Exploratory Study in Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases

Study Overview
=================
Brief Summary
-----------------
The correlation between the values of angiogenesis-related growth factors in plasma and efficacy, and biomarkers relevant as prognostic factors or predictive factors for sensitivity or resistance to treatment will be examined exploratively.

Detailed Description
-----------------
The correlation between the values of angiogenesis-related growth factors in plasma and efficacy, and biomarkers relevant as prognostic factors or predictive factors for sensitivity or resistance to treatment will be examined exploratively.

Official Title
-----------------
An Exploratory Study to Evaluate Biomarkers as Predictive and /or Prognostic Factors of Benefit From Randomized Phase ll Study of mFOLFOX6+Bevacizumab or mFOLFOX6+Cetuximab in Liver Only Metastasis From KRAS Wild Type Colorectal Cancer

Conditions
-----------------
Liver Metastasis, Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Drug: Cetuximab
* Drug: L-OHP
* Drug: l-LV
* Drug: 5-FU
* Drug: 5-FU


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who registered the ATOM trial and signed informed consent prior to initiation of any trial-specific procedure and treatment. Exclusion Criteria: None

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mFOLFOX + Bmab<br>mFOLFOX plus bevacizumab | Drug: Bevacizumab<br>* 5 mg/kg intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Avastin;Drug: L-OHP<br>* 85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Oxaliplatin;Drug: l-LV<br>* 200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Levofolinate;Drug: 5-FU<br>* 400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Fluorouracil;Drug: 5-FU<br>* 2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Fluorouracil;|
| Active Comparator: mFOLFOX + Cmab<br>mFOLFOX plus cetuximab | Drug: Cetuximab<br>* 250 mg/m2 intravenously administered over 60 minutes (400 mg/m2 over 120 minutes as the initial dose) on day 1 and day 8 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Erbitux;Drug: L-OHP<br>* 85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Oxaliplatin;Drug: l-LV<br>* 200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Levofolinate;Drug: 5-FU<br>* 400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Fluorouracil;Drug: 5-FU<br>* 2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.<br>* Other names: Fluorouracil;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the values of angiogenesis-related growth factors in plasma with Progression-free survival (PFS) | To evaluate the values of angiogenesis-related growth factors in plasma with PFS centrally assessed | Baseline, Cycle 8, Progression Disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the correlation of values of angiogenesis-related growth factors in plasma with efficacy and adverse events | Response rate, Tumor shrinkage rate, Liver resection rate, R0 liver resection rate( pathologically confirmed ), Progression-free survival(CT/MRI image assessed by the attending physician), Time to treatment-failure, Overall survival, Incidence of adverse events (drag-related, surgery-related) , Exploratory endpoints | Baseline, Cycle 8, Progression Disease | 
| Progression-free survival among the RAS wild type subpopulation |  | assessed every 8 weeks, up to 4 years | 
| Exploratory analysis of the relevance of tumor size and expression level of angiogenesis-related growth factors in plasma |  | Baseline, Cycle 8, Progression Disease | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver only metastasis from KRAS Exon 2 wild type, Liver only metastasis from RAS wild type