Cetuximab+mFOLFOX6 VS. mFOLFOX6 Alone in RAS/BRAF Wild Type Patients With High-Risk Resectable CRLM

Study Overview
=================
Brief Summary
-----------------
For patients with initially resectable colorectal cancer liver metastases who have high-risk factors, neoadjuvant therapy is currently considered a consensus approach. However, there is ongoing debate regarding the optimal treatment strategy. Our study aims to investigate whether the addition of cetuximab to neoadjuvant chemotherapy improves outcomes compared to neoadjuvant chemotherapy alone. The objective of this phase III clinical trial is to determine whether the combination of cetuximab and mFOLFOX6 chemotherapy is superior to neoadjuvant mFOLFOX6 chemotherapy alone for patients with initially resectable colorectal cancer liver metastases who have wild-type RAS/BRAF and high-risk factors.

Detailed Description
-----------------
Primary • To determine whether the addition of cetuximab to neoadjuvant mFOLFOX6 chemotherapy results in improved event-free survival when compared with neoadjuvant mFOLFOX6 chemotherapy alone in patients with high-risk & RAS/BRAF-wild-type & resectable colorectal liver metastases. Secondary To evaluate the overall survival of patients treated with these regimens. To evaluate the quality of life of patients treated with these regimens. To evaluate the preoperative remission rate, safety, surgical complications, actual resection rate, pathological resection status of patients treated with these regimens.

Official Title
-----------------
Pre-and Post-operative Cetuximab Plus mFOLFOX6 Versus mFOLFOX6 Alone in RAS/BRAF Wild Type Patients With High-Risk Resectable Colorectal Liver Metastases

Conditions
-----------------
Colorectal Cancer, Liver Metastases

Intervention / Treatment
-----------------
* Drug: mFOLFOX6 + Cetuximab
* Drug: mFOLFOX 6


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological proof of colorectal adenocarcinoma; Age ≥ 18 years and ≤75 years; RAS wild type； CRS≥3； Simultaneous liver-limited metastases; At least one measurable liver metastases; World Health Organization (WHO) performance status 0-1; Life expectancy ≥ 3 months; Adequate hematologic function: absolute neutrophil count (ANC)≥1.5×109/l, platelets≥100×109/l, and hemoglobin(HB) ≥ 9g/dl; Adequate liver and renal function: total bilirubin ≤2.0 mg/dl, serum transaminases ≤ 5x upper limit of normal(ULN), and serum creatinine ≤ 1.5x ULN and creatinine clearance ≥ 30 ml/min; Written informed consent. Exclusion Criteria: Previous systemic treatment for metastatic disease; Previous surgery for metastatic disease; Extrahepatic metastases; Unresectable primary tumor; Major cardiovascular events (myocardial infarction, severe/unstable angina, congestive heart failure, CVA) within 12 months before randomisation; Acute or subacute intestinal obstruction; Second primary malignancy within the past 5 years; Drug or alcohol abuse; No legal capacity or limited legal capacity; Pregnant or lactating women; Uncontrolled hypertension, or unsatisfactory blood pressure control with ≥3 antihypertensive drugs; Peripheral neuropathy;

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mFOLFOX6 + Cetuximab<br>Cetuximab + mFOLFOX6: Cetuximab (500mg/m2 IV ) will be given. Oxaliplatin (85 mg/m2 IV over 2 h on day 1), Leucovorin calcium (350 mg/m2 IV over 2 h on day 1) plus a bolus of 5FU (400 mg/m2) followed by a 46h-48h IV infusion of 5FU 2400 mg/m2 will be repeated for every 2 weeks. The regimens repeat every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: mFOLFOX6 + Cetuximab<br>* Cetuximab + mFOLFOX6: Cetuximab (500mg/m2 IV ) will be given. Oxaliplatin (85 mg/m2 IV over 2 h on day 1), Leucovorin calcium (350 mg/m2 IV over 2 h on day 1) plus a bolus of 5FU (400 mg/m2) followed by a 46h-48h IV infusion of 5FU 2400 mg/m2 will be repeated for every 2 weeks. The regimens repeat every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.<br>|
| Active Comparator: mFOLFOX6<br>mFOLFOX6: Oxaliplatin (85 mg/m2 IV over 2 h on day 1), Leucovorin calcium (350 mg/m2 IV over 2 h on day 1) plus a bolus of 5FU (400 mg/m2) followed by a 46h-48h IV infusion of 5FU 2400 mg/m2 will be repeated for every 2 weeks. The regimens repeat every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: mFOLFOX 6<br>* mFOLFOX6: Oxaliplatin (85 mg/m2 IV over 2 h on day 1), Leucovorin calcium (350 mg/m2 IV over 2 h on day 1) plus a bolus of 5FU (400 mg/m2) followed by a 46h-48h IV infusion of 5FU 2400 mg/m2 will be repeated for every 2 weeks. The regimens repeat every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | The Event-free survival (EFS) was defined as the period from the start of initial medication to the date of tumor relapse, progression, or death | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | The overall survival (OS) was defined as the period from the start of initial medication until death from any cause, at which point the data was censored. | 5 years | 
| postoperative hospital stay | The postoperative hospital stay is defined as the number of date from the first day after operation to discharge. | 30 days post operatively | 
| postoperative complication | Patients will be evaluated for surgical morbidity during 1 month. Postoperative morbidity will be scored according 'Clavien-Dindo Grade'. | After surgery during one month | 
| postoperative mortality | any death occured within 90 days after the last resection of primary and metastatic lesions | After surgery during 90 days |