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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Melanoma	Other: sequencing	Not Applicable

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	288 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Diagnostic
Official Title:	cKIT, BRAF/NRAS Mutations in Advanced Melanoma : Clinical Outcome in Response to Tyrosine-kinase Inhibitors - KitMel Project
Study Start Date :	January 2011
Actual Primary Completion Date :	March 2012
Actual Study Completion Date :	February 2014

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
melanoma; melanoma	Other: sequencing; sequencing

Outcome Measures

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible) [ Time Frame: Day 1 ]
   c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)

Secondary Outcome Measures :

1. level of c-Kit determined by immunohistochemistry [ Time Frame: Day 1 ]
   level of c-Kit determined by immunohistochemistry
2. 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). [ Time Frame: 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).

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• melanoma
• white caucasian population

Contacts and Locations

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Locations

France
Centre Eugène Marquis
Rennes, Bretagne, France, 35000
Rennes University Hospital
Rennes, Bretagne, France, 35033

Sponsors and Collaborators

Rennes University Hospital

QIAGEN Gaithersburg, Inc

Investigators

Principal Investigator:	Marie-Dominique Galibert, PU-PH	Rennes University Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Rennes University Hospital
ClinicalTrials.gov Identifier:	NCT01543113 History of Changes
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 )
First Posted:	March 2, 2012
Last Update Posted:	February 24, 2014
Last Verified:	February 2014

Keywords provided by Rennes University Hospital:

melanoma; white-caucasian population

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal	Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas