Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors

Inclusion Criteria:

* Male or female ≥ 18 years old
* Histologically confirmed diagnosis of colorectal cancer
* Asymptomatic or resected primary tumor
* Metastatic colorectal cancer patient not eligible for curative surgery
* At least one target lesion:

  * Unidimensionally measurable on cross-sectional imaging
  * In an area not previously irradiated
* Disease progression after failure of active drugs (5-Fu or 5-Fu prodrugs, irinotecan, oxaliplatin, bevacizumab)
* Patients with bone metastases are eligible if they have other measurable lesions
* WHO performance status ≤ 2
* Confirmation of KRAS mutation in codons 12 or 13 in the primary tumor or metastases
* Total bilirubin ≤ 1.5 ULN, ALT or AST ≤ 2.5 ULN (or \< 5 in case of liver impairment)
* Haemoglobin ≥ 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3
* Serum creatinine ≤ 1.5 ULN
* Negative pregnancy test in women of childbearing potential
* Use of an effective contraceptive method during the whole treatment and up to 3 months after the completion of treatment in males and females
* Life expectancy of at least 3 months
* Informed consent signed prior any study specific procedures
* Tumor evaluation should be performed within 3 weeks prior to starting treatment

Exclusion Criteria:

* History of Gilbert's syndrome
* Symptomatic brain metastases or carcinomatous meningitis
* Bone-only metastases
* History or presence of other cancers within the past 5 years (except curatively treated non-melanoma skin cancer and in situ cervical cancer)
* Prior surgery or radiotherapy within 4 weeks before entering the study
* Cardiac arrhythmia requiring treatment (except for beta-blockers and digoxin), unstable cardiac disease, myocardial infarction within the previous 6 months, \> grade II NYHA heart failure, uncontrolled hypertension
* Kalemia lower than normal serum potassium value
* From ECG, QTc interval \> 470 ms
* History of acute or chronic pancreatitis
* History of epileptic seizures requiring long-term anticonvulsant therapy
* History of organ transplantation with use of immunosuppression therapy
* Severe bacterial or fungal infection (Grade \> 2 NCI-CTCAE v.4.0)
* Known HIV infection
* Long-term use of CYP 3A4 enzyme-inducing agents such as rifampicin, St. John's Wort (hypericum perforatum), phenytoin, carbamazepine, phenobarbital, dexamethasone, and ketoconazole
* Pregnant or breastfeeding women
* Bowel malabsorption or extended bowel resection that could affect the absorption of sorafenib, occlusive syndrome, inability to take oral medications
* Inflammatory bowel disease with chronic diarrhea (NCI-CTCAE v.4.0)
* Participation in another clinical trial 30 days prior to study entry
* Concurrent treatment with any other investigational product or anticancer therapy (except for irinotecan or sorafenib)
* Psychological, social, geographical disorders or any other condition that would preclude study compliance (treatment administration and study follow-up).