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Melanoma: HELP
Articles by Thomas Jouary
Based on 30 articles published since 2009
(Why 30 articles?)
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Between 2009 and 2019, T. Jouary wrote the following 30 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline French updated recommendations in Stage I to III melanoma treatment and management. 2017

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J F / De La Fouchardiere, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Dermatology Department, CHU Montpellier. · Dermatology Department, CHU Dijon. · Laboratory of Biochemistry, CHU Nantes. · Dermatology Department, CHU Rennes. · Laboratory of Pathology, AP-HP Ambroise Paré Hospital, Boulogne, France. · Laboratory of Pathology, Centre Léon Bérard Lyon. · Department of Nuclear medicine, CHU Bordeaux. · Dermatology Department, CH Pau. · Department of Radiology, Institut Gustave Roussy Villejuif. · Department of Radiotherapy, Centre Oscar Lambret Lille. · Institut Curie, Paris, France. · 1 Avenue du 6 Juin, 1945, 14000 Caen, France. · Louvain Catholic University, Brussels, Belgium. ·J Eur Acad Dermatol Venereol · Pubmed #28120528.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé in France. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2 cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in Stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of Stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3 years) is recommended for patients, but with greater emphasis on imaging.

2 Guideline [Update to the recommendations for management of melanoma stages I to III]. 2016

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J-F / De La Fouchardière, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Département de dermatologie, hôpital Saint-Éloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré-Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire Sud et Pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, centre hospitalier de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · 1, avenue du 6-Juin, 14000 Caen, France. · Université catholique de Louvain, 10, avenue Hippocrate, 1200 Bruxelles, Belgique. ·Ann Dermatol Venereol · Pubmed #27527567.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3years) is recommended for patients, but with greater emphasis on imaging.

3 Guideline [Guidelines for stage I to III melanoma]. 2016

Guillot, Bernard / Dalac, Sophie / Denis, Marc / Dupuy, Alain / Emile, Jean François / De La Fouchardiere, Arnaud / Hindie, Elif / Jouary, Thomas / Lassau, Nathalie / Mirabel, Xavier / Piperno Neumann, Sophie / De Raucourt, Sixtine / Vanwijck, Romain. ·Département de dermatologie, hôpital Saint-Eloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire sud et pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, CH de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Sixtine, 1, avenue du 6 juin, 14000 Caen, France. · Université catholique de Louvain, avenue Hippocrate, 10 B-1200 Bruxelles, Belgique. ·Bull Cancer · Pubmed #27456259.

ABSTRACT: -- No abstract --

4 Review [Systemic treatment of melanoma brain metastases]. 2015

Le Rhun, É / Mateus, C / Mortier, L / Dhermain, F / Guillot, B / Grob, J-J / Lebbe, C / Thomas, M / Jouary, T / Leccia, M-T / Robert, C. ·Neuro-oncologie, département de neurochirurgie, hôpital Roger-Salengro, CHRU, rue Émile-Laine, 59037 Lille cedex, France; Oncologie médicale, centre Oscar-Lambret, 3, rue Frédéric-Combemale, BP 307, 59020 Lille cedex, France; Inserm U1192, laboratoire Prism, université Lille 1, bâtiment SN3 1(er) étage, 59655 Villeneuve-d'Ascq cedex, France; Groupe de réflexion sur la prise en charge des métastases cérébrales (GRPCMaC), 13273 Marseille cedex 09, France. Electronic address: emilie.lerhun@chru-lille.fr. · Département de dermatologie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. · Département de dermatologie, centre hospitalier régional et universitaire de Lille, 2, avenue Oscar-Lambret, 59037 Lille cedex, France. · Groupe de réflexion sur la prise en charge des métastases cérébrales (GRPCMaC), 13273 Marseille cedex 09, France; Département de radiothérapie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France; Réunion de concertation pluridisciplinaire de neuro-oncologie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. · Département de dermatologie, centre hospitalier universitaire, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France; Université Montpellier 1, 5, boulevard Henri-IV, CS 19044, 34967 Montpellier cedex 2, France. · Département de dermatologie, centre hospitalo-universitaire, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France. · Département de dermatologie, hôpital Saint-Louis, Assistance publique-Hôpitaux de Paris, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Service de dermatologie, pôle d'oncologie-radiothérapie, de dermatologie et des soins palliatifs, groupe hospitalier Saint-André, centre hospitalier universitaire de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux, France. · Clinique de dermatologie, d'allergologie et de photobiologie, centre hospitalier Albert-Michallon, boulevard de la Chantourne, BP 217, 38043 Grenoble cedex 9, France; Inserm U832, institut A.-Bonniot, 38043 Grenoble cedex 09, France. ·Cancer Radiother · Pubmed #25656856.

