Folfiri/aflIbercept in Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status

Study Overview
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Brief Summary
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The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody. All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

Detailed Description
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The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody. Eligible patients will be prospectively allocated to either of two groups according to VEGFR2 levels (ELISA-based technique, pg/ml) at study entry. Others angiogenetic factors levels concentration before and during treatment. VEGF, PlGF, HGF, VEGFR1, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations will be evaluated before each cycle according to an ELISA-based technique All patients will undergo a blood test for retrieving circulating tumor DNA (Liquid Biopsy) at selected time-points before and during treatment for determining whether the status of selected tumor biomarkers evolve during tumor progression by comparing different ctDNA samples. All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

Official Title
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seconD-line Folfiri/aflIbercept in proSpecTIvely Stratified, Anti-EGFR resistaNt, Metastatic coloreCTal Cancer patIents With RAS Validated Wild typE Status

Conditions
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Advanced Colorectal Cancer

Intervention / Treatment
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* Procedure: Aflibercept, 5fluorouracil, Folinic Acid andIrinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Histological confirmation of colorectal cancer Confirmed RAS wild type patient treated with an oxaliplatin-anti EGFR treatment in 1st line At least one lesion measurable with CT or MRI scan Radiologically documented progression while on or after discontinuation of treatment with FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab) Radiologically documented progressing disease after FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab) Life expectancy plus 3 months Netrophils count ³ 1.5 x 109/L Platelets count ³ 100 x 109/L Hemoglobin ³ 9 g/dL Creatinine £ 1.5 mg/dL, Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour.Bilirubin £ 1.5 x ULN AST and ALT £ 2.5 x ULN (< 5 ULN in case of liver metastases) Informed written consent ECOG Performance Status < 2 Age plus18 yrs Regular follow-up feasible. For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment, Female patients must commit to using reliable and appropriate methods of contraception until at least six months after the end of study treatment Exclusion Criteria: • Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy), Treatment with any other investigational medicinal product within 28 days prior to First Study treatment. Other serious and uncontrolled non-malignant disease, History or evidence upon physical examination of CNS metastasis unless adequately treated Gilbert's syndrome Intolerance to atropine sulfate or loperamide Known dihydropyrimidine dehydrogenase deficiency Treatment with CYP3A4 inducers unless discontinued > 7 days prior to First Study treatment. 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 in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years, Major surgery or traumatic injury within the last 28 days or until the surgical wound is fully healed whichever came later Pregnant or breastfeeding women, Patients with known allergy to any excipient to study drugs, Bowel obstruction. Uncontrolled infections Known drugs or alcohol abuse History of severe cardiovascular disease within 6 months prior to First Study treatment Uncontrollable hypertension, when treated with three or more drugs.

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
Interventional Model Description: Biologically enriched phase II clinical trial. All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: standard chemotherapy for advanced colorectal cancer<br>All patients will receive aflibercept in combination with FOLFIRI according to the Italian label. | Procedure: Aflibercept, 5fluorouracil, Folinic Acid andIrinotecan<br>* All patients will receive aflibercept in combination with FOLFIRI according to the Italian label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) according to VEGFR2 levels, evaluating the difference in terms of median OS among patients with high VEGFR2 activity and patients with low VEGFR2 activity | Overall survival time is defined as the time from inclusion to the date of death. If subject has not died, survival will be censored on the last date the subject was known to be alive (last date of follow-up) | From date of randomization until the date of death from any cause, whichever came first, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) defined as the interval between the start of Aflibercept-FOLFIRI therapy to tumor progression or death or last follow up visit if not progressed | PFS time will defined as the time of inclusion until the date of first observed disease progression or death due to any cause, if death occurs before progression is documented | time from the start of treatment untill the date of first documented progression or death from any cause, whichever came first, assessed up to 3 years | 
| Response rate (RR) defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), v. 1.1 | All patients must be considered in response analysis, including those who discontinue treatment or who die for any reason prior to respnse evaluation | Response of treatment is evaluated according to the RECIST criteria at the end of chemotherapyassessed up to 24 weeks | 
| Toxicity Profile defined according to the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03 | Treatment-emergent adverse events, drug-related adverse events and safety laboratory parameters will be analysed by CTCAE grade | every 4 cycles of chemotherapy (each cycle is 15 days), up to 16 weeks | 
| Angiogenetic factors levels concentration before and during treatment. | Angiogenetic factors levels concentration (VEGF, PlGF, HGF, VEGF-R, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations) | evaluated before treatment and before each cycle (each cycle is 15 days) according to an ELISA-based technique, through completion, an overage of 1 year |