Masitinib for Severe Mast Cell Activation Syndrome

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an experimental drug, masitinib, to determine its effectiveness for people with severe mast cell activation syndrome (MCAS) who have not found relief from other treatments. The study compares two different doses of masitinib to a placebo (a substance with no active drug) to assess its efficacy and safety. Suitable participants are those experiencing severe MCAS symptoms, such as intense itching or frequent flushing, despite unsuccessful attempts with other treatments. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that masitinib has been studied for conditions like Alzheimer's disease and rheumatoid arthritis. In these studies, participants generally tolerated masitinib well, though some experienced side effects such as upset stomach, rash, and fatigue.

In Alzheimer's research, masitinib appeared to slow memory and thinking problems, with manageable side effects. In rheumatoid arthritis studies, masitinib was found to be safe, with side effects similar to other treatments.

Masitinib is also approved for treating certain tumors in dogs, suggesting a level of safety. However, safety in humans might differ.

The trial under consideration is in the early stages of testing masitinib in humans for this condition. At this point, the main focus is on safety. Although the treatment has been tested in humans, researchers are still closely monitoring it to better understand its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about masitinib for severe Mast Cell Activation Syndrome (MCAS) because it offers a new approach by targeting the activity of mast cells directly. Unlike standard treatments that primarily focus on alleviating symptoms, like antihistamines and corticosteroids, masitinib works by inhibiting specific enzymes that play a role in mast cell survival and activation. This could potentially lead to more effective management of MCAS by addressing the root cause rather than just the symptoms. Additionally, the treatment involves a carefully controlled dose escalation, ensuring safety while exploring its full therapeutic potential.

What evidence suggests that this trial's treatments could be effective for severe MCAS?

Research suggests that masitinib, one of the treatments studied in this trial, might help treat severe mast cell activation syndrome (MCAS). It blocks a specific part of the cell that aids mast cell growth and function, potentially reducing symptoms from excessive mast cell activity. Earlier studies showed masitinib's promise in treating conditions involving mast cells, such as systemic mastocytosis, which resembles MCAS. Although more research is needed, these findings strongly suggest it could be effective for severe MCAS. Participants in this trial will receive either masitinib at different dosages or a placebo, alongside best supportive care. ^{1 3 6 7 8}

Who Is on the Research Team?

Julien Rossignol, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05449444

NCT05449444 | Masitinib for the Treatment of Severe Mast ... 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 ...

2. withpower.com withpower.com/trial/phase-2-mast-cell-activation-syndrome-6-2022-348df

Masitinib for Severe Mast Cell Activation Syndrome Masitinib has been evaluated for treating systemic mastocytosis, showing potential as a treatment option due to its selectivity and ability to inhibit certain ...

3. ab-science.com ab-science.com/wp-content/uploads/2011/09/1316704478_masitinibscientificcommunicationsjul2011.pdf

MASITINIB SCIENTIFIC DATA FOR VETERINARY MEDICINE OBJECTIVE: To evaluate the effectiveness of masitinib for the treatment of nonresectable mast cell tumors (MCTs) in dogs at 12 and 24 months after onset of ...

4. ema.europa.eu ema.europa.eu/en/documents/scientific-discussion/masivet-epar-scientific-discussion_en.pdf

scientific discussion - European Medicines Agency In vitro masitinib selectively and effectively inhibits the c-Kit tyrosine kinase receptor (the mast cell growth factor receptor) and shows the highest affinity ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23845124/

Masitinib mesylate for metastatic and non-resectable ... Masitinib mesylate is a tyrosine kinase inhibitor approved for the treatment of gross, non-metastatic grade II and III canine mast cell tumours (MCTs).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11021265/

Masitinib as a neuroprotective agent: a scoping review of ... Clinical studies have shown that masitinib can slow cognitive decline in patients with mild to moderate Alzheimer's disease [10]. Furthermore, ...

7. ema.europa.eu ema.europa.eu/en/documents/assessment-report/masipro-epar-refusal-public-assessment-report_en.pdf

Masipro, INN - masitinib - European Medicines Agency Patients can be classified depending on the degree of mast cell infiltration, mast cell activation, and the severity of symptoms. Of the ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2714151/

Masitinib in the treatment of active rheumatoid arthritis This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy ...