cKIT, BRAF/NRAS Mutations in Advanced Melanoma : Clinical Outcome in Response to Tyrosine-kinase Inhibitors - KitMel Project (KitMel)

Background: Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients. Until now, available therapies were few and unreliable, but recent understanding of melanomas' molecular pathways has improve their classification and new clinical strategies have been proposed.

Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alteration being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). These include Superficial Spreading Melanomas (SSM) and Nodular Melanomas (NM). Other studies showed that c-Kit mutations are presently the predominant activating mutation (20 - 40 %) in Acro-Lentiginous Melanomas (ALM), Mucous Melanomas (MM) and in melanomas arising on CSD skin. c-Kit mutation pattern is more complex with four exons being affected leading to different mutations, which incidence and biological impact are less documented.

BRAF/NRAS genetics alterations drive constantly cell growth, being thus attractive targets. Spectacular results have indeed been obtained with the BRAF inhibitor that targets the V600E BRAF-mutated form. Data from GIST disease revealed that the different c-Kit mutations modulate differently c-Kit function and the response to targeted therapies.

Because c-Kit targeted therapy is a critical clinical issue, the investigators aimed to identify the most frequent mutations present in our population to propose appropriate screening test and adapt the therapy.

Methods: 250 melanoma samples corresponding to an homogeneous white-Caucasian population (Brittany, France) will be screened. c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible). c-Kit copy number will be quantified by q-PCR and level of c-Kit determined by immunohistochemistry (IHC, CD117). Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).

Expected Results:

Taken together, the investigators anticipate that the present genetic analysis of the tumours from patients with advanced melanoma will first document the type and frequency of cKit mutations, will confirm or not that BRAF, NRAS and cKit mutations are mutually exclusive and document their repartition in the melanomas sub-types. Finally this study will clue researchers in to how well patients will respond to a therapy that targets the growth-promoting proteins BRAF/NRAS and cKIT.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Other: sequencing

• Study Type: Interventional
• Enrollment (Actual): 288
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bretagne
    • Rennes, Bretagne, France, 35033
      • Rennes University Hospital
    • Rennes, Bretagne, France, 35000
      • Centre Eugene Marquis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• melanoma
• white caucasian population

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: melanoma	Other: sequencing; sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)	c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
level of c-Kit determined by immunohistochemistry	level of c-Kit determined by immunohistochemistry	Day 1
Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).	Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).	Day 1

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Collaborators: QIAGEN Gaithersburg, Inc
• Investigators: Principal Investigator: Marie-Dominique Galibert, PU-PH, Rennes University Hospital

Publications and helpful links

General Publications

• Pracht M, Mogha A, Lespagnol A, Fautrel A, Mouchet N, Le Gall F, Paumier V, Lefeuvre-Plesse C, Rioux-Leclerc N, Mosser J, Oger E, Adamski H, Galibert MD, Lesimple T. Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma. J Eur Acad Dermatol Venereol. 2015 Aug;29(8):1530-8. doi: 10.1111/jdv.12910. Epub 2015 Jan 26.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: February 21, 2012
• First Submitted That Met QC Criteria: March 1, 2012
• First Posted (Estimate): March 2, 2012

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: melanoma; white-caucasian population
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: LOC/10-16 - KitMel; 2010-A01310-39 (Other Identifier: AFSSAPS); 10/43-785 (Other Identifier: CPP Ouest V (Rennes)); 11.272 (Other Identifier: CCTIRS); 911305 (Other Identifier: CNIL)