Efficacy and Safety of Oral Masitinib Versus Placebo in Patients with Smouldering or Indolent Severe Systemic Mastocytosis Unresponsive to Symptomatic Treatment
- Trial ID
- 2024-514538-19-00
- Protocol
- AB15003
- Sponsor
- Ab Science
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase III study is to evaluate the **efficacy** and **safety** of oral masitinib compared to placebo in patients with Smouldering or Indolent Severe Systemic **mastocytosis** with handicap, who are unresponsive to optimal symptomatic treatment. This is clinically relevant as it addresses the need for effective treatment options in a patient population that does not respond adequately to existing therapies, potentially improving patient outcomes and quality of life.
Secondary objectives include assessing the efficacy of oral masitinib versus placebo on:
- Cumulative response on four handicaps: Pruritus, Flushes, Depression, and Fatigue Severity Scale (FSS)
- Cumulative response on four handicaps: Pruritus, Flushes, Depression, and Fatigue Impact Scale (FIS)
- Cumulative response on two handicaps: Pruritus and Flushes
- Cumulative response on each individual handicap: Pruritus, Flushes, Depression, FSS, and FIS
- Tryptase level
- Urticaria Pigmentosa
- Quality of life
- Safety
Participants
The clinical trial involves participants diagnosed with **mastocytosis**, specifically Smouldering Systemic Mastocytosis (SSM) or Indolent Systemic Mastocytosis (ISM), who are experiencing severe symptoms unresponsive to optimal symptomatic treatment. The study population includes both male and female subjects aged between 18 to 75 years, with a weight greater than 45 kg and a Body Mass Index (BMI) ranging from 18 to 35 kg/m². Participants are required to maintain a stable dose of Anti-H1 for a minimum of four weeks prior to screening and throughout the study period. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must adhere to highly effective contraception methods during the study and for a specified period after the last treatment intake. The selection criteria ensure that participants have documented treatment failures with at least two symptomatic treatments at optimized doses within the last two years. The trial aims to evaluate the efficacy and safety of oral masitinib compared to a placebo in this patient population.
Plans and Procedures
The clinical trial is a **randomized**, double-blind, placebo-controlled, phase III study designed to evaluate the efficacy and safety of oral **masitinib** in patients with Smouldering or Indolent Severe Systemic **mastocytosis** unresponsive to optimal symptomatic treatment. The trial is structured as a 24-week study with a possible extension, involving two parallel groups with a 1:1 randomization ratio. Participants will receive either masitinib or a placebo, administered orally in the form of coated tablets. The trial aims to assess the primary endpoint of cumulative response by patient handicap from week 8 to week 24, with secondary endpoints including biological and skin parameters, and quality of life assessments.
The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as documented mastocytosis and severe symptoms over a 14-day run-in period. Participants must also have experienced treatment failures with at least two symptomatic treatments. Following successful screening, participants will be randomized and begin the treatment phase. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. The end-of-study visit will conclude the trial, where final assessments will be conducted.
Participant involvement is expected to last for the duration of the 24-week treatment period, with the possibility of extension based on individual response and study outcomes. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The trial is anticipated to end by December 31, 2025, with recruitment starting on March 11, 2024. The study is not classified as low intervention and is conducted under the authorization of relevant regulatory bodies.
Treatment
The clinical trial involves the administration of **masitinib**, a tyrosine kinase inhibitor, in the form of a **coated tablet**. Masitinib is administered orally with a maximum daily dose of 4.5 mg/kg and a maximum total dose of 756 mg/kg over a treatment period of 24 weeks. The pharmaceutical form is a coated tablet, and the active substance is chemically derived. The trial aims to evaluate the efficacy and safety of masitinib in patients with Smouldering or Indolent Severe Systemic mastocytosis who are unresponsive to optimal symptomatic treatment.
In addition to masitinib, the trial includes a **placebo** group to serve as a comparator. The placebo is designed to match the 100 mg and 200 mg masitinib doses, although the specific pharmaceutical form and active substance details are not provided. The placebo is administered orally, following the same schedule as the masitinib treatment, to ensure blinding and maintain the integrity of the study design.
Efficacy
The efficacy of oral **masitinib** in the treatment of patients with Smouldering or Indolent Severe Systemic mastocytosis will be assessed through a 24-week, prospective, multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial. The primary endpoint for evaluating efficacy is the cumulative response on three handicaps, measured from week 8 to week 24, in the intention-to-treat (ITT) population. Secondary endpoints include assessments of handicaps, biological and skin parameters, and quality of life. These parameters will be collected and analyzed at specified timepoints throughout the study duration to determine the therapeutic impact of masitinib compared to placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient with one of the following documented mastocytosis: • Smouldering Systemic Mastocytosis (SSM) • Indolent Systemic Mastocytosis (ISM)
- An excess of mast cells or a presence of abnormal mast cells in at least two organs (among skin, bone-marrow and GI Tract)
- 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.
- 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
- 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
- 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
- Age between 18 to 75 years (inclusive).
- Weight > 45 kg and BMI between 18 and 35 kg/m2
- 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)
- Patient must be able and willing to comply with study visits and procedures.
- Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures.
- 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
- Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM.
- Previous treatment with any Tyrosine Kinase Inhibitor within the past 2 months prior to baseline.
- History of unresponsiveness or intolerance to imatinib or masitinib
- 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.
- Treatment with any investigational agent within 8 weeks prior to screening
- 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%
- 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.
- Patient who had major surgery within 2 weeks prior to screening visit.
- Known hypersensitivity to masitinib or to any of its excipients
- Patient taking concomitant treatment or therapies associated with severe drug-induced skin toxicity.
- Patient with history of drug-induced severe skin toxicities at screening
- Female patients who are pregnant or are breastfeeding
- 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
- 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,
- 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.
- 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.
- 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.
- Patient with interstitial lung disease or pulmonary fibrosis
- 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.
- 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
- Patients who have received a live vaccine within 30 days prior to first IMP administration
- Patients treated concomitantly with Breast Cancer Resistance Protein (BCRP) substrates, inhibitors or inducers (e.g. anthracyclines, mitoxantrone, methotrexate, topotecan, irinotecan)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 11 Mar 2024 | 30 |
 Poland | Not Recruiting | 11 Mar 2024 | 15 |
 Spain | Not Recruiting | 11 Mar 2024 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo to 100mg masitinib | Placebo | N/A | — | — | — | N/A |
Placebo to 200mg masitinib | Placebo | N/A | — | — | — | N/A |
masitinib | Test | COATED TABLET | ORAL | 4.5 | 24 | PRD110277 |
masitinib | Test | COATED TABLET | ORAL | 6.0 | 24 | PRD10419816 |