ABSTRACT: Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

5 Review [What's new in skin cancers?]. 2014

Jouary, Th. ·Service d'oncologie médicale, hôpital François-Mitterrand, 4, boulevard Hauterive, 64000 Pau, France; Service de dermatologie, hôpital Saint-André, 1, rue Jean-Burguet, 33075 Bordeaux, France. Electronic address: thomas.jouary@ch-pau.fr. ·Ann Dermatol Venereol · Pubmed #25539755.

ABSTRACT: The present "what's new in oncology in 2014?" is in keeping with data reported in the past years. Indeed, metastatic melanoma still keeps the lion's share. The results of the combinations schedules with BRAF and MEK inhibitors showed an improvement in progression-free survival. Otherwise, resistance mechanisms to MAPKinase pathway inhibitors are of interest worldwide. Nevertheless, more fundamental and transversal researches are currently being investigated than validated schedules in daily clinical practice. Following anti-CTLA-4 drugs, second-generation immunotherapies, including anti-PD1 and PD-L1 molecules, confirmed their results in extended cohorts. In the setting of localized melanoma, the final results from MLST-1, Morton's study, regarding the sentinel node procedure versus observation alone, prompted a new enhancement in the sentinel node controversy. From another point of view, "what is not new in oncology in 2014?" In this area, the absence of original investigations on the primary melanoma detection in France and the absence of innovations in the adjuvant treatment of melanoma after surgery should be mentioned. While recent revolutionary drugs, i.e. targeted therapies and immunotherapies, will know advances under the resistance pressure in a near future, a revolution is still awaited in melanoma earlier stages.

6 Clinical Trial MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. 2018

Dreno, Brigitte / Thompson, John F / Smithers, Bernard Mark / Santinami, Mario / Jouary, Thomas / Gutzmer, Ralf / Levchenko, Evgeny / Rutkowski, Piotr / Grob, Jean-Jacques / Korovin, Sergii / Drucis, Kamil / Grange, Florent / Machet, Laurent / Hersey, Peter / Krajsova, Ivana / Testori, Alessandro / Conry, Robert / Guillot, Bernard / Kruit, Wim H J / Demidov, Lev / Thompson, John A / Bondarenko, Igor / Jaroszek, Jaroslaw / Puig, Susana / Cinat, Gabriela / Hauschild, Axel / Goeman, Jelle J / van Houwelingen, Hans C / Ulloa-Montoya, Fernando / Callegaro, Andrea / Dizier, Benjamin / Spiessens, Bart / Debois, Muriel / Brichard, Vincent G / Louahed, Jamila / Therasse, Patrick / Debruyne, Channa / Kirkwood, John M. ·Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France. · Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. · Petrov Research Institute of Oncology, St Petersburg, Russia. · Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. · Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. · Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France. · Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France. · Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Dermato-oncology Department, General University Hospital, Prague, Czech Republic. · Columbus Clinic Center, Milan, Italy. · Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. · Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France. · Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. · Cancer Research Center, Moscow, Russia. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. · Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. · Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. · Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. · GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. · GlaxoSmithKline, Rixensart, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. · GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. · GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. · UPMC Hillman Cancer Center, Pittsburgh, PA, USA. ·Lancet Oncol · Pubmed #29908991.

