A Trial to Assess Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors (NEXIRI 2)

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).