RecruitingPhase 3NCT04781270

mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS Mutant Unresectable Colorectal Liver-limited Metastases

mFOLFOXIRI Plus Bevacizumab Versus mFOLFOX6 Plus Bevacizumab for the First Line Treatment of RAS Mutant Unresectable Colorectal Liver-limited Metastases

Sponsor

Fudan University

Enrollment

308 participants

Start Date

Apr 15, 2021

Study Type

INTERVENTIONAL

Conditions

Colorectal Carcinoma Liver Metastases

Summary

Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined. In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be tested for RAS and BRAF tumor mutation status. Patients with RAS mutant and BRAF wild type will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab and modified FOLFOX6 (mFOLFOX6) plus bevacizumab. Patient imaging will be reviewed for resectability by MDT, consisting of at least one radiologist and three liver surgeons every assessment. MDT review will be performed prior to randomization as well as during treatment, as described in the protocol.

Eligibility

Min Age: 18 YearsMax Age: 75 Years

Inclusion Criteria12

Histological proof of colorectal adenocarcinoma;
Age ≥ 18 years and ≤75 years;
Simultaneous liver-limited metastases;
Initially unresectable liver metastases determined by a local MDT;
RAS mutation and BRAF V600E wild-type;
At least one measurable liver metastasis;
Initially resectable primary tumor or primary tumor already resected;
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 Criteria12

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;

Interventions

DRUGmFOLFOXIRI regimen

oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1

DRUGmFOLFOX regimen

oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1

DRUGBevacizumab

5 mg/kg on day 1