ABSTRACT: BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

7 Clinical Trial STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network. 2018

Delyon, Julie / Chevret, Sylvie / Jouary, Thomas / Dalac, Sophie / Dalle, Stephane / Guillot, Bernard / Arnault, Jean-Philippe / Avril, Marie-Françoise / Bedane, Christophe / Bens, Guido / Pham-Ledard, Anne / Mansard, Sandrine / Grange, Florent / Machet, Laurent / Meyer, Nicolas / Legoupil, Delphine / Saiag, Philippe / Idir, Zakia / Renault, Victor / Deleuze, Jean-François / Hindie, Elif / Battistella, Maxime / Dumaz, Nicolas / Mourah, Samia / Lebbe, Celeste / Anonymous3181409. ·Service de Dermatologie, and CIC (Centre d'Investigations Cliniques), AP-HP, Hôpital Saint-Louis, Paris, France; INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: julie.delyon@aphp.fr. · Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Biostatistique et Information Médicale, AP-HP, Hôpital Saint-Louis, Paris, France. · Unité Onco-dermatologie, Hôpital François Mitterrand, Pau, France. · Service de Dermatologie, CHU Dijon Bourgogne, Dijon, France. · Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Claude Bernard Lyon 1 University, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France. · Montpellier University Hospital, Montpellier, France. · Service de Dermatologie, CHU Amiens-Picardie, Amiens, France. · Service de Dermatologie, AP-HP, Hôpital Cochin, Paris, France; Université Paris Descartes, Paris, France. · Unité d'oncologie thoracique et cutanée, Hopital Dupuytren, Limoges, France. · Service de Dermatologie, Centre hospitalier régional d'Orléans, Orléans, France. · Dermatology Department, CHU de Bordeaux, Bordeaux, France. · Dermatology Department, CHU de Clermont Ferrand, Clermont Ferrand, France. · Dermatology Department, Reims University Hospital, Reims, France. · Department of Dermatology, Centre Hospitalier Regional et Universitaire (CHRU) de Tours, Tours, France; Inserm U930, University Francois Rabelais de Tours, Tours, France. · Dermatologie, Institut Universitaire du Cancer et CHU de Toulouse, Toulouse, France; Inserm UMR 1037, CRCT, Toulouse, France. · Dermatology Department, University Hospital of Brest, Brest, France. · Université de Versailles St-Quentin, EA 4340, Boulogne-Billancourt, France; Service de Dermatologie Générale et Oncologique, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France. · AP-HP, Département de la Recherche Clinique et du Développement, AP-HP, Hôpital Saint-Louis, Paris, France. · Laboratory for Bioinformatics, CEPH-Fondation Jean Dausset, Paris, France. · Centre National de Génotypage, CEA, Evry, France; CEPH-Fondation Jean Dausset, Paris, France. · Service de Médecine Nucléaire, CHU de Bordeaux, LabEx TRAIL, Université de Bordeaux, Bordeaux, France. · Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM, UMR_S1165, Paris, France; Pathology department, Hopital Saint-Louis, AP-HP, Paris, France. · INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France. · INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratoire de Pharmacologie Biologique, AP-HP, Hôpital Saint-Louis, Paris, France. · Service de Dermatologie, and CIC (Centre d'Investigations Cliniques), AP-HP, Hôpital Saint-Louis, Paris, France; INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. ·J Invest Dermatol · Pubmed #28843487.

