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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Detailed Description
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Description: The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Official Title
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Randomized Phase II Study of mFOLFOX6 + Bevacizumab or mFOLFOX6 + Cetuximab in Liver Only Metastasis From KRAS Wild Type Colorectal Cancer

Conditions
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Liver Only Metastasis From KRAS Exon 2 Wild Type (Under Protocol 1.0-1.2 Edition) and RAS Wild Type (Under Protocol 2.0 Edition) Colorectal Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed colorectal cancer (adenocarcinoma) excluding vermiform appendix cancer and proctos cancer. RAS wild type Synchronous* or metachronous liver limited meitastasis with no extrahepatic desiease shychronous liver limited metastasis with primary lesion less than two thirds of the circumference patients with primary lesion more than two thirds of the circumference can be enrolled after primary resection Patients who has one or more lesion(s) of diameter 1 cm or larger (RECEST v1.1) be able to assess continuously on the basis of the protocol by contrast enhanced CT or contrast enhanced MRI of the liver: (1)Liver metastases 5 or more (2)Liver metastases with 5 cm or larger in greatest dimension (3)Unresectable considering remaining hepatic function (4)Invasion into all hepatic veins or inferior vena cava (5)Invasion into both right and left hepatic arteries or portal veins 5.No prior chemotherapy for colorectal cancer including hepatic arterial infusion. Excluding postoperative and preoperative chemoradiotherapy except for rectal cancer with synchronous liver metastases. Patients received postoperative chemotherapy containing oxaliplatin have to be enrolled after 24 weeks from the last oxaliplatin administration. 6.No previous treatment including ablation therapy, cryotherapy and chemotherapy for metastases 7.Age at enrollment is >=20 and =<80 years 8.The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 9.Life expectancy from the day of enrollment is 3 months or longer 10.Major organ functions less than 14 days prior to entry meet the following criteria. Neu >= 1500/mm3 Pt >= 10.0x10^4/mm3 Hb >= 9.0 g/dL T-bil =< 2.0 mg/dL AST and ALT =< 200 IU/L sCr =< 1.20 mg/dL INR < 1.5 Proteinuria =< 2+ 11.Written informed consent Exclusion Criteria: Previously experienced severe allergic reaction to drugs Receiving anti-platelet drugs (aspirin >= 325 mg/day) or NSAIDs Receiving chronic systemic corticosteroid treatment Surgery/ biopsy with skin incision or traumatic injury with suture less than 14 days prior to entry. Excluding, suture for implanted venous reservoirs with catherter is allowed. Severe postoperative complications (e.g. postoperative infection, anastomic dehiscence or paralytic ileus) Diagnosed as hereditary colorectal cancer Active other malignancies Cerebrovascular disease or symptoms less than 1 year prior to entry Pleural effusion, ascites or cardiac effusion requiring drainage Hemorrhage/bleeding, paralytic ileus, obstruction or ulceration of gastrointestinal tract Perforation of gastrointestinal tract less than 1 year prior to entry Presence of active infection HBs antigen or HCV antibody positive Uncontrolled comorbidity including hypertension, diabetes, arrhythmia, or other diseases (such as cardiac disorder, interstitial pneumonia or renal disorder) Presence of >= grade 2 diarrhea Presence of >= grade 1 peripheral neuropathy Pregnant or lactating women. Women and men with childbearing potential unwilling to use effective means of contraception Psychosis or psychiatric symptoms who are not able to comply with the protocol Any other medical conditions disable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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: 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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | assessed by Independent Review Committee | assessed every 8 weeks, up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  | assessed every 8 weeks, up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bevacizumab, Cetuximab, KRAS wild type colorectal cancer, RAS wild type colorectal cancer, liver metastasis