Patient case: 49-year-old male with melanoma; genetic feature: extensive tumor infiltrating lymphocytes

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

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.

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  Patients with progressive disease after 3 months therapy will be withdrawn.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

Relevance to patient case: not relevant