ABSTRACT: Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

8 Clinical Trial Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017

Long, G V / Flaherty, K T / Stroyakovskiy, D / Gogas, H / Levchenko, E / de Braud, F / Larkin, J / Garbe, C / Jouary, T / Hauschild, A / Chiarion-Sileni, V / Lebbe, C / Mandalà, M / Millward, M / Arance, A / Bondarenko, I / Haanen, J B A G / Hansson, J / Utikal, J / Ferraresi, V / Mohr, P / Probachai, V / Schadendorf, D / Nathan, P / Robert, C / Ribas, A / Davies, M A / Lane, S R / Legos, J J / Mookerjee, B / Grob, J-J. ·Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA. · Moscow City Oncology Hospital #62, Moscow, Russia. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University of Tübingen, Tübingen, Germany. · Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany. · Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. · Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Novartis Pharmaceuticals Corporation, East Hanover, USA. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France. ·Ann Oncol · Pubmed #28475671.

ABSTRACT: Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

9 Clinical Trial First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. 2016

Le Tourneau, C / Dreno, B / Kirova, Y / Grob, J J / Jouary, T / Dutriaux, C / Thomas, L / Lebbé, C / Mortier, L / Saiag, P / Avril, M F / Maubec, E / Joly, P / Bey, P / Cosset, J M / Sun, J S / Asselain, B / Devun, F / Marty, M E / Dutreix, M. ·Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud 75005, France. · EA7285, Versailles-Saint-Quentin-en-Yvelines University, Versailles 78000, France. · CHU de Nantes-Hôtel Dieu, Nantes 44093, France. · Radiotherapy Department, Institut Curie, Paris 75005, France. · La Timone Hospital-APHM, Aix-Marseille University, Marseille 13385, France. · Dermatology department, Saint-André Hospital, CHU de Bordeaux, Bordeaux 33000, France. · Lyon Sud Hospital Center, Lyon 1 University, Pierre Benite 69495, France. · Saint-Louis Hospital, APHP, Paris 75010, France. · Dermatology department, CHRU of Lille, Lille 59037, France. · Ambroise Paré Hospital, Boulogne Billancourt 92104, France. · Cochin hospital, APHP, Paris 75014, France. · Bichat Hospital, Paris 75877, France. · CHU Rouen, Charles-Nicolle, Rouen 76000, France. · Institut Curie, Paris 75005, France. · DNA Therapeutics, Evry 91058, France. · Department of Biostatistics, Institut Curie, Paris 75005, France. · Institut Curie, Orsay 91405, France. · CNRS-UMR3347, INSERM-U1021, Paris-Sud University, Orsay 91405, France. ·Br J Cancer · Pubmed #27140316.

ABSTRACT: BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

10 Clinical Trial Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 2015

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean-Jacques / Chiarion-Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Swann, Suzanne / Legos, Jeffrey J / Jin, Fan / Mookerjee, Bijoyesh / Flaherty, Keith. ·Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Moscow City Oncology Hospital, Moscow, Russia. · Department of Medicine, University of Athens, Medical School, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Royal Marsden Hospital, London, UK. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France. · University Hospital Schleswig-Holstein, Kiel, Germany. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France. · Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia. · Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain. · Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. · University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany. · Istituto Nazionale Tumori Regina Elena, Rome, Italy. · Volograd Regional Oncology Dispensary #3, Volzhsky, Russia. · Elbe Klinikum Stade, Stade, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · University Hospital Essen, Essen, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Merck & Co, Kenilworth, NJ, USA. · Massachusetts General Hospital Cancer Center, Boston MA, USA. ·Lancet · Pubmed #26037941.

ABSTRACT: BACKGROUND: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. METHODS: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. FINDINGS: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. INTERPRETATION: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. FUNDING: GlaxoSmithKline.

11 Clinical Trial Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. 2014

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean Jacques / Chiarion Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymyr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Casey, Michelle / Ouellet, Daniele / Martin, Anne-Marie / Le, Ngocdiep / Patel, Kiran / Flaherty, Keith. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25265492.

ABSTRACT: BACKGROUND: Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS: In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS: The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS: A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).

