Amplification, Malignant Skin Melanoma T0, Stage III Melanoma, Stage IV Melanoma
Conditions
Keywords
Malignant Skin Melanoma T0, stage III unresectable melanomas,, or stage IV melanomas with c-KIT mutation, or amplification.
Brief 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 Patients with progressive disease after 3 months therapy will be withdrawn.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
Interventions
DRUGNilotinib
Nilotinib 400 mg twice per day
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response | 6 months | Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease control | 6 months | Complete or partial response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST). |
| Objective response | 3 months | Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST). |
| Metabolic response | 6 months | Metabolic response as evaluated by TEP-SCAN |
| Tolerance | 1 year | Tolerance will be evaluated according to National Cancer Institute (NCI) Criteria for Adverse Events, CTCAE v3.0 |
Countries
France
Contacts
Primary ContactZakia Idir, PhD
Outcome results
None listed