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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ab Science

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

26 Nov 2025 → ongoing

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-514538-19-00

EudraCT number

2016-001447-39

WHO UTN

U1111-1314-1165

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Safety

The objective of the trial is 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.

Secondary objectives 1

1. 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

Conditions and MedDRA coding

Mastocytosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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 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, contingent 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 handicap(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 Antileucotriene, 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: for 8 months for female patients; and 5 months for male patients and their partners 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 22

1. Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM.
2. Previous treatment with any Tyrosine Kinase Inhibitor within the past 2 months prior to baseline.
3. History of unresponsiveness or intolerance to imatinib or masitinib
4. 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.
5. Treatment with any investigational agent within 8 weeks prior to screening
6. Patients with current or a history of severe cardiovascular disease: - Ischemic heart disease (myocardial infarction, unstable angina pectoris, acute coronary syndrome, coronary revascularization procedure) - Congestive heart failure of NYHA Class III or IV - Stroke, including a transient ischemic attack - Conduction disorders such as second degree or third-degree atrioventricular block not successfully treated with a pacemaker or bi-fascicular block, uncontrolled atrial arrhythmia - Repolarization disorders such as QTc Fridericia interval > 450 milliseconds for males and > 470 milliseconds for females, torsades de pointe, ventricular tachycardia - Drug induced heart failure or ischemic heart disease - Radiotherapy induced cardiomyopathy - Family history of unexpected death of cardiovascular origin - Edema of cardiac origin and left ventricular ejection fraction ≤50%
7. 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) • Diabetes • Kidney disease • Smoking (10 pack-year calculated as (packs smoked per day) × (years as a smoker), 20 cigarettes per pack) • 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 the country specific version is not available, EU one should be used.
8. Patient who had major surgery within 2 weeks prior to screening visit.
9. Known hypersensitivity to masitinib or to any of its excipients
10. Patient taking concomitant treatment or therapies associated with severe drug-induced skin toxicity.
11. Patient with history of drug-induced severe skin toxicities at screening
12. Female patients who are pregnant or are breastfeeding
13. 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
14. Patient with history of severe bone marrow disorders such as agranulocytosis or aplasia, or with abnormal laboratory results from local laboratory assessments at screening and baseline defined as:  Patient with neutropenia (ANC < 1,500/mm3) at screening or baseline.  Patient with active or latent infection detected at screening by usual diagnosis methods: o Tuberculosis: IGRA (Interferon Gamma Release Assay) or identification of Mycobacterium tuberculosis by culture of any biological sample if available, o Viral hepatitis B: HBs antigen positive, o Viral hepatitis C: RT-PCR positive,
15. Patient with history of hepatic disorders, with a known liver disease or recent alcohol abuse, or with abnormal laboratory results defined as: o Hepatic transaminase levels >2 ULN at baseline, or o Total bilirubin level >1.5 ULN at baseline, or o Both hepatic transaminase levels and total bilirubin levels outside the normal ranges at screening and baseline, or o Albuminaemia <1 x LLN at screening and baseline, or o Patient with concomitant medication known to be associated with severe hepatotoxicity.
16. 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) - In case of proteinuria ≥1+ on the dipstick, proteinuria to creatininuria ratio will be assessed on urine sampled in the morning. If this ratio > 20 mg/mmol, the patient should be excluded.
17. Vulnerable population defined as: - Life expectancy < 6 months - Patients with a diagnosis of cancer within five years before screening except for basal cell carcinoma. - Patients with known diagnosis of human immunodeficiency virus (HIV) infection.
18. Patient with interstitial lung disease or pulmonary fibrosis
19. 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.
20. 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
21. Patients who have received a live vaccine within 30 days prior to first IMP administration
22. Patients treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary analysis (response on 3 handicaps) will be done on the ITT population. It is based on the cumulative response by patient handicap from week 8 to week 24

Secondary endpoints 3

1. 1.Handicaps
2. 2. Biological and Skin Parameters
3. 3. Quality of Life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ab Science

Sponsor organisation

Ab Science

Address

3 Avenue George V

City

Paris

Postcode

75008

Country

France

Scientific contact point

Organisation

Ab Science

Contact name

Christian Fassotte

Public contact point

Organisation

Ab Science

Contact name

Alain Moussy

Locations

3 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 3 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications