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

• ClinicalTrials.gov Identifier: NCT01543113
• Recruitment Status: Completed
• First Posted: March 2, 2012
• Last Update Posted: February 24, 2014
• Sponsor: Rennes University Hospital
• Collaborator: QIAGEN Gaithersburg, Inc
• Information provided by (Responsible Party): Rennes University Hospital

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 288 participants
• Allocation: N/A
• 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

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

Outcome Measures

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

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

Criteria

Inclusion Criteria:

• melanoma
• white caucasian population

Contacts and Locations

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

• Responsible Party: Rennes University Hospital
• ClinicalTrials.gov Identifier: NCT01543113
• 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