Masitinib in Severe Indolent or Smoldering Systemic Mastocytosis

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.

Inclusion Criteria:

1. Patient with one of the following documented mastocytosis as per WHO classification:
Smouldering Systemic Mastocytosis, Severe Indolent Mastocytosis

2. 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

3. 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

4. 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

5. Patients with OPA ≥ 2 (moderate to intolerable general handicap)

6. ECOG ≤ 2

7. Patient with adequate organ function

Exclusion Criteria:

1. 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)

2. Previous treatment with any Tyrosine Kinase Inhibitor

3. 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.

4. 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

5. Change in the symptomatic treatment of mastocytosis or administration of any new
treatment of mastocytosis within 4 weeks prior to baseline

6. Treatment with any investigational agent within 4 weeks prior to baseline