Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer (Everest2)

• PFS rate at 9 months in the dose escalation arm [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  To provide a precise estimate (+/- 10%) of the progression-free survival rate at 9 months, in patients without skin toxicity at 3 weeks (according to NCI CTCAE v. 4.0), treated with FOLFIRI + escalating dose of cetuximab (arm A). It is expected that the PFS rate will be similar to that observed after standard cetuximab treatment + FOLFIRI in patients with grade 1-4 skin toxicity in a K-Ras wild type population (CRYSTAL study)
  
  

• Safety profile (NCI-CTCAE v. 4.0) of the combination in treatment arms [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]

  To evaluate PFS, OS, overall response and response rate in liver-limited disease, disease control rate, duration of response, general resection rate and R0 resection rate for metastatic lesions, skin toxicity, general safety, biomarkers, proteomics, expression profiling, mutations in each of the treatment arms.

  To evaluate pharmacokinetic parameters in patients in both treatment arms in selected centers

  
  
• Skin toxicity and correlations between outcome, PK and dose escalations [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]
  
• Overall response and response rate in liver-limited disease [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  
• Disease control rates [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  
• Duration of response [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  
• Progression free survival and overall survival [ Time Frame: 6 years ] [ Designated as safety issue: No ]
  
• R0 resection rate for metastatic lesions [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]
  
• Pharmacokinetic parameters in patients in both treatment arms in selected centers only [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  
• To perform biomarker analyses: proteomics, microarray and PCR studies on plasma and tumour respectively, in both treatment arms. [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  

Colorectal carcinoma (CRC) is the third most common form of cancer worldwide and remains a leading malignancy both in incidence and mortality.

In the light of existing knowledge, the investigators propose a phase II open label, two arm study in patients presenting with K-Ras wild-type metastatic colorectal tumours in the first line setting. The standard combination of irinotecan plus infusional 5-FU/LV (FOLFIRI) and cetuximab will be given to all patients entering the study. As the investigators hypothesize that increasing the dose of cetuximab might increase the intensity of skin reactions that directly correlates with outcome, in patients experiencing no skin toxicity, the dose of cetuximab will be escalated from 250 mg/m2 to 350 mg/m2 and then up to 500 mg/m2, in order to better define the effect of dose escalation in the first-line setting in a K-Ras wild type tumour population and in an attempt to increase efficacy.

Pharmacokinetic studies will be performed to document PK parameters of cetuximab in patients from both arms in selected centers.

Translational research studies are planned for all patients. Some more in depth molecular testing will be performed in a subset of patients from whom three serial tissue samples from accessible metastases by biopsy are available.