A 24-week with possible extension, prospective, multicenter, randomized, double blind, placebo-controlled, 2-parallel group with a randomization 1:1, phase III study to compare efficacy and safety of oral masitinib to placebo in treatment of patients with Smouldering or Indolent Severe Systemic mastocytosis with handicap, unresponsive to optimal symptomatic treatment
- Conditions
- systemic mast cell disease (SMCD)10018849
- Registration Number
- NL-OMON55076
- Lead Sponsor
- AB Sciences
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 3
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
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%) according to the Systematic Coronary Risk Estimation
(SCORE):
• Hypertension (uncontrolled)
• Diabete
• Kidney disease,
• Current tabagism (>= 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) <= 1.5 x 109/L
• Haemoglobin <= 10 g/dL
• Platelets (PLT) <= 100 x 109/L
• Albuminemia <= 1 x LLN
12. Patient with history of hepatic disorders, recent alcohol abuse or recent
history of hepatic impairment defined as hepatic transaminase levels >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 < 60 mL/min (Cockcroft and Gault formula)
- Proteinuria > 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary objective is to assess the efficacy of oral masitinib versus<br /><br>placebo on the cumulative response on 3 handicaps (Pruritus, Flush,<br /><br>depression) of patients with Smouldering or Indolent Severe Systemic<br /><br>mastocytosis with handicap unresponsive to optimal symptomatic treatment.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary objectives are to assess the oral masitinib versus placebo on the<br /><br>following:<br /><br>• Efficacy on cumulative response on 4 handicaps (Pruritus, Flushes,<br /><br>Depression, FSS)<br /><br>• Efficacy on cumulative response on 4 handicaps (Pruritus, Flushes,<br /><br>Depression, FIS)<br /><br>• Efficacy on cumulative response on 2 handicaps (Pruritus, Flushes)<br /><br>• Efficacy on cumulative response on each of the individual handicaps<br /><br>(Pruritus, Flushes,<br /><br>Depression, FSS, FIS)<br /><br>• Efficacy on tryptase level<br /><br>• Efficacy on Urticaria Pigmentosa<br /><br>• Efficacy on Quality of life<br /><br>• Safety</p><br>