12 Clinical Trial Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. 2014

Leyvraz, S / Piperno-Neumann, S / Suciu, S / Baurain, J F / Zdzienicki, M / Testori, A / Marshall, E / Scheulen, M / Jouary, T / Negrier, S / Vermorken, J B / Kaempgen, E / Durando, X / Schadendorf, D / Gurunath, R Karra / Keilholz, U. ·Oncology Department, University Hospital, Lausanne, Switzerland. ·Ann Oncol · Pubmed #24510314.

ABSTRACT: BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

13 Clinical Trial Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. 2014

McArthur, Grant A / Chapman, Paul B / Robert, Caroline / Larkin, James / Haanen, John B / Dummer, Reinhard / Ribas, Antoni / Hogg, David / Hamid, Omid / Ascierto, Paolo A / Garbe, Claus / Testori, Alessandro / Maio, Michele / Lorigan, Paul / Lebbé, Celeste / Jouary, Thomas / Schadendorf, Dirk / O'Day, Stephen J / Kirkwood, John M / Eggermont, Alexander M / Dréno, Brigitte / Sosman, Jeffrey A / Flaherty, Keith T / Yin, Ming / Caro, Ivor / Cheng, Suzanne / Trunzer, Kerstin / Hauschild, Axel. ·Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institut Gustave Roussy, Paris, France. · Royal Marsden Hospital, London, UK. · The Netherlands Cancer Institute, Amsterdam, Netherlands. · University of Zurich, Zurich, Switzerland. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · Princess Margaret Hospital and University Health Network, Toronto, ON, Canada. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · The University of Tübingen, Tübingen, Germany. · Istituto Europeo di Oncologia, Milan, Italy. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · University of Manchester, Manchester, UK. · APHP Oncodermatology, Hôpital Saint Louis University, Paris, France. · Saint André Hospital, Bordeaux, France. · University Hospital Essen, Essen, Germany. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France. · Nantes University Hospital, Nantes, France. · Vanderbilt University School of Medicine, Nashville, TN, USA. · Massachusetts General Hospital, Boston, MA, USA. · Genentech Inc, San Francisco, CA, USA. · Roche Molecular Systems Inc, Pleasanton, CA, USA. · F Hoffmann-La Roche, Basel, Switzerland. · University of Kiel, Kiel, Germany. ·Lancet Oncol · Pubmed #24508103.

ABSTRACT: BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech.

14 Clinical Trial Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study. 2013

Grob, Jean Jacques / Jouary, Thomas / Dréno, Brigitte / Asselineau, Julien / Gutzmer, Ralf / Hauschild, Axel / Leccia, Marie Thérèse / Landthaler, Michael / Garbe, Claus / Sassolas, Bruno / Herbst, Rudolf A / Guillot, Bernard / Chene, Genevieve / Pehamberger, Hubert. ·Aix-Marseille University, CRO2, Service de Dermatologie, Hopital de Timone, 264 Rue St Pierre, 13885 Marseille CEDEX 05, Marseille, France. jean-jacques.grob@ap-hm.fr ·Eur J Cancer · Pubmed #22975216.

ABSTRACT: AIM: Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. PATIENTS AND METHODS: Patients with resected melanoma ≥1.5mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3-4. RESULTS: Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73-1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80-1.32) and OS (HR 1.09, 95% CI 0.82-1.45). Peg-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p<0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. CONCLUSION: This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.

15 Clinical Trial Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. 2012

Hauschild, Axel / Grob, Jean-Jacques / Demidov, Lev V / Jouary, Thomas / Gutzmer, Ralf / Millward, Michael / Rutkowski, Piotr / Blank, Christian U / Miller, Wilson H / Kaempgen, Eckhart / Martín-Algarra, Salvador / Karaszewska, Boguslawa / Mauch, Cornelia / Chiarion-Sileni, Vanna / Martin, Anne-Marie / Swann, Suzanne / Haney, Patricia / Mirakhur, Beloo / Guckert, Mary E / Goodman, Vicki / Chapman, Paul B. ·University Hospital, Schleswig-Holstein, Department of Dermatology, Kiel, Germany. ahauschild@dermatology.unikiel.de ·Lancet · Pubmed #22735384.

