What is the mechanism of action of this treatment?

Selective tyrosine kinase inhibitors (TKIs) like Bezuclastinib work by inhibiting specific enzymes involved in the signaling pathways that cause the proliferation and survival of mast cells. In Systemic Mastocytosis (SM), mutations in the KIT gene lead to uncontrolled mast cell growth. TKIs target these enzymes, reducing mast cell proliferation and alleviating symptoms. This mechanism is crucial for SM patients as it addresses the root cause of the disease, potentially leading to better symptom control and improved quality of life.

What side effects are associated with this type of intervention?

Common treatments for systemic mastocytosis, particularly those involving tyrosine kinase inhibitors like bezuclastinib, often include drugs such as imatinib, midostaurin, and avapritinib. Known side effects of these treatments can include gastrointestinal issues (nausea, vomiting, diarrhea), fatigue, edema, and cytopenias (anemia, neutropenia, thrombocytopenia). Additionally, patients may experience liver enzyme abnormalities and, less commonly, cardiovascular events. It is important for patients to discuss these potential side effects with their healthcare provider to manage and mitigate risks effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for Systemic Mastocytosis, particularly focusing on tyrosine kinase inhibitors (TKIs). Midostaurin (Rydapt) is a notable TKI that has been approved for the treatment of aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia. Avapritinib (Ayvakit) is another TKI approved for the treatment of advanced systemic mastocytosis, including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. These drugs work by inhibiting the activity of the KIT D816V mutation, which is commonly found in patients with systemic mastocytosis.

What other types of research exist?

Promising novel alternatives to Bezuclastinib for Systemic Mastocytosis patients include Avapritinib and Midostaurin. Both are selective tyrosine kinase inhibitors that have shown efficacy in treating systemic mastocytosis. Avapritinib, in particular, has been approved for advanced systemic mastocytosis and is being studied for non-advanced forms. Midostaurin is also approved for advanced systemic mastocytosis and has demonstrated significant clinical benefits.

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Tyrosine Kinase Inhibitor

Bezuclastinib for Systemic Mastocytosis

Phase 2

Recruiting

Research Sponsored by Cogent Biosciences, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

For patients receiving corticosteroids, the dose must be ≤10 mg/day of prednisone or equivalent

Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2

Must not have

Diagnosed with mastocytosis of the skin without systemic involvement

Diagnosed with bone marrow mastocytosis, advanced systemic mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Summary

This trial is testing a new drug called bezuclastinib, given with usual care, in patients with nonadvanced systemic mastocytosis whose symptoms are not well-managed. The drug aims to reduce the activity of cells that cause symptoms, potentially leading to better symptom control.

Who is the study for?

This trial is for patients with a condition called systemic mastocytosis, specifically the indolent or smoldering types. Participants should have moderate-to-severe symptoms despite current treatments and be in fairly good health overall (ECOG 0-2). They can't join if they've had significant bleeding recently, need blood thinners, have certain advanced forms of the disease, skin-only mastocytosis, previous KIT inhibitor therapy (except approved ones), recent cytoreductive therapy or radiation.

What is being tested?

The study tests bezuclastinib tablets against placebo tablets to see which is better at managing systemic mastocytosis when added to standard care. It's randomized and double-blind meaning neither doctors nor patients know who gets the real drug versus placebo. The trial has three parts; after completing Parts 1a/1b/2 with either drug or placebo, participants may move on to Part 3 for bezuclastinib treatment.

What are the potential side effects?

While specific side effects are not listed here, typical risks might include allergic reactions to medication components, potential liver issues since it's processed by the body there, digestive disturbances like nausea or diarrhea as common with oral drugs and possible fatigue.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am taking 10 mg or less of prednisone daily or its equivalent.

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I can take care of myself and am up and about more than half of my waking hours.

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I have moderate-to-severe symptoms despite taking at least 2 treatments for 14 days.

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I have been diagnosed with a slow-progressing form of systemic mastocytosis.

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I have been diagnosed with Smoldering systemic mastocytosis.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been diagnosed with mastocytosis that affects only my skin.

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I have been diagnosed with a type of advanced mastocytosis.

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I haven't had serious bleeding or needed blood-thinning medication in the last month.

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I need more than 10 mg/day of prednisone or its equivalent.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Part 1: Determine recommended dose of bezuclastinib (CGT9486) in subjects with NonAdvSM

Part 2: Efficacy of bezuclastinib at the selected dose versus placebo

Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events

Secondary study objectives

Part 1: Assess the pharmacokinetics (PK) of bezuclastinib in subjects with NonAdvSM

Part 2: Determine responder rates of subjects treated with bezuclastinib at the selected dose versus placebo

Part 3: To determine the efficacy of bezuclastinib at the selected dose

+2 more

Trial Design

9Treatment groups

Experimental Treatment

Placebo Group

Group I: (Part 3) Bezuclastinib + BSCExperimental Treatment2 Interventions

Group II: (Part 2) Bezuclastinib Selected Dose + BSCExperimental Treatment1 Intervention

Group III: (Part 1b) Bezuclastinib Dose 2 + BSCExperimental Treatment1 Intervention

Group IV: (Part 1b) Bezuclastinib Dose 1 + BSCExperimental Treatment1 Intervention

Group V: (Part 1a) Bezuclastinib Dose 2 + BSCExperimental Treatment1 Intervention

Group VI: (Part 1a) Bezuclastinib Dose 1 + BSCExperimental Treatment1 Intervention

Group VII: (Part 2) Placebo + BSCPlacebo Group1 Intervention

Group VIII: (Part 1a) Placebo + BSCPlacebo Group1 Intervention

Group IX: (Part 1b) Placebo + BSCPlacebo Group1 Intervention

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Selective tyrosine kinase inhibitors (TKIs) like Bezuclastinib work by inhibiting specific enzymes involved in the signaling pathways that cause the proliferation and survival of mast cells. In Systemic Mastocytosis (SM), mutations in the KIT gene lead to uncontrolled mast cell growth. TKIs target these enzymes, reducing mast cell proliferation and alleviating symptoms. This mechanism is crucial for SM patients as it addresses the root cause of the disease, potentially leading to better symptom control and improved quality of life.

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