Sorafenib With Irinotecan in Metastatic Colorectal Cancer (mCRC) and K-RAS Mutation

SORAFENIB (NEXAVAR®) in Combination With Irinotecan in the Second Line Treatment or More of Metastatic Colorectal Cancer With K-RAS Mutation : a Multicentre Two-part Phase I/II Study.

A multicentre two-part phase I/II study evaluating response and safety of SORAFENIB in combination with irinotecan in the second line treatment or more of metastatic colorectal cancer with K-RAS mutation.

Inclusion Criteria:

• Age > 18
• Written informed consent
• Histologically proven adenocarcinoma of the colon or rectum asymptomatic primary tumour or surgically removed mCRC patients with previously unresectable metastatic disease
• Patient with at least one tumoral lesion: measurable in a unidimensional way with a spiral scanner according to RECIST, no previous irradiation in this area
• Disease progression after irinotecan-based chemotherapy
• Disease progression after one or more previous lines of chemotherapy received in metastatic situation
• WHO <= 2
• Patient having a mutated KRAS on 12 or 13 codons on the primary tumour or a metastasis
• Adequate liver function : Bilirubin ≤ 1,5 x UNL, ASAT ou ALAT ≤ 2,5 x UNL (or < 5 x UNL for subjects having a hepatic insufficiency in connection with hepatic metastases)
• Polynuclear neutrophils ≥ 1 500/mm3
• Haemoglobin > 10g/dl
• Platelets ≥ 100 000/mm3
• Amylase and lipase < 1,5 x UNL
• Serum Creatinin < 1,5 x UNL
• Adapted contraceptive measures during treatment and continued at least three months after end of the treatment
• Life expectancy > 3 months
• Affiliated to or benefiting from health insurance

Exclusion Criteria:

• Gilbert's disease
• Brain metastases or carcinomatous symptomatic meningitis
• Exclusive bone metastasis
• Previous cancers not considered as cured in the 5 years before inclusion (except for baso-cellular skin carcinoma) Surgery (except diagnostic biopsy) or radiotherapy within 4 weeks before inclusion
• Disorders of the cardiac rhythm requiring an anti-asynchronous treatment (except beta blockers or digoxine within the framework of a chronic auricular fibrillation), unstable coronaropathy or myocardial infarction < 6 months, congestive cardiac failure > Rank II NYHA (Grade 2), uncontrolled arterial hypertension
• Previous epilepsy crises requiring long term antiepileptic treatment Previous organ transplant requiring immunosuppressor treatment Severe bacterial or fungus infection (> Grade 2 NCI CTC version 3) Known HIV Infection
• Long term treatment by known inductors of the CYP 3A4 like Rifampicin, Millepertuis (hypericum perforatum), Phenytoin, Carbamazepin, Phenobarbital, Dexamethasone et Ketonazole
• Known allergy to one of the therapeutic agents
• Reasons (psychological, family, social or geographical) that could compromise the participation of the patient in the study
• Intestinal malabsorption or gastro-intestinal surgery being able to affect Sorafenib absorption. Occlusive or sub-occlusive syndrome.
• Dysphagic patient or patient not being able to take treatment by orally inflammatory
• Chronic digestive disease involving chronic diarrhoea (NCI N+Bethesda >= 1.2g)
• Participation in another clinical trial within 30 days before the start of this study
• Other concomitant experimental drugs or other concomitant anticancer agents (except Irinotecan and Sorafenib)
• Medical or psychological state that in the opinion of the investigator will not allow the patient to terminate the study or to understand and sign the informed consent form
• Pregnancy and breast-feeding