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

Phase II Multicentric Uncontrolled 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.

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Patients with progressive disease after 3 months therapy will be withdrawn.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

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.