ABSTRACT: BACKGROUND: Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma. METHODS: We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. FINDINGS: Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups. INTERPRETATION: Dabrafenib significantly improved progression-free survival compared with dacarbazine. FUNDING: GlaxoSmithKline.

16 Clinical Trial Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies. 2011

Eisen, T / Marais, R / Affolter, A / Lorigan, P / Robert, C / Corrie, P / Ottensmeier, C / Chevreau, C / Chao, D / Nathan, P D / Jouary, T / Harries, M / Negrier, S / Montegriffo, E / Ahmad, T / Gibbens, I / James, M G / Strauss, U P / Prendergast, S / Gore, M E. ·Department of Oncology (R4), Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. tgqe2@cam.ac.uk ·Br J Cancer · Pubmed #21750549.

ABSTRACT: METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

17 Clinical Trial Improved survival with vemurafenib in melanoma with BRAF V600E mutation. 2011

Chapman, Paul B / Hauschild, Axel / Robert, Caroline / Haanen, John B / Ascierto, Paolo / Larkin, James / Dummer, Reinhard / Garbe, Claus / Testori, Alessandro / Maio, Michele / Hogg, David / Lorigan, Paul / Lebbe, Celeste / Jouary, Thomas / Schadendorf, Dirk / Ribas, Antoni / O'Day, Steven J / Sosman, Jeffrey A / Kirkwood, John M / Eggermont, Alexander M M / Dreno, Brigitte / Nolop, Keith / Li, Jiang / Nelson, Betty / Hou, Jeannie / Lee, Richard J / Flaherty, Keith T / McArthur, Grant A / Anonymous4380696. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. chapmanp@mskcc.org ·N Engl J Med · Pubmed #21639808.

ABSTRACT: BACKGROUND: Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS: We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

18 Article [New lines of research in the treatment of melanoma]. 2014

Jouary, Thomas. · ·Rev Prat · Pubmed #24649553.

ABSTRACT: -- No abstract --

19 Article Ipilimumab in melanoma patients with brain metastasis: a retro-spective multicentre evaluation of thirty-eight patients. 2014

Konstantinou, Maria-Polina / Dutriaux, Caroline / Gaudy-Marqueste, Caroline / Mortier, Laurent / Bedane, Christophe / Girard, Céline / Thellier, Sophie / Jouary, Thomas / Grob, Jean-Jacques / Richard, Marie-Aleth / Templier, Caroline / Sakji, Lilia / Guillot, Bernard / Paul, Carle / Meyer, Nicolas. ·Department of Dermatology, Toulouse III University and Larrey Hospital, 31059 Toulouse Cedex 9, France. ·Acta Derm Venereol · Pubmed #23824275.

ABSTRACT: Treatment with ipilimumab, a monoclonal antibody that antagonizes cytotoxic T-lymphocyte antigen-4 (CTLA-4), results in improved survival of patients with stage IIIc-IV melanoma. However, there is a lack of data on the efficacy of ipilimumab in patients with brain metastases. To evaluate the efficacy of ipilimumab for the treatment of brain metastasis in melanoma, a multicentre, retrospective analysis of 38 patients with brain metastases in melanoma, treated with ipilimumab in the context of the French Expanded Access Program, was performed. Three patients had a 3 partial response, 5 stable disease, 15 disease progression and 15 patients died during the induction phase due to disease progression. Median overall survival was 101 days (range 54-154). The brain metastases control rate was 16% (6/38). Ipilimumab may be effective in a few patients with central nervous system metastasis. However, patients with brain metastases and a low life expectancy may not benefit sufficiently from treatment with ipilimumab.

