Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Bevacizumab With FOLFOX or FOLFIRI.

Study Overview
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Brief Summary
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The study is designed to analyze the pathological tumor response on resected colorectal cancer metastases after preoperative treatment with bevacizumab combined with FOLFOX or FOLFIRI regimen in a prospective cohort and to correlate this response with patient's outcome.

Detailed Description
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This is a phase II , openlabel, randomized study in patients with confirmed diagnosis of resectable metastatic colorectal adenocarcinoma , who have not received prior chemotherapy for their metastatic disease. The study is designed to compare pathological responses observed after pre-operative chemotherapy bevacizumab with FOLFOX or FOLFIRI.

Official Title
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Randomized Phase 2 Study Comparing Pathological Responses on Colorectal Cancer Metastases After Preoperative Treatment Combining Bevacizumab With FOLFOX or FOLFIRI

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Procedure: Metastases resection
* Drug: Bevacizumab
* Drug: 5 FU
* Drug: Oxaliplatin
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Female or male patients with at least 18 years at the time the informed consent is signed 2.ECOG (Eastern Cooperative Oncology Group)performance status 0 or 1 3.Histological or cytological confirmed diagnostic of adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Wild-type or mutated KRAS tumor status. 4.Patients must present a resectable metastatic disease for which the decision of preoperative chemotherapy is considered. Resectability could be planned in one or multiple stage if indicated. As commonly admitted, resectability means the surgical clearance (+/- radiofrequency ablation) of all detectable (liver) lesions with tumor-free margins and compatible with an adequate hepatic reserve. Practically, bilateral tumor location, number and location of lesions, and inadequate hepatic reserve remain the main decisional factors. 5.Partial and minor resection of metastatic disease is allowed within 3 months before inclusion if patient has never received chemotherapy for mCRC. 6.Extra hepatic metastatic location is limited to 1 site. Extra-hepatic location must be easily resectable in one stage surgery. 7.Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to inclusion (12 months for oxaliplatin). Previous radiotherapy to the pelvis is not an exclusion criterion. 8.Adequate haematological, renal and hepatic function as follows: Haematological Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L Renal Creatinine < 1.5 x ULN (Upper Limit of Normal) Hepatic Bilirubin < 1.5 X ULN AST(Aspartate aminotransferase), ALT (Alanine Aminotransferase) < 5 x ULN Phos Alc. < 5 x ULN 9.Proteinuria <2+ (dipstick urinalysis) or =1g/24hour. 10.No history of myocardial infarction and/or stroke within 6 months prior to randomization. No uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy. 11.Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception. 12.Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception. 13.Life expectancy of at least 3 months without any active treatment. Exclusion Criteria: 1.Non resectable mCRC (metastatic ColoRectal Cancer) (if resectability remains uncertain or unprobable after 3 months chemotherapy, patient is excluded from the trial). 2.Prior chemotherapy or systemic therapy for mCRC. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to inclusion. Oxaliplatin-based chemotherapy must be completed more than 1 year prior to inclusion. 3.Prior utilization of bevacizumab, aflibercept (or other anti-VEGF(vascular endothelial growth factor) therapy). 4.Previous radiotherapy delivered to the upper abdomen. 5.Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiologic assessment. 6.Prior major liver resection: remnant liver < 50% of the initial liver volume. 7.Non-malignant disease that would render the patient unsuitable for treatment according to this protocol. 8.Concurrent central nervous systems metastases 9.Peripheric neuropathy ≥ grade 2. 10.Interstitial lung disease 11.Pregnant or breast feeding. 12.The patient has previous or concomitant malignancies, except: Invasive malignancies in remission for more than 5 years and non melanoma skin cancer or carcinoma in situ of the cervix.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Folfox: oxaliplatin +leucovorin+ 5FU<br>FOLFOX (oxaliplatin +leucovorin+ 5FU) +bevacizumab+ metastases resection | Procedure: Metastases resection<br>* Surgery of colorectal cancer metastases will be proceeded after 3 to 6 cycles of chemotherapy ( folfox or folfiri) + bevacizumab .<br>Drug: Bevacizumab<br>* Bevacizumab 5 mg/kg in 100 ml NaCl 0.9% IV infusion 3 to 5 cycles. No bevacizumab for ultimate cycle .<br>* Other names: Avastin;Drug: 5 FU<br>* Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, IV infusion 3 to 6 cycles 5-FU bolus 400 mg/m2, IV bolus 3 to 6 cycles 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion 3 to 6 cycles<br>* Other names: 5-Fluorouracile;Drug: Oxaliplatin<br>* oxaliplatin 85 mg/m² in 150 ml NaCl 0.9%, IV infusion 3 to 6 cycles<br>* Other names: Eloxatin;|
| Active Comparator: FOLFIRI: irinotecan+leucovorin+5FU<br>FOLFIRI (irinotecan+leucovorin+5FU) +bevacizumab +metastases resection | Procedure: Metastases resection<br>* Surgery of colorectal cancer metastases will be proceeded after 3 to 6 cycles of chemotherapy ( folfox or folfiri) + bevacizumab .<br>Drug: Bevacizumab<br>* Bevacizumab 5 mg/kg in 100 ml NaCl 0.9% IV infusion 3 to 5 cycles. No bevacizumab for ultimate cycle .<br>* Other names: Avastin;Drug: 5 FU<br>* Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, IV infusion 3 to 6 cycles 5-FU bolus 400 mg/m2, IV bolus 3 to 6 cycles 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion 3 to 6 cycles<br>* Other names: 5-Fluorouracile;Drug: Irinotecan<br>* Irinotecan 180 mg/m² in 150 ml NaCl 0.9%, IV infusion 3 to 6 cycles<br>* Other names: Irinosin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the major pathological response rate | This is at the surgery time. The metastases resection must be process after 6 cycles of randomized chemotherapy + target therapy. It depend but it will be normally 3 months after patient inclusion in the study | After surgery (Metastases resection-average 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | at 6 months and at 12 months after randomization | 
| Overall Survival | The overall survival will be analyzed at the end of the study (3 years of recruitment and one years of follow-up) | At the end of the study | 
| Clinical Response Rate |  | At time of surgery - average 3 months | 
| Metabolic Response Rate |  | At time of surgery - Average 3 months | 
| Post operative complication |  | One month after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, colorectal, cancer, liver, Bevacizumab, Pathological response