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

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.


Eligibility Criteria:
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