The primary objective of the study is to increase by 15% the complete macroscopic resection rate of predominantly liver metastases from metastatic colorectal cancer through combining systemic cetuximab and hepatic artery infusion of three-drug chemotherapy (irinotecan, oxaliplatin and 5-fluorouracil).

Primary end-point: incidence of complete macroscopic resections of liver metastases (R0+R1).

Secondary end-points:

• the rate of histologic complete responses,
• the individual rates of R0 and R1 resections,
• the rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy,,
• the relapse-free survival curve and median in the resected patients,
• the progression-free and the overall survival in the patients receiving at least 4 full courses of HAI therapy and in all the patients (intent to treat),
• the objective response rate,
• the rate of adverse events,
• the dose intensities over 3, 6 and 9 courses,
• the per-operative and post-operative complications associated to liver surgery.

The study also includes a pharmacokinetic analysis, a translational research and a rest/activity monitoring investigation.

Open, label, European, non randomized, multicenter, phase II study of intravenous cetuximab (ERBITUX®) and hepatic artery infusion of three-drug chemotherapy (irinotecan, 5-fluorouracil and oxaliplatin) using conventional or chronomodulated delivery (according to institution experience) in patients with liver metastases from colorectal cancer.

Patients undergo partial hepatectomy after 6 ± 3 courses of therapy whenever possible. The minimum of 3 and the maximum of 9 courses before liver surgery depend upon results from iterative onco-surgical evaluations. A minimum of 6 and up to 9 additional courses of therapy will be administered after surgery, depending upon results of liver surgery, pathology report and patient's status. Overall, the patients will receive 9 to 18 courses of protocol therapy.

The interval between the last course of cetuximab-HAI chemotherapy and surgery will be 2 to 4 weeks. Post operative treatment will be initiated 2 to 4 weeks after liver surgery.

TRANSLATIONAL RESEARCH:

1. Pharmacokinetics:

   For a subset of 16 patients (8 on conventional administration and 8 on chronotherapeutic delivery), plasma pharmacokinetics of irinotecan, 5-FU and oxaliplatin and main metabolites will be evaluated after the first course.

2. Rest-Activity monitoring:

   Rest-activity will be monitored with a wrist-worn actigraph (Ambulatory Monitoring, USA) for 1 week prior to treatment onset and during the 2 weeks following treatment onset (3 weeks). This evaluation will be repeated before, during and after the 4th treatment course and before during and after 7th treatment course. Participation of the centers to this investigation will be left optional.

   Time series will be analyzed before, during and after chemotherapy course, with the time courses of the following parameters:

   • Autocorrelation coefficient at 24 h (r24)
   • Dichotomy index I\

• Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of liver metastases (new confirmation of metastatic disease is required in case the time interval from last histological diagnosis to enrolment exceeds 3 years).

• Patient with wild type (WT) KRAS tumor status

• Patient whose liver metastases are considered to be non resectable with curative intent in medico-surgical staff meeting. In particular patients with at least one of the following criteria, which prevent complete local treatment of liver metastasis with surgery alone or surgery plus radiofrequency ablation because:

  • less than 30% estimated residual liver after resection
  • disease in contact with liver main vessels
  • documented progressive disease on imaging documents or doubling of serum levels of carcino-embryonic antigen (CEA) or CA19.9 over the past 90 days or less

• Patient with up to three resectable extrahepatic nodules of <= 10 mm

• One, two or three prior chemotherapy lines for colorectal cancer.

• Written informed consent.

• Age >=18 years.

• Patient must be able to comply with the protocol.

• Life expectancy of at least 3 months.

• At least one measurable metastatic liver lesion (as per RECIST criteria).

• World Health Organization performance status of 0 or 1.

• Adequate hematological function: absolute neutrophil count (ANC) >=1.0 x 10^9/L; platelets >=75 x 10^9/L, hemoglobin (Hb) >=8.5 g/dL.

• International normalized ratio (INR) <=1.5 and activated partial thromboplastin time (aPTT) <=1.5 x upper limit of normal (ULN) within 7 days prior to starting study treatment, in the absence of anticoagulant therapy.

• Liver function: serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <5 x ULN (liver metastases).

• Serum creatinine <= 1.5 x ULN.

• Fertile women and men of childbearing potential (<2 years after last menstruation in women) must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).

Exclusion Criteria:

• Patient whose primary tumor or metastasis displays mutation of K-Ras (codon 12 and/or 13).
• Unresectable extrahepatic diseases.
• More than three resectable extrahepatic nodules.
• Size of extra hepatic nodules > 1 cm
• Prior HAI of the 3 drugs.
• More than 2 prior surgical attempts for metastatic disease
• Prior radiotherapy for metastatic disease
• Known documented intolerance or hypersensitivity to any of the drugs used.
• Sensory neuropathy grade 3 (National Cancer Institute-Common Terminology Criteria for Adverse Events -NCI-CTCAE, Version 3.0).
• Past or current history (within the last 2 years prior to treatment start) of malignancy other than colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
• Serious, non healing wound, ulcer, or bone fracture.
• Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that puts the patient at high risk for treatment-related complications.
• Pregnancy or lactation
• Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.

Prior systemic administration of cetuximab or other anti-EGFR agent is not an exclusion criterion.