Masitinib for Severe Mast Cell Activation Syndrome

Recruiting at 3 trial locations

Overseen By Clinical Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AB Science

Must be taking: Anti-H1

Must not be taking: Tyrosine kinase inhibitors

Disqualifiers: Systemic indolent mastocytosis, pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 24

Duration: 24 weeks

72 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stay on a stable dose of Anti-H1 medication for at least 4 weeks before screening and throughout the study. Other medications for MCAS should not be changed or started within 4 weeks prior to screening.

What data supports the effectiveness of the drug masitinib for treating severe mast cell activation syndrome?

Masitinib is a drug that has shown promise in treating systemic mastocytosis, a condition related to mast cell activation, by targeting specific receptors involved in the disease. It is more selective in its action compared to other similar drugs, which may make it a useful option for certain patients. ^{1 2 3 4 5}

What safety data exists for masitinib in humans?

Masitinib has been evaluated for treating systemic mastocytosis, showing potential as a treatment option due to its selectivity and ability to inhibit certain cell activities. While specific human safety data is limited, animal studies have shown good efficacy and acceptable toxicity. ^{1 3 6 7 8}

How is the drug masitinib unique for treating severe mast cell activation syndrome?

Masitinib is unique because it is a selective tyrosine kinase inhibitor that specifically targets c-Kit and Lyn kinases, which are involved in the activation and proliferation of mast cells. This makes it particularly effective in controlling symptoms related to mast cell disorders, unlike other treatments that may not target these specific pathways. ^{1 9 10 11 12}

What is the purpose of this trial?

This trial tests if masitinib, a pill, can help people with severe MCAS who haven't improved with other treatments. It works by calming down cells that cause allergic reactions and inflammation.

Research Team

Julien Rossignol, MD

Principal Investigator

Reference Centre for Mastocytosis (CEREMAST), Necker Hospital, Paris, France

Eligibility Criteria

This trial is for patients with severe Mast Cell Activation Syndrome (MCAS) who haven't responded to other treatments. They must have had significant symptoms like intense itching, frequent flushes, or depression during a two-week period and failed at least two optimized dose treatments in the past two years. Participants should be on a stable anti-histamine regimen and not pregnant or breastfeeding.

Inclusion Criteria

I have been on a stable dose of Anti-H1 medication for at least 4 weeks.

I have severe itching, frequent hot flashes, or significant depression.

I've tried at least two treatments for my condition without success in the last two years.

Exclusion Criteria

I have a slow-growing form of mastocytosis affecting my whole body.

I have been treated with a Tyrosine Kinase Inhibitor before.

I haven't changed my MCAS treatment or started any new one in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral masitinib or placebo with dose escalation over a 24-week period

24 weeks

Visits at baseline and every visit until Week 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Best supportive care
• Masitinib

Trial Overview The trial tests how effective and safe different doses of oral masitinib are compared to a placebo in treating severe MCAS unresponsive to optimal symptomatic treatment. Patients will receive either masitinib at 4.5 mg/kg/day, masitinib at 6.0 mg/kg/day, placebo, or best supportive care.

Participant Groups

Group I: Masitinib (6.0) & BSC Experimental Treatment 2 Interventions

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.

Group II: Masitinib (4.5) & BSC Experimental Treatment 2 Interventions

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.

Group III: Placebo & BSC Placebo Group 2 Interventions

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.

Masitinib is already approved in European Union, United States for the following indications:

Approved in European Union as Masivet for:

• Mast cell tumors in dogs

Approved in United States as Kinavet for:

• Mast cell tumors in dogs

Who Is Running the Clinical Trial?

AB Science

Lead Sponsor

Trials

39

Recruited

15,700+

Findings from Research

Masitinib, a new potential treatment for systemic mastocytosis (SM), is more selective for c-kit receptors compared to other tyrosine kinase inhibitors, which may enhance its effectiveness in targeting the disease.

