept: Irinotecan:180 mg/m2 intravenous infusion, folinic acid (dl racemic): 400 mg/m2 intravenous infusion, followed by 5-fluorouracil (5-FU): 400 mg/m2 intravenous bolus, followed by 5-FU: 2400 mg/m2 continuous intravenous infusion over 46 hours. * folinic acid: 400 mg/m² (racémic) or 200 mg/m² (L-form)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FOLFIRI+aflibercept efficacy in terms of Progression-free survival (PFS) with or without ACE polymorphisms. |  | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) with or without AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Objective Response Rate (ORR) with or without ACE polymorphisms, AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Disease Control Rate (DCR) with or without ACE polymorphisms, AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Time to progression (TP) with or without ACE polymorphisms, AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Time to treatment failure (TTF) with or without ACE polymorphisms, AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Overall survival (OS) with or without ACE polymorphisms, AGTR1 polymorphisms, according Serum-level sACE |  | 30 months | 
| Number of participants with adverse events as assessed by CTCAE v4.0. |  | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic colorectal cancer, FOLFIRI, aflibercept, oxaliplatin, ACE polymorphisms