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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.

Phase 2
18 Years
Open (Enrolling)
Malignant Skin Melanoma T0, Stage III Melanoma, Stage IV Melanoma, Amplification

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Trial Information

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 (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

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Patients with progressive disease after 3 months therapy will be withdrawn.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

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response

Outcome Description:

Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Celeste Lebbe, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Hôpital Saint-Louis, Paris, France


France: Ministry of Health

Study ID:




Start Date:

July 2010

Completion Date:

December 2013

Related Keywords:

  • Malignant Skin Melanoma T0
  • Stage III Melanoma
  • Stage IV Melanoma
  • Amplification
  • Malignant Skin Melanoma T0
  • stage III unresectable melanomas,
  • or stage IV melanomas with c-KIT mutation
  • or amplification.
  • Melanoma
  • Skin Neoplasms