Olivier Lortholary1, Marie Olivia Chandesris2, Cristina Bulai Livideanu3, Carle Paul3, Gérard Guillet4, Ewa Jassem5, Marek Niedoszytko5, Stéphane Barete6, Srdan Verstovsek7, Clive Grattan8, Gandhi Damaj9, Danielle Canioni10, Sylvie Fraitag10, Ludovic Lhermitte11, Sophie Georgin Lavialle12, Laurent Frenzel13, Lawrence B Afrin14, Katia Hanssens15, Julie Agopian15, Raphael Gaillard16, Jean-Pierre Kinet17, Christian Auclair18, Colin Mansfield19, Alain Moussy19, Patrice Dubreuil20, Olivier Hermine21. 1. Department of Infectious Diseases and Tropical Medicine and Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Centre de Référence des Mastocytoses, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Université Paris Descartes, Paris, France. 2. Department of Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France. 3. Department of Dermatology, Mastocytosis Competence Center, Paul Sabatier University, Hôpital Larrey, Toulouse, France. 4. Department of Dermatology, CHU Poitiers, University Hospital, Poitiers, France. 5. Department of Allergology, Medical University of Gdansk, Gdansk, Poland. 6. Department of Dermatology and Allergology, Centre de Référence des Mastocytoses, Université Pierre et Marie Curie, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, France. 7. Hanns A Pielenz Clinical Research Center for Myeloproliferative Neoplasms, Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA. 8. Department of Dermatology, Norfolk & Norwich University Hospital, Norwich, UK. 9. Department of Haematology, University Hospital of Caen, Institut d'Hématologie de Basse Normandie, School of Medicine, University of Lower Normandy, Caen, France. 10. Department of Pathology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France. 11. INSERM U1151 and Laboratory of Onco-Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France. 12. Department of Internal Medicine, DHU I2B, Université Pierre et Marie Curie, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, France. 13. Department of Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Institut Imagine INSERM U1163 and CNRS ERL8654, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France. 14. Division of Hematology, Oncology & Transplantation, University of Minnesota, Minneapolis, MN, USA. 15. Centre de Référence des Mastocytoses, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; AB Science, Paris, France. 16. Human Histopathology and Animal Models, Infection and Epidemiology Department, Institut Pasteur; Université Paris Descartes; Centre Hospitalier Sainte-Anne, Paris, France. 17. Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA. 18. Laboratoire de Biologie et Pharmacologie appliqué, CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Université Paris Saclay, Paris, France; AB Science, Paris, France. 19. AB Science, Paris, France. 20. Centre de Référence des Mastocytoses, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; INSERM U1068, CRCM (Signaling, Hematopoiesis and Mechanism of Oncogenesis), Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France; AB Science, Paris, France; INSERM, La Ligue Nationale Contre le Cancer (équipe labelliseé), Paris, France. 21. Department of Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Institut Imagine INSERM U1163 and CNRS ERL8654, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; AB Science, Paris, France. Electronic address: ohermine@gmail.com.
Abstract
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) orplacebo (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).
RCT Entities:
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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