20 Article Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing. 2013

Boursault, Lucile / Haddad, Véronique / Vergier, Béatrice / Cappellen, David / Verdon, Severine / Bellocq, Jean-Pierre / Jouary, Thomas / Merlio, Jean-Philippe. ·Department of Dermatology, CHU Bordeaux, Bordeaux, France. ·PLoS One · Pubmed #23976959.

ABSTRACT: BRAF inhibitors have demonstrated improvement of overall survival in patients with metastatic melanoma and BRAF(V600) mutations. In order to evaluate BRAF tumor heterogeneity between primary and metastatic site, we have evaluated the performance of immunohistochemistry (IHC) with an anti-BRAF(V600E) antibody in both localization by comparison with high resolution melting analysis followed by Sanger sequencing in a parallel blinded study. A total of 230 samples distributed as primary melanoma (n = 88) and different types of metastatic samples (n = 142) were studied in 99 patients with advanced or metastatic melanoma (stage III or IV). The prevalence of each BRAF mutation was c.1799T>A, BRAF(V600E) (45.2%), c.1799_1800TG>AA, BRAF(V600E2) (3.0%), c.1798_1799GT>AA, BRAF(V600K) (3.0%), c.1801 A>G, BRAF(K601E) (1.3%), c.1789_1790CT>TC, BRAF(L597S) (0.4%), c.1780G>A, BRAF(D594N) (0.9%) respectively. IHC was positive in 109/112 samples harboring BRAF(V600E/E2) mutations and negative in other cases. The cytoplasmic staining was either strongly positive in tumor cells of BRAF(V600E) mutated cases. It appeared strong brown, different from the vesicular grey cytoplasmic pigmentation of melanophages. Concordance between the two techniques was 96.4%. Sensitivity of IHC for detecting the BRAF(V600E/E2) mutations was 97.3%, while specificity was 100%. Both our IHC and molecular study demonstrated homogeneity between primary and metastatic sites for BRAF status in melanoma. This study also provides evidence that IHC may be a cost-effective first-line method for BRAF(V600E) detection. Thereafter, molecular techniques should be used in negative, ambiguous or non-contributive cases.

21 Article Metastatic melanoma with leukaemia-like evolution. 2013

Bertolotti, Antoine / Conte, Héléne / Amazan, Emmanuelle / Dutriaux, Caroline / Ezzedine, Khaled / Parrens, Marie / Vergier, Béatrice / Taieb, Alain / Jouary, Thomas. ·Department of Dermatology, Hopital Saint Andre, FR-33075 Bordeaux, France. ·Acta Derm Venereol · Pubmed #23529281.

ABSTRACT: -- No abstract --

22 Article Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. 2013

Puntervoll, Hanne Eknes / Yang, Xiaohong R / Vetti, Hildegunn Høberg / Bachmann, Ingeborg M / Avril, Marie Françoise / Benfodda, Meriem / Catricalà, Caterina / Dalle, Stéphane / Duval-Modeste, Anne B / Ghiorzo, Paola / Grammatico, Paola / Harland, Mark / Hayward, Nicholas K / Hu, Hui-Han / Jouary, Thomas / Martin-Denavit, Tanguy / Ozola, Aija / Palmer, Jane M / Pastorino, Lorenza / Pjanova, Dace / Soufir, Nadem / Steine, Solrun J / Stratigos, Alexander J / Thomas, Luc / Tinat, Julie / Tsao, Hensin / Veinalde, Ruta / Tucker, Margaret A / Bressac-de Paillerets, Brigitte / Newton-Bishop, Julia A / Goldstein, Alisa M / Akslen, Lars A / Molven, Anders. ·Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway. ·J Med Genet · Pubmed #23384855.

ABSTRACT: BACKGROUND: CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. METHODS: All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. RESULTS: Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). CONCLUSION: Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.

