Efficacy of Nilotinib in First or Second Line Treatment of Primary Melanomas Stage III Unresectable Melanomas.

Inclusion Criteria:

* Patients with histologically proven melanoma with either c-KIT mutation or C-KIT amplification (without BRAF or NRAS mutation)
* Unresectable primary or stage III or stage IV melanoma
* Measurable disease (RECIST)
* The inclusion of patients with primary tumor or metastasis accessible to sequential biopsies will be favored. If such lesions are present, biopsies are mandatory and not optional
* No more than 1 previous specific therapy excluding tyrosine kinase inhibitors. 4 weeks wash out will be needed after cytotoxic therapy , 12 weeks wash out after anti -CTLA4 therapy or any immunological treatment
* No radiotherapy within 4 weeks ; previously irradiated lesion will not be considered as measurable unless progression at inclusion
* ECOG performance status \< 2
* WBC ≥ 3,000/mm³
* PNN ≥ 1,500/mm³ (G-CSF allowed)
* platelets ≥ 100,000/mm³
* Hb ≥ 9.0 g/dL ( transfusions allowed as well as recombinant erythropoetin)
* Creatinin clearance \> 40ml/mn
* Normal kalemia
* Normal magnesemia
* Total bilirubin \<1.5N ; ASAT and ALAT \<2.5N
* PT/INR and PTT normal
* NYHA class \< 3
* Signed Written Informed Consent
* Affiliated to the National Health Insurance

Exclusion Criteria:

* Patients refusal
* Age \< 18 years
* Fertile women who do not want or cannot use effective contraception during the study and up to 8 weeks after the end of study
* Women pregnant or nursing
* Women with positive pregnancy test at inclusion or before treatment initiation
* Fertile and sexually active men whose partner are fertile women who do not use effective contraception
* Clinical and/or radiographic evidence of active cerebral metastases
* Severe evolutive infection
* Known HIV infection
* Concomitant therapy with any other anti-cancer, immunomodulator or immunosuppressing agent or radiotherapy (except palliative care if bone metastases, after acceptance of principal investigator).
* Previous use of tyrosine kinase inhibitors
* More than one line of prior systemic therapies of melanoma by anti-cancer agent or immunotherapy.
* Received experimental treatment within 4 weeks of inclusion
* Pace-maker
* Cardiac dysfunction, as evaluated by one of:

  * Ejection fraction \< 45% (less than 28 days from inclusion)
  * Congenital prolonged QT
  * QTc \> 450 ms
  * Ventricular tachyarrhythmia within the past 6 months
  * Bradycardia at rest \< 50/mn
  * Major conduction dysfunction
  * Myocardial infarction within the previous 6 months
  * Unstable angina
* Uncontrolled hypertension
* Digestive disease that may inhibited NILITINIB absorption
* Concomitant medication that may increase QT
* Taking CYP3A4 inhibitors
* Eating Sevilla oranges (or Sevilla oranges derivates), grapefruit (or grapefruit juice), grapes (or grapes juice), pomegranate (or pomegranate juice)
* Hereditary galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.