Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study

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 effiect 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; diffierence 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% diffierence 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 effiective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).

Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer

“…Pre-clinical studies using anti-c-kit antibodies [ 40 ], anti-TNF-α antibodies [ 41 ], or the mast cells stabilizer disodium cromoglycate (cromolyn) [ 42 ] have demonstrated promising results in mouse models. Masatinib is a tyrosine kinase inhibitor that targets c-kit receptors and is clinically developed and approved for treatment of recurrent or unresectable grade III dog mast cell tumors and is the first approved anticancer drug in veterinary medicine [ 43 ]. Masatinib has been translated to human clinical trials for its evaluation in gastro intestinal stromal tumor (GIST), mastocytosis and pancreatic cancer [ 44 , 45 ].…”

Comparative aspects of mast cell neoplasia in animals and the role of KIT in prognosis and treatment

“…Various TKIs have been investigated for therapeutic use against mastocytosis. Imatinib and masitinib mesylate show efficacy for patients with wild-type KIT mast cell neoplasia (Lortholary et al, 2017).…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…These receptors synergistically signal proliferation and migration of cancer and hematopoietic cells, including macrophages. By targeting c-Kit, Lyn, and Fyn, masitinib is particularly efficient in controlling the survival, differentiation, and degranulation of mast cells and, thus, modulating the mast cell-induced array of proinflammatory and vasoactive effects (25,28). Accordingly, clinical trials have shown therapeutic effects of masitinib in cases of mastocytosis, a rare disease characterized by abnormal accumulation and activation of mast cells in various tissues and organs (28).…”

“…By targeting c-Kit, Lyn, and Fyn, masitinib is particularly efficient in controlling the survival, differentiation, and degranulation of mast cells and, thus, modulating the mast cell-induced array of proinflammatory and vasoactive effects (25,28). Accordingly, clinical trials have shown therapeutic effects of masitinib in cases of mastocytosis, a rare disease characterized by abnormal accumulation and activation of mast cells in various tissues and organs (28). Masitinib was also shown to beneficially modulate CNS function in multiple sclerosis (29), stroke (30), and Alzheimer' s disease (31).…”