23 Article [Linear porokeratosis]. 2011

Darrigade, A-S / Conte, H / Ip Kan Fong, H / Taïeb, A / Jouary, T. ·Unité de dermatologie-cancérologie, service de dermatologie, hôpital Saint-André, 1, rue Jean-Burguet, 33075 Bordeaux cedex, France. ·Ann Dermatol Venereol · Pubmed #22078049.

ABSTRACT: -- No abstract --

24 Article Assessment of tyrosinase variants and skin cancer risk in a large cohort of French subjects. 2011

Hu, Hui-Han / Guedj, Mickael / Descamps, Vincent / Jouary, Thomas / Bourillon, Agnes / Ezzedine, Khaled / Taieb, Alain / Bagot, Martine / Bensussan, Armand / Saiag, Philippe / Grandchamp, Bernard / Basset-Seguin, Nicole / Soufir, Nadem. ·Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat Claude Bernard, APHP, IFR02, 75018, Paris, France. ·J Dermatol Sci · Pubmed #21906913.

ABSTRACT: BACKGROUND: Tyrosinase (TYR) is a key pigmentation gene that is highly polymorphic and responsible for the most common form of autosomal recessive albinism, OCA1. OBJECTIVE: To assess the role of frequent and rare TYR variants in predisposition to skin cancer (SK) in the French population. METHODS: We genotyped a frequent TYR variant (p.R402Q) in 1273 patients {1047 cutaneous melanoma (CM) and 226 basal cell carcinoma (BCC)} and 925 controls, and the full coding region of TYR was sequenced in 287 patients suspected of genetic predisposition to SK (familial and/or multiple SK and/or onset before 40 years) and 187 controls. RESULTS: The homozygous p.R402Q variant was significantly associated with SK risk (P value=0.008; OR=1.57), and was mostly associated with multiple CM risk (P value=0.021; OR=2.50) and familial CM risk (P value=0.022; OR=2.16). In addition, 19 rare TYR variants, mainly albinism mutations, were identified in 15 patients and 8 controls. Among these, 3 clearly deleterious mutations (1 non-sense and 2 affecting mRNA splicing) were identified in 3 patients, one of which was homozygous. CONCLUSION: Our data confirmed the association of TYR p.R402Q with SK risk in the French population, and support that rare deleterious TYR variants may also play a role in multi-factorial genetic predisposition to SK. These results should be confirmed by replications studies.

25 Article [Metastatic cutaneous hematoma variant from melanoma: five cases]. 2011

Pham-Ledard, Anne / Taieb, Alain / Vergier, Béatrice / Jouary, Thomas. ·CHU de Bordeaux, hôpital Saint-André, service de dermatologie, Bordeaux, France. lien.phamledard@gmail.com ·Bull Cancer · Pubmed #21414891.

ABSTRACT: INTRODUCTION: Melanoma is an aggressive tumor with high metastatic potential. We described herein five patients with metastatic cutaneous hematoma variant from melanoma. OBSERVATIONS: Patients were four men and one woman, four were already known for melanoma. In one case, the occurrence of hematoma leads to the diagnosis of metastatic melanoma. These hematomas were true hematomas, which had appeared spontaneously and in some cases a nodule or lymphadenopathy was clinically found. A biopsy was performed in two cases, showing the sub-cutaneous metastasis with hemorrhages (histological hematoma) and vascular proliferation within tumor cells. Patients were not treated by anti-coagulants or antiagregants and biological tests were not exhibiting any coagulation trouble. Evolution was rapidly dramatic with generalized metastatic disease and death. DISCUSSION: Metastatic cutaneous hematoma is a particular type of cutaneous metastasis, poorly reported in the literature. This phenomenon could be explained by local tumoral neoangiogenesis and hematogenous metastatic spread. CONCLUSION: We report five cases of metastatic cutaneous hematomas of melanoma. This clinical presentation doesn't seem to be so rare. This clinical variant should be known from oncologists in order to perform a biopsy looking for a metastatic cutaneous involvement from melanoma.

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