1. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study
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Cristina Bulai Livideanu, Olivier Hermine, Carle Paul, Sophie georgin Lavialle, Sylvie Fraitag, Katia Hanssens, Clive Grattan, Gérard Guillet, Gandhi Damaj, Marie-Olivia Chandesris, Jean-Pierre Kinet, Raphaël Gaillard, Laurent Frenzel, Lawrence B. Afrin, Danielle Canioni, Stéphane Barete, Ludovic Lhermitte, Srdan Verstovsek, Christian Auclair, Ewa Jassem, Julie Agopian, Colin Mansfield, Olivier Lortholary, Patrice Dubreuil, Alain Moussy, Marek Niedoszytko, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Centre de référence des mastocytoses (CEREMAST), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Gdańsk (UG), Université Pierre et Marie Curie - Paris 6 (UPMC), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Norfolk & Norwich University Hospital, Norfolk & Norwich University Hospital, Colney Lane, Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), AB Science, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), AB Science (Paris, France)., Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Université de Toulouse (UT), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MITOYAN, Louciné
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Male ,0301 basic medicine ,Urticaria ,MESH: Exanthema ,Pyridines ,[SDV]Life Sciences [q-bio] ,Severity of Illness Index ,chemistry.chemical_compound ,MESH: Aged, 80 and over ,Piperidines ,Clinical endpoint ,MESH: Protein Kinase Inhibitors ,MESH: Urticaria ,MESH: Double-Blind Method ,Systemic mastocytosis ,MESH: Mastocytosis, Systemic ,MESH: Treatment Outcome ,Aged, 80 and over ,MESH: Aged ,education.field_of_study ,MESH: Middle Aged ,Masitinib ,General Medicine ,Middle Aged ,Rash ,3. Good health ,[SDV] Life Sciences [q-bio] ,MESH: Diarrhea ,Treatment Outcome ,MESH: Young Adult ,Benzamides ,Female ,medicine.symptom ,Mastocytosis ,Adult ,Diarrhea ,medicine.medical_specialty ,Population ,MESH: Thiazoles ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH: Asthenia ,Placebo ,Article ,Young Adult ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Double-Blind Method ,Mastocytosis, Systemic ,MESH: Severity of Illness Index ,Internal medicine ,medicine ,Humans ,education ,Protein Kinase Inhibitors ,Aged ,MESH: Humans ,business.industry ,Hamilton Rating Scale for Depression ,Repeated measures design ,MESH: Adult ,Exanthema ,medicine.disease ,MESH: Male ,Surgery ,Thiazoles ,030104 developmental biology ,chemistry ,Asthenia ,business ,MESH: Female - Abstract
Summary Background Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).
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- 2017
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