The drug shows promise in inhibiting mast cell degranulation, cytokine production, and migration, suggesting it could be a significant therapeutic option for certain patients with SM, although further research is needed to establish response measurement methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of masitinib for treating systemic mastocytosis. Laforgia, M., Marech, I., Nardulli, P., et al.[2021]

Avapritinib is a highly selective inhibitor of the KIT D816V mutation and has been approved for treating advanced systemic mastocytosis (AdvSM), showing the ability to achieve complete and durable clinical responses in patients.

The phase 1 EXPLORER and phase 2 PATHFINDER trials confirmed that avapritinib can lead to molecular remission of the KIT D816V mutation, although managing AdvSM can be complicated due to its diverse mutational landscape.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avapritinib for advanced systemic mastocytosis. Gotlib, J., Reiter, A., DeAngelo, DJ.[2023]

The prognosis for patients with advanced systemic mastocytosis and primary eosinophilic neoplasms has improved significantly due to targeted therapies like midostaurin and avapritinib, which can reduce mast cell burden and alleviate organ damage.

Avapritinib has shown the potential to achieve molecular remission and improve survival rates compared to historical treatments, indicating a shift in the natural history of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms. Gotlib, J.[2023]

Recent updates to the classification of systemic mastocytosis (SM) have been proposed by expert committees, emphasizing the importance of mast cell cytomorphology and myeloid-lineage restriction in diagnosing advanced forms of the disease.

New treatments, such as KIT-targeting tyrosine kinase inhibitors (like midostaurin and avapritinib), have shown effectiveness in reducing symptoms and mast cell burden in advanced systemic mastocytosis, but their impact on overall survival compared to older treatments has not yet been evaluated in controlled studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced systemic mastocytosis-Revised classification, new drugs and how we treat. Pardanani, A., Reichard, K., Tefferi, A.[2023]

Midostaurin, an oral multikinase/KIT inhibitor, has been approved for the treatment of advanced systemic mastocytosis (advSM) based on phase 2 clinical studies, showing its efficacy in managing this condition characterized by neoplastic mast cell accumulation.

Adverse events (AEs) from midostaurin can be challenging to differentiate from symptoms of the disease itself, which may lead to unnecessary treatment discontinuation; therefore, effective management strategies for AEs are crucial to ensure patients can continue benefiting from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical management of adverse events in patients with advanced systemic mastocytosis receiving midostaurin. Gotlib, J., Kluin-Nelemans, HC., Akin, C., et al.[2021]

In a study of 39 dogs with macroscopic mast cell tumors treated with masitinib, 82.1% showed a clinical response, with 38.5% achieving complete remission and 43.6% showing partial response, indicating its efficacy.

Masitinib was generally well-tolerated, with a median survival time of 159 days, although 64.1% of dogs experienced adverse effects, the most common being elevated liver enzymes and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical response of masitinib mesylate in the treatment of canine macroscopic mast cell tumours. Grant, J., North, S., Lanore, D.[2021]

Masitinib, a selective oral tyrosine kinase inhibitor, showed significant efficacy in reducing symptoms associated with indolent mastocytosis in a study of 25 patients over 12 weeks, with improvements in flushes, depression, and pruritus by 64%, 43%, and 36% respectively.

The treatment was generally well-tolerated, with most adverse events being mild to moderate, although one patient experienced a serious but reversible side effect (agranulocytosis), indicating that masitinib could be a viable long-term treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Paul, C., Sans, B., Suarez, F., et al.[2021]

In a phase 3 study involving 135 patients with indolent or smouldering systemic mastocytosis, masitinib demonstrated a significant cumulative response of 18.7% compared to 7.4% for placebo, indicating its efficacy in improving severe symptoms.

Masitinib was generally well tolerated, with common side effects including diarrhea and rash, but no life-threatening toxicities were reported, suggesting a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lortholary, O., Chandesris, MO., Bulai Livideanu, C., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

An evaluation of masitinib for treating systemic mastocytosis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Avapritinib for advanced systemic mastocytosis. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Advanced systemic mastocytosis-Revised classification, new drugs and how we treat. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Practical management of adverse events in patients with advanced systemic mastocytosis receiving midostaurin. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Clinical response of masitinib mesylate in the treatment of canine macroscopic mast cell tumours. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of masitinib in cats. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Safety of masitinib mesylate in healthy cats. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. [2021]