systemic mast cell disease (SMCD)
Conditions
Interventions
2-parallel-group, trial comparing the oral masitinib at 3 mg/kg/day with a
switch after 4 weeks of treatment to 4.5 mg/kg/day and a switch after another 4
weeks of treatment to 6 mg/kg/day (each swi
Sponsors
AB Sciences
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Patient with one of the following documented mastocytosis: • Smouldering Systemic Mastocytosis (SSM) • Indolent Systemic Mastocytosis (ISM) 2. An excess of mast cells or a presence of abnormal mast cells in at least two organs (among skin, bone-marrow and GI Tract) 3. Patients meet the used classification of systemic mastocytosis (SM) based on the presence of one of the three criteria: • Bone marrow biopsy and/or aspirate associated with at least a sign of abnormality of mast cells: - Abnormal aggregates of mast cells in a sample in bone marrow: The criterion is deemed satisfied if the aggregate: i) is quantified and is strictly above 15 mast cells per aggregated (corresponding to WHO major criterion), or ii) is not quantified but is described as nodule, seat, cluster, focus, or granuloma and therefore pathological; - >=25% atypical mast cells in a sample of bone marrow (corresponding to WHO minor criterion); - c-Kit point mutation at codon 816 in bone marrow (corresponding to WHO minor criterion); - Abnormal mast cells in the sample of bone marrow while microscopic testing that can be described by the following words: Spindled; Abnormal; Atypical; Fusiform; Dystrophic; Pathologic; Dysmorphic (corresponding to WHO minor criterion); - Abnormal immunohistochemistry signs: mast cells in bone marrow express CD2 or/and CD25 present (corresponding to WHO minor criterion); - Abnormal infiltration of mast cells in the bone marrow: The criterion is deemed satisfied if the infiltration: i) is quantified and is strictly above 3% in the biopsy, or ii) is not quantified but is abnormal as described with infiltration, accumulation of mast cells, or proliferation and therefore pathological. • Detection of c-Kit 816 mutation in the bone marrow without evidence of mast cells in bone marrow but with evidence of c-Kit 816 mutation in skin, justifying clonality; • Excess of mast cells in digestive organs. 4. Patient with severe symptoms of mastocytosis over the 14-day run-in period defined as at least one of the following: • Pruritus score >= 9 • Number of flushes per week >= 8 • Hamilton rating scale for depression (HAMD-17) score >= 19 5. Patient with documented treatment failures of his/her symptom (s) (within last two years) with at least two of the symptomatic treatments used at optimized dose (Minimal duration of each treatment should be at least 8 weeks): • Anti-H1 • Anti-H2 • Proton pump inhibitor • Antidepressants • Cromoglycate Sodium • Antileukotriene 6. Patients must be on a stable dose of Anti-H1 for a minimum of 4 weeks before screening and should remain at a stable dose throughout the study period. For other symptomatic treatments, if the patient takes Corticosteroids, Anti-H2 or PPI or Antidepressants or Cromoglycate Sodium or Antileukotriene, the treatment must have started at least 4 weeks before Screening and must be stable throughout the study. 7. Age between 18 to 75 years (inclusive). 8. Weight > 45 kg and BMI between 18 and 35 kg/m2 9. Contraception: • The patient and his/her partner must use a highly effective method during the study and for 3 months and 1 week after the last treatment intake. • Highly effective methods of contraception include: - Combined (estrogen and progestogen containing) hormonal contraception ass
Exclusion criteria
Exclusion criteria: 1. Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM. 2. Previous treatment with any Tyrosine Kinase Inhibitor. 3. Any change in the symptomatic treatment of SM, including the systemic corticosteroids, or administration of any new treatment for SM within 4 weeks prior to screening. 4. Treatment with any investigational agent within 8 weeks prior to screening. 5. Patients with (an history of) severe cardiovascular disease: • Myocardial infarction • Unstable angina pectoris • Coronary revascularization procedure • Congestive heart failure of NYHA Class III or IV • Stroke, including a transient ischemic attack • Second degree or third-degree atrioventricular block not successfully treated with a pacemaker • Bi-fascicular block • QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females • Drug induced heart failure or ischemic heart disease • Radiotherapy induced cardiomyopathy • Family history of unexpected death of cardiovascular origin. 6. Patients, with two or more of the risk factors listed below assessed by cardiologist as Very High Risk (calculated SCORE >=10%.) or High Risk calculated SCORE >=5% and = 10 Pack-year: equivalent to 1 pack of 20 cigarettes per 10 years with the formula N (number of packs of 20 cigarettes smoked daily) x T (number years smoking)). Patients who stopped smoking 6 months prior to evaluation are not concerned. • Hypercholesterolemia • COPD This assessment is done according to the Systematic Coronary Risk Estimation (SCORE) using the country specific free full version of HeartScore°, the interactive tool for predicting and managing the risk of heart attack and stroke in Europe, available at https://www.heartscore.org/en_GB/access. If country specific version is not available, EU one should be used. 7. Patient who had major surgery within 2 weeks prior to screening visit. 8. Known hypersensitivity to masitinib or to any of its excipients. 9. Patient taking concomitant treatment or therapies associated with severe drug-induced skin toxicity. 10. Female patients who are pregnant or are breastfeeding. 11. Patient with following laboratory results out of the ranges detailed below at screening: • Absolute neutrophil count (ANC) 3 x ULN or total bilirubin level > 1.5 x ULN 13. Patient with severe pre-existing renal impairment, or with abnormal laboratory results from local laboratory assessments at screening: - Creatinine clearance 30 mg/dL (1+) on dipstick; in case of the proteinuria >= 1+ on the dipstick, 24 hours proteinuria must be > 1.5g/24 hours 14. Vulnerable population defined as: - Life expectancy < 6 months - Patient with < 5 years free of malignancy. - Patient with known diagnosis of human immunodeficiency virus (HIV) infection. 15. Patient with history of poor compl
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary objective is to assess the efficacy of oral masitinib versus placebo on the cumulative response on 3 handicaps (Pruritus, Flush, depression) of patients with Smouldering or Indolent Severe Systemic mastocytosis with handicap unresponsive to optimal symptomatic treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives are to assess the oral masitinib versus placebo on the following: • Efficacy on cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FSS) • Efficacy on cumulative response on 4 handicaps (Pruritus, Flushes, Depression, FIS) • Efficacy on cumulative response on 2 handicaps (Pruritus, Flushes) • Efficacy on cumulative response on each of the individual handicaps (Pruritus, Flushes, Depression, FSS, FIS) • Efficacy on tryptase level • Efficacy on Urticaria Pigmentosa • Efficacy on Quality of life • Safety | — |
Countries
Netherlands
Outcome results
None listed