efficacy of nilotinib in first or second line treatment of primary melanomas stage iii unresectable melanomas.

Conditions: Malignant Skin Melanoma T0; Stage III Melanoma; Stage IV Melanoma; Amplification

Summary: nilomel is a phase ii multicentric uncontrolled open national trial assessing the efficacy of nilotinib in first or second line treatment of primary melanomas , stage iii unresectable melanomas, or stage iv melanomas with c-kit mutation or amplification. the primary objective is overall response rate (partial and complete response) according to recist 1.1 criteria, assessed using ct-scan (stage iv melanoma) or mri (unresectable melanoma) after 6 months therapy with nilotinib 800 mg/d. secondary objectives include: * disease control rate (complete, partial response and stable disease) * metabolic response * tolerance nci ctcae version 3.0 * biomarkers associated to response and disease control.

nilomel is a phase ii multicentric uncontrolled open national trial assessing the efficacy of nilotinib in first or second line treatment of primary melanomas , stage iii unresectable melanomas, or stage iv melanomas with c-kit mutation or amplification (in case of c-kit amplification, no b-raf nor n-ras mutation should be detected). the primary objective is overall response rate (partial and complete response) according to recist 1.1 criteria, assessed using ct-scan (stage iv melanoma) or mri (unresectable melanoma) after 6 months therapy with nilotinib 800 mg/d. secondary objectives include: * disease control rate (complete, partial response and stable disease) according to recist * metabolic response rate (tep-scan) * tolerance nci ctcae version 3.0 * biomarkers associated to response and disease control (evaluated at m0, m1 and m6). protein analysis of c-kit, pi3k, mapk and stat signalling pathways as well as pdgfr and ephrin signalling pathways. patients with progressive disease after 3 months therapy will be withdrawn. patient with stable disease after 3 months will continue nilotinib until evaluation at 6 months. patients with stable disease or progressive disease at 6 months will continue nilotinib until progression. the trial has been planned using a one-stage design (fleming tr) . we considered that a response rate under 7.5% would define the null hypothesis of no efficacy . to detect a response rate of 30% or more with power 90% using a one-sided test at the 0.05 level, 25 patients have to be recruited. accrual for 2.5 years total study duration: 3 years

Eligibility criteria:
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.

Keywords: malignant skin melanoma t0 stage iii unresectable melanomas, or stage iv melanomas with c-kit mutation or amplification.