Masitinib for the Treatment of Severe Mast Cell Activation Syndrome

A 24-week, Multicenter, Randomized, Double Blind, Placebo-controlled, Dose-range Finding Phase II Study to Compare Efficacy and Safety of Oral Masitinib to Placebo in Treatment of Patients With Severe Mast Cell Activation Syndrome (MCAS) With Handicap Unresponsive to Optimal Symptomatic Treatment

To evaluate the efficacy and safety of two dosing schemes of oral masitinib versus matching placebo in the treatment of patients suffering from severe MCAS with handicap unresponsive to optimal symptomatic treatment.

Study Overview

• Status: Recruiting
• Conditions: Mast Cell Activation Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Masitinib 4.5 mg/kg/day; Other: Best supportive care; Drug: Masitinib 6.0 mg/kg/day

Detailed Description

Multicenter, double-blind, placebo-controlled trial comparing two different dosing schemes over a 24-week treatment period.

Dosing scheme #1: Oral masitinib treatment at 3 mg/kg/day for 4 weeks, then a switch to 4.5 mg/kg/day for the remainder of the treatment period, versus placebo with a matching titration scheme. Randomization 2: 1 (Masitinib MCAS: Placebo MCAS).

Dosing scheme #2: Oral masitinib treatment at 3 mg/kg/day for 4 weeks, then a switch to 4.5 mg/kg/day for 4 weeks, then a second switch to 6 mg/kg/day for the remainder of the treatment period versus placebo treatment with a matching titration scheme. Randomization 2: 1 (Masitinib MCAS: Placebo MCAS)

• Study Type: Interventional
• Enrollment (Anticipated): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Recruiting
    • Centre Hospitalier Universitaire Amiens-Picardie
  • Paris, France
    • Recruiting
    • Necker-Enfants Malades Hospital, Centre de référence des Mastocytoses (CEREMAST)
  • Toulouse, France
    • Recruiting
    • CHU Toulouse
• United States
  • Missouri
    • Weldon Spring, Missouri, United States, 63304
      • Recruiting
      • St Charles Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria include:

• Patient with mast cell activation syndrome (MCAS).
• Patient with severe symptoms 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.
• 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.

Exclusion Criteria include:

• Previous treatment with any Tyrosine Kinase Inhibitor.
• Any change in the symptomatic treatment of MCAS, including systemic corticosteroids, or administration of any new treatment for MCAS within 4 weeks prior to screening.
• Patient with systemic indolent mastocytosis.
• Female patients who are pregnant or are breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Masitinib (4.5) & BSC; Masitinib 4.5 mg/kg/day administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC). Participants receive masitinib (3.0 mg/kg/day) for 4 weeks, given orally twice daily, with a dose escalation to 4.5 mg/kg/day for the remainder of the treatment period. Each ascending dose titration is subjected to a safety control.	Drug: Masitinib 4.5 mg/kg/day; Masitinib 4.5 mg/kg/day; Other Names: AB1010; Other: Best supportive care; Optimal concomitant symptomatic treatments. Includes: H1- and H2-antihistamines, sodium cromoglicate, antidepressants, antileukotrienes, proton pump inhibitors, and corticosteroids.; Other Names: BSC
EXPERIMENTAL: Masitinib (6.0) & BSC; Masitinib 6.0 mg/kg/day administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC). Participants receive masitinib (3.0 mg/kg/day) for 4 weeks, given orally twice daily, with a dose escalation to 4.5 mg/kg/day for4 weeks of treatment, then a second dose escalation to 6 mg/kg/day for the remainder of the treatment period. Each ascending dose titration is subjected to a safety control.	Other: Best supportive care; Optimal concomitant symptomatic treatments. Includes: H1- and H2-antihistamines, sodium cromoglicate, antidepressants, antileukotrienes, proton pump inhibitors, and corticosteroids.; Other Names: BSC; Drug: Masitinib 6.0 mg/kg/day; Masitinib 6.0 mg/kg/day; Other Names: AB1010
PLACEBO_COMPARATOR: Placebo & BSC; Placebo administered as an add-on to optimal concomitant symptomatic treatment (i.e. best supportive care, BSC). Participants receive a matched dose placebo, given orally twice daily.	Drug: Placebo; Matching placebo; Other Names: Placebo Oral Tablet; Other: Best supportive care; Optimal concomitant symptomatic treatments. Includes: H1- and H2-antihistamines, sodium cromoglicate, antidepressants, antileukotrienes, proton pump inhibitors, and corticosteroids.; Other Names: BSC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed response at 50%	Confirmed response at 50%, defined as an improvement with respect to the baseline values of 50% for Pruritus, Flushes and Depression (HAMD-17 score) which should be confirmed from the previous visit. Handicaps at baseline defined as: pruritus score ≥ 9; number of flushes per week ≥ 8; HAMD-17 score ≥ 19.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative response	Cumulative (every patient visit) response at 75% on 3 handicaps (pruritus, flush, depression) from week 8 to week 24. Analysis will be performed using Generalized Estimating Equations (GEE) model with stratification.	week 8 to week 24
Confirmed response (75%)	Confirmed response at 75%, defined as an an improvement with respect to the baseline values of 75% for Pruritus, Flushes and Depression (Hamilton Depression Rating Scale) which should be confirmed from the previous visit. The Hamilton Depression Rating Scale (HAMD-17) has 17 items and is scored between 0 and 4 points. Scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression; the maximum score being 52.	24 weeks
Patient-Reported Outcome for Symptom Severity (PROSS)	Changes in MCAS symptom severity will also be assessed using the Patient-Reported Outcome for Symptom Severity (PROSS) questionnaire. Total and individual symptom scores will be determined at baseline and at every visit until Week 24.The PROSS questionnaire has 11 items and is scored between 0 and 10 points. A score of 0 is an absence of the symptom and a score of 10 is very severe; the maximum score being 110.	24 weeks

Collaborators and Investigators

• Sponsor: AB Science

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2022
• Primary Completion (ANTICIPATED): December 31, 2024
• Study Completion (ANTICIPATED): December 31, 2024

Study Registration Dates

• First Submitted: July 2, 2022
• First Submitted That Met QC Criteria: July 6, 2022
• First Posted (ACTUAL): July 8, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 3, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Disease; Hypersensitivity; Neoplasms, Connective Tissue; Immune Complex Diseases; Syndrome; Mastocytosis
• Other Study ID Numbers: AB20006; 2021-005406-96 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No Masitinib is under clinical investigation and has not yet been approved in any sought-after indication by any health authority worldwide. As such, there is no plan for data-sharing at this point in time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No