Clinical trial NCT04333108: Masitinib in Severe Indolent or Smoldering Systemic Mastocytosis Unresponsive to Optimal Symptomatic Treatment
Official title: Phase 3 Study to Compare Oral Masitinib to Placebo in Treatment of Patients With Smouldering or Indolent Severe Systemic Mastocytosis, Unresponsive to Optimal Symptomatic Treatment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Indolent Systemic Mastocytosis
Keywords: Mastocytosis with handicap
Mastocytosis
Mast cell
Mast cell infiltration
Skin
Bone marrow
Pruritus
Flushes
c-kit
c-kit mutation
Wild Type
Mutation Asp-816-Val(D816V)
Indolent systemic mastocytosis
smoldering systemic mastocytosis
Lead sponsor: AB Science
Sponsor class: INDUSTRY
First posted: 2020-04-03
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of oral masitinib versus placebo in the treatment of patients suffering from smouldering or indolent systemic mastocytosis with severe symptoms of mast cell mediator release, unresponsive to optimal symptomatic treatment.

Detailed description: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cell activity via inhibition of c-Kit, Lyn and Fyn kinase signaling pathways. This is a multicenter, randomized, double-blind, placebo-controlled, 2-parallel-group, trial comparing oral masitinib versus placebo in the treatment of patients suffering from smouldering or indolent systemic mastocytosis with severe symptoms of mast cell mediator release (also referred to as handicaps), unresponsive to optimal symptomatic treatment. The treatment period is 24 weeks. Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment, followed by dose escalation to 6.0 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control.

Eligibility criteria: Inclusion Criteria:

1. Patient with one of the following documented mastocytosis subtypes (variants): Smouldering Systemic Mastocytosis, Indolent Systemic Mastocytosis
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. Patient with documented systemic mastocytosis and evaluable disease based upon histological criteria
4. Patient with documented treatment failure of his/her symptom(s) (within the past 2 years) with at least two of the symptomatic treatments used at optimized dose: Anti H1, Anti H2, Proton pump inhibitor, Antidepressants, Cromoglycate Sodium, Antileukotriene.
5. Patient with severe symptoms of mastocytosis over the 14-day run-in period including at least one among pruritus, flushes, and depression: pruritus score ≥ 9, number of flushes per week ≥ 8, Hamilton rating scale for depression (HAMD-17) score ≥ 19.

Exclusion Criteria:

1. Patient with one of the following mastocytosis: Cutaneous Mastocytosis, Systemic Mastocytosis with an Associated clonal Hematologic Non Mast cell lineage Disease (SM-AHNMD), Mast cell leukemia (MCL), Aggressive systemic mastocytosis (ASM)
2. Previous treatment with any Tyrosine Kinase Inhibitor
3. Treatment with any investigational agent within 8 weeks prior to screening.

Primary outcomes:
measure: Cumulative response (3R75%)
timeFrame: 24 weeks
Secondary outcomes:
measure: Cumulative response (4R75%)
timeFrame: 24 weeks
measure: Cumulative response (2R75%)
timeFrame: 24 weeks
measure: Cumulative response
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Amiens
country: France
facility: Centre Hospitalier Universitaire d'Amiens
city: Besançon
country: France
facility: Hospital Jean-Minjoz
city: Grenoble
country: France
facility: Grenoble University Hospital
city: Lille
country: France
facility: Hospital Claude Huriez
city: Marseille
country: France
facility: Marseille University Hospital Timone
city: Paris
country: France
facility: Centre de référence de Mastocytose (CEREMAST)
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire
city: Berlin
country: Germany
facility: University Hospital Charité
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Gdańsk
country: Poland
facility: Medical University of Gdańsk
city: Kraków
country: Poland
facility: The University Hospital in Krakow (Szpital Uniwersytecki w Krakowie)
city: Bucharest
country: Romania
facility: University Hospital in Bucharest (Spitalul Universitar de Urgență București)
city: Saint Petersburg
country: Russian Federation
facility: Almazov National Medical Research Centre
city: Dnipropetrovs'k
country: Ukraine
facility: Dnipropetrovsk Clinical Association of Emergency Medical Care of Dnipropetrovsk Regional
city: Poltava
country: Ukraine
facility: Private Enterprise Private Manufacturing Company Acinus
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
Study officials:
affiliation: Centre Hospitalier Universitaire, Service de Dermatologie, Toulouse -France
name: Cristina Bulai Livideanu, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Paul C, Sans B, Suarez F, Casassus P, Barete S, Lanternier F, Grandpeix-Guyodo C, Dubreuil P, Palmerini F, Mansfield CD, Gineste P, Moussy A, Hermine O, Lortholary O. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol. 2010 Dec;85(12):921-5. doi: 10.1002/ajh.21894.
citation: Lortholary O, Chandesris MO, Bulai Livideanu C, Paul C, Guillet G, Jassem E, Niedoszytko M, Barete S, Verstovsek S, Grattan C, Damaj G, Canioni D, Fraitag S, Lhermitte L, Georgin Lavialle S, Frenzel L, Afrin LB, Hanssens K, Agopian J, Gaillard R, Kinet JP, Auclair C, Mansfield C, Moussy A, Dubreuil P, Hermine O. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017 Feb 11;389(10069):612-620. doi: 10.1016/S0140-6736(16)31403-9. Epub 2017 Jan 7.
citation: Latham BD, Oskin DS, Crouch RD, Vergne MJ, Jackson KD. Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib. Chem Res Toxicol. 2022 Sep 19;35(9):1467-1481. doi: 10.1021/acs.chemrestox.2c00057. Epub 2022 Sep 1.