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

Phase 2

• Conditions: Malignant Skin Melanoma T0; Stage III Melanoma; Stage IV Melanoma; Amplification
• Interventions: Drug: Nilotinib

• Registration Number: NCT01168050
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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Patients with progressive disease after 3 months therapy will be withdrawn.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

Study Timeline

• Study Start: 2010-07
• Study First Submitted: 2010-07-21
• Study First Submitted QC: 2010-07-21
• Study First Posted: 2010-07-22
• Status Verified: 2011-02
• Last Update Submitted: 2011-02-07
• Last Update Posted: 2011-02-08
• Primary Completion: 2013-12
• Study Completion: 2013-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 25

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nilotinib	Nilotinib	-

Primary Outcome Measures

Name	Time	Method
Objective response	6 months	Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).

Secondary Outcome Measures

Name	Time	Method
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
Disease control	6 months	Complete or partial response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST).
Tolerance	1 year	Tolerance will be evaluated according to National Cancer Institute (NCI) Criteria for Adverse Events, CTCAE v3.0

Trial Locations

Locations (1)

Hôpital Saint-Louis; 🇫🇷 Paris, France