Masitinib in Severe Indolent or Smoldering Systemic Mastocytosis

Phase 3

Completed

Brief Summary: The objective of this study is to compare the safety and efficacy of masitinib (AB1010) to placebo in patients with mastocytosis with handicap.

Detailed Description: This was a prospective, multicenter, randomized, placebo-controlled, parallel-group, phase 3 study, conducted in 15 countries, evaluating the efficacy and safety of masitinib (6 mg/kg/day administered orally in two daily intakes over 24-weeks with a double-blind extension period possible) for the treatment of indolent systemic mastocytosis, smoldering mastocytosis or cutaneous mastocytosis, in patients with mast cells mediator release symptoms that are refractory to conventional symptomatic treatment.

A study protocol amendment restricted enrolment to patients with severe indolent and smoldering systemic mastocytosis. The objective of this phase 3 study was therefore to evaluate masitinib efficacy and safety in severe systemic mastocytosis patients, with or without D816V mutation of c-Kit. The primary objective of the phase 3 study was to detect a statistically significant difference between masitinib (plus optimal concomitant symptomatic treatments) and placebo (plus optimal concomitant symptomatic treatments) in cumulative response on four severe symptoms, referred to also as handicaps.

Recruitment & Eligibility

Inclusion Criteria

Patient with one of the following documented mastocytosis as per WHO classification: Smouldering Systemic Mastocytosis, Severe Indolent Mastocytosis
Patient with documented mastocytosis and evaluable disease based upon histological criteria: typical infiltrates of mast cells in a multifocal or diffuse pattern in skin and/or bone marrow biopsy
Patient with documented treatment failure of his/her handicap(s) with at least one of the following therapy used at optimized dose: Anti H1, Anti H2, Proton pump inhibitor, Osteoclast inhibitor, Cromoglycate Sodium, Antileukotriene
Handicapped status defined as at least two of the following handicaps, including at least one among pruritus, flushes, depression and fatigue: pruritus score ≥ 9, number of flushes per week ≥ 8, Hamilton rating scale for depression (HAMD-17) score ≥ 19, number of stools per day ≥ 4, number of mictions per day ≥ 8, Fatigue Impact Scale total score (asthenia) ≥ 75
Patients with OPA ≥ 2 (moderate to intolerable general handicap)
ECOG ≤ 2
Patient with adequate organ function

Exclusion Criteria

Patient with one of the following mastocytosis: Cutaneous Mastocytosis, Not documented Smouldering Systemic Mastocytosis or Indolent Systemic Mastocytosis, Systemic Mastocytosis with an Associated clonal Hematologic Non Mast cell lineage Disease (SM-AHNMD), Mast cell leukemia (MCL), Aggressive systemic mastocytosis (ASM)
Previous treatment with any Tyrosine Kinase Inhibitor
Patient with recent cardiac history of: Acute coronary syndrome, Acute heart failure, Significant ventricular arrhythmia; patient with cardiac failure class III or IV; Syncope without known aetiology within 3 months, uncontrolled severe hypertension.
Patient with any condition that the physician judges could be detrimental to subjects participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events Previous treatment
Change in the symptomatic treatment of mastocytosis or administration of any new treatment of mastocytosis within 4 weeks prior to baseline
Treatment with any investigational agent within 4 weeks prior to baseline

Arm && Interventions

Group	Intervention	Description
Masitinib & BSC	Best Supportive Care	Masitinib (6 mg/kg/day) administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC)
Placebo & BSC	Placebo	Matching placebo administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC)
Placebo & BSC	Best Supportive Care	Matching placebo administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC)
Masitinib & BSC	Masitinib	Masitinib (6 mg/kg/day) administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC)

Primary Outcome Measures

Name	Time	Method
Cumulative response (4R75%)	24 weeks	The prospectively declared primary endpoint (4R75%) was cumulative response in at least one of four severe baseline symptoms of mast cell mediator release (pruritus, flushes, depression, or asthenia). Response was defined as a 75% improvement from baseline for any of these four symptoms. Cumulative response was defined as the number of actual responses between weeks 8 and 24, divided by the total number of possible responses over the same treatment period (ie, with five scheduled visits, each patient had a maximum of five to 20 possible responses depending on the number of severe baseline symptoms).

Secondary Outcome Measures

Name	Time	Method
Cumulative response (3R75%)	24 weeks	Cumulative response in at least one of three severe baseline symptoms (pruritus, flushes, or depression)
Cumulative response (2R75%)	24 weeks	Cumulative response in at least one of three severe baseline symptoms (pruritus or flushes)

Locations (24): UC Davis Health System , Department of Dermatology
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Sacramento, California, United States
MD Anderson Cancer Centre
🇺🇸
Houston, Texas, United States
Hôpital Nord
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Marseille, France
Hôpital Ambroise Paré
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Marseille, France
Hôpital Central
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Nancy, France
CHU Hôtel Dieu
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Nantes, France
Hôpital l'Archet II
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Nice, France
Hôpital Necker
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Paris, France
CHU Lyon Sud
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Pierre Bénite, France
CHU Milétrie
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Poitiers, France
Hôpital Tenon
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Paris, France
CHU Hôpital Sud
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Rennes, France
Hôpital Purpan
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Toulouse, France
CHU Clermont Ferrand
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Clermont Ferrand, France
Hôpital Claude Huriez
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Lille, France
CHU Dupuytren
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Limoges, France
Centre Hospitalier Lyon Sud
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Pierre-Bénite, France
CHU de Saint-Etienne
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Saint-Etienne, France
Hôpital Avicenne
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Bobigny, France
CHU de Caen
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Caen, France
CHU d'Amiens
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Amiens, France
CHU de Brest
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Brest, France
Hôpital Bretonneau
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Tours, France
Hôpital des Hauts Clos
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Troyes, France