To evaluate the efficacy and safety of oral masitinib versus placebo in the treatment of patients suffering from Smouldering or Indolent SevereSystemic mastocytosis with handicap unresponsive to optimal symptomatic treatment.
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
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
Background summary
Mast cells play a pivotal role in the pathogenesis of mastocytosis. Mast cell
function (growth, differentiation and survival) is dependent on the stem cell
factor (SCF) ligation of c-Kit, the transmembrane receptor that stimulates mast
cell activation through initiation of intracellular signaling pathways
necessary for mast cell function. In indolent systemic mastocytosis, 10% of
patients present with WT c-Kit receptors and 90% present with D816V mutant
c-Kit receptors. The D816V mutation is associated with ligandindependent
constitutive activation of c-Kit signaling, leading to uncontrolled mast cell
proliferation, resistance to apoptosis and mediator release.
Considering the role of c-Kit in mastocytosis, targeted kinase therapies have
been investigated as treatment options. Encouraging
results obtained with imatinib provide rationale to investigate further the
effect of c-kit inhibitors in mastocytosis.
Masitinib is able to regulate mast cell activity mainly due to its inhibitory
potential against c-Kit, but also by inhibiting the signaling
kinases Lyn and Fyn [Dubreuil et al, 2009]. Similar to other tyrosine kinase
inhibitors (TKI), masitinib exerts its mode of action via
binding to the ATP binding pocket of its target kinases and thereby inhibiting
the phosphorylation-dependent signaling pathways
Study objective
To evaluate the efficacy and safety of oral masitinib versus placebo in the
treatment of patients suffering from Smouldering or Indolent Severe
Systemic mastocytosis with handicap unresponsive to optimal symptomatic
treatment.
Study design
Randomized, double-blind, placebo-controlled, 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 switch being subjected to a toxicity control) versus
placebo over a 24-week treatment period.
140 patients in total
70 patients per group
Intervention
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 switch being subjected to a toxicity
control) versus placebo over a 24-week treatment period
Study burden and risks
Visits performed every 4 weeks until week 24 + weekly phone calls between each
visits until week 12.
After these 24 weeks, the patient can enter in extension period with a visit
every 12 weeks. At end of study, a final visit will be scheduled:
- Screening visit: Patient will have to read and sign informed consent form. If
patient fulfills screening criteria, bone marrow aspirate/biopsy will be taken
if not done earlier, handicap questionnaires will be completed, haematology,
biochemistry and urinalysis samples will be taken, pregnancy test will be done
if applicable.
- Baseline visit: Within 2 weeks after screening when all results are
available. Doctor checks inclusion and exclusion criteria, questionnaires,
physical examination, ECG, blood samples and urinalysis samples are taken.
Pregnancy test will be done if applicable.
- W1, W2, W3, W5, W6, W7, W9, W10, W11 - TREATMENT PERIOD: Haematology test
will be done and a weekly phone call from site will be done until W11.
- W4, W8, W12, W16 AND W20 - TREATMENT PERIOD: questionnaires, physical
examination, blood samples and urinalysis samples will be taken. ECG will be
done at week 12.
- W24 - TREATMENT PERIOD: Bone marrow aspirate/biopsy will be taken if
applicable, questionnaires, physical examination, blood samples and urinalysis
samples will be taken. ECG will be done.
- EVERY 12 WEEKS AFTER W24 - TREATMENT PERIOD: questionnaires, physical
examination, blood samples and urinalysis samples will be taken, urinary
cytology (week 48 only).
- End of Study visit - Final visit: Bone marrow aspirate/biopsy will be done,
questionnaires, physical examination, blood samples and urinalysis samples will
be taken, urinary cytology. ECG will be done.
At each of these visits, the study doctor will ask patient about any other
medicines taken since the last visit, and how patient feels.
ECG will be done at baseline, every 12 weeks and at final visit.
Pregnancy test will be done for female patients of childbearing potential at
screening, baseline, then from baseline every 4 weeks till 24 weeks i.e. main
study phase and every 12 weeks in the extension phase till 96 weeks.
WHAT ARE THE POTENTIAL BENEFITS?
The benefit of taking part in this study is that your disease and general
health will be checked regularly. Taking part in this study may or may not make
your health better. However, the information from this study may help us to
learn more about the treatment of mastocytosis and may help future patients.
SIDE EFFECTS OBSERVED IN PATIENTS TREATED WITH MASITINIB:
Side effects reported by more than 20% of the patients:
• Feeling sick with nausea and vomiting, diarrhea or indigestion and loss of
appetite
• Rash on one small part of the body and red skin with itching
• Feeling tired
Side effects reported between 10-20% of the patients
• Swelling such as swollen lips and puffy eyes
• Mild to moderate headaches
• Muscle pain and spasm (Body pains)
Side effects reported between 5-10% of the patients
• Signs of infection such as fever, severe chills (shivering/feeling cold),
sore throat or mouth ulcers.
• Severe nausea with loss of appetite, diarrhea and abdominal pain
• Extensive rash with red skin, raised red skin patches, itching, burning
sensation, pustular eruption (small collection of pus in the top layer of skin)
SPECIFIC RISKS OF TREATMENT WITH MASITINIB DURING THE FIRST 2 MONTHS OF
TREATMENT:
o Risk of severe neutropenia
o Risk of severe skin toxicity
POTENTIAL RISKS ASSOCIATED WITH MASITINIB TREATMENT:
o Cardiac function
o Renal function
o Risks on fertility, pregnancy and breast feeding
RISKS RELATED TO STUDY PROCEDURES:
Other risks or discomforts you may experience during this study include pain,
risk of bleeding and/or bruising at the blood puncture site.
AB Science 3 Avenue George V
PARIS 75008
NL
AB Science 3 Avenue George V
PARIS 75008
NL
Listed location countries
Age
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
associated with inhibition of ovulation: oral, intravaginal, or transdermal
- Progestogen-only hormonal contraception associated with inhibition of
ovulation: oral, injectable, or implantable
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal ligation
- Vasectomized male (azoospermia assessed medically)
- Sexual abstinence (Its reliability should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient)
10. Patient must be able and willing to comply with study visits and procedures.
11. Patient able to understand, sign, and date the written informed consent
form at the screening visit prior to any protocol-specific procedures.
12. Patient able to understand the patient card and follow the patient card
procedures in case of signs or symptoms of severe neutropenia, or severe
cutaneous toxicity
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%) 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 compliance, or current or past psychiatric
disease that might interfere with the ability to comply with the study
procedures or give informed consent according to the judgment of the
investigator or institutionalized by court decision.
16. Patient with any condition that the physician judges could be detrimental
to patient participating in this study; including any clinically important
deviations from normal clinical laboratory values or concurrent medical
conditions
17. Patients who have received live vaccine within 30 days prior to first IMP
administration.
18. Patients treated concomitantly with strong inducers of CYP3A4, substrates
of CYP3A4 with a narrow therapeutic index, or inhibitors of CYP2C8.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001447-39-NL |
| ClinicalTrials.gov | NCT04333108 |
| CCMO | NL74292.078.20 |