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

A Randomized Phase II Trial Assessing Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors After Failure of All Drugs Known to be Effective

The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.

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).