Bezuclastinib for Systemic Mastocytosis

Recruiting at 42 trial locations

Overseen By Hina Jolin, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cogent Biosciences, Inc.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

140 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called bezuclastinib (also known as CGT9486 tablets) for individuals with Advanced Systemic Mastocytosis (AdvSM), a rare condition involving an overgrowth of mast cells. This overgrowth can cause serious problems, including aggressive forms and those linked to blood disorders. The trial aims to assess how effectively bezuclastinib manages these symptoms. Ideal participants are those already diagnosed with forms of AdvSM, such as Aggressive Systemic Mastocytosis or Mast Cell Leukemia, who face issues affecting daily life. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in managing AdvSM.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have received any cytoreductive therapy or investigational agents less than 14 days before the study, and certain medications like cladribine, interferon alpha, pegylated interferon, and antibody therapy must be stopped 28 days before. Additionally, you cannot take strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives before the first dose of the study drug.

Is there any evidence suggesting that Bezuclastinib is likely to be safe for humans?

Research has shown that bezuclastinib is generally well-tolerated. In one study, patients with non-advanced systemic mastocytosis who took bezuclastinib reported fewer symptoms than those on a placebo, suggesting the treatment's safety. Some patients might experience side effects, but these are usually mild. Another study highlighted that bezuclastinib targets a common mutation in these conditions, which often reduces unwanted side effects. While this specific trial lacks extensive safety data, earlier studies and the treatment's design suggest that bezuclastinib is generally safe. If positive results continue, it could become a valuable option for those with advanced systemic mastocytosis. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for systemic mastocytosis?

Bezuclastinib is unique because it targets the KIT D816V mutation, which is a key player in systemic mastocytosis. This mutation is not typically targeted by standard treatments like midostaurin or avapritinib, which are more general tyrosine kinase inhibitors. By focusing specifically on the KIT D816V mutation, bezuclastinib has the potential to be more effective and cause fewer side effects. Researchers are excited because this targeted approach could mean better outcomes for patients with fewer complications.

What evidence suggests that Bezuclastinib might be an effective treatment for Advanced Systemic Mastocytosis?

Research has shown that bezuclastinib, the treatment under study in this trial, may help treat systemic mastocytosis, a condition characterized by the overproduction of mast cells, leading to various health problems. In earlier studies, patients taking bezuclastinib experienced fewer symptoms related to mastocytosis, suggesting that the drug helps manage excess mast cell production. These studies reported improvements in patients' health and a reduction in disease-related issues. Although more research is needed to confirm these results, the initial findings are promising for those with advanced systemic mastocytosis. ^{1 2 3 6 7}

Who Is on the Research Team?

Rachael Easton, MD, Ph.D.

Principal Investigator

Cogent Biosciences, Inc.

Are You a Good Fit for This Trial?

This trial is for patients with Advanced Systemic Mastocytosis, including Aggressive SM, SM with an Associated Hematologic Neoplasm, or Mast Cell Leukemia. Participants must have measurable disease and be in a stable enough condition (ECOG 0 to 3). They can't join if they have HIV, hepatitis B/C, other recent cancers, significant heart issues or bleeding events, unresolved toxicity from past treatments or need certain medications like strong CYP3A4 inhibitors.

Inclusion Criteria

I can care for myself but may not be able to do heavy physical work.

Measurable disease according to modified IWG-MRT-ECNM criteria. (A subset of patients evaluable per mIWG-MRT-ECNM will be included in the study)

Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits

Exclusion Criteria

I haven't had specific cancer treatments in the last 14 to 28 days.

Seropositive for human immunodeficiency virus (HIV) 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody

I haven't taken strong CYP3A4 affecting drugs recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CGT9486 for the treatment of Advanced Systemic Mastocytosis

18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bezuclastinib
• CGT9486 tablets

Trial Overview The study is testing Bezuclastinib's effectiveness on Advanced Systemic Mastocytosis. It's an open-label Phase 2 trial where all participants receive the drug. The goal is to see how well it treats different types of this mast cell cancer by monitoring changes in the disease according to specific criteria.

How Is the Trial Designed?

Group I: bezuclastinib Experimental Treatment 1 Intervention

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

Approved in European Union as Bezuclastinib for:

• Orphan designation for Gastrointestinal stromal tumours and Systemic mastocytosis

Approved in United States as Bezuclastinib for:

• Orphan designation for Gastrointestinal stromal tumours and Systemic mastocytosis

Who Is Running the Clinical Trial?

Cogent Biosciences, Inc.

Lead Sponsor

Trials

11

Recruited

1,100+

Published Research Related to This Trial

A new risk score called the mutation-adjusted risk score (MARS) was developed for patients with advanced systemic mastocytosis (AdvSM), based on a study of 383 patients, which helps predict overall survival by identifying key risk factors such as age, anemia, thrombocytopenia, and specific gene mutations.

The MARS score effectively categorizes patients into low, intermediate, and high-risk groups for survival outcomes, and it is independent of the WHO classification, potentially enhancing treatment strategies for this rare condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. Jawhar, M., Schwaab, J., Álvarez-Twose, I., et al.[2020]

In a study of 105 patients with systemic mastocytosis, the KIT D816V mutation was found in 88% of cases, with varying allele burdens across different disease subgroups, indicating its potential role in disease classification.

The KIT D816V allele burden not only correlates with serum tryptase levels but also serves as a prognostic marker for survival, suggesting its importance in monitoring treatment response and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease. Hoermann, G., Gleixner, KV., Dinu, GE., et al.[2022]

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]

In a study of 42 patients with systemic mastocytosis treated with cladribine, the overall response rates were 77% for advanced systemic mastocytosis (adv-SM) and 70% for indolent/smouldering systemic mastocytosis (ISM/SSM), indicating that cladribine is an effective treatment option for both forms of the disease.

The presence of the KITD816V mutation was a strong predictor of response to cladribine in advanced SM, with 90% of patients with the mutation responding, while those without it showed no response, suggesting that this mutation could help guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. Tefferi, A., Kittur, J., Farrukh, F., et al.[2022]

In a study of 13 patients with aggressive systemic mastocytosis (ASM) treated with midostaurin, 77% showed clinical improvement within two months, indicating its efficacy in this patient population.

Among the eight patients evaluated, 50% had an objective response, with significant reductions in serum tryptase levels and bone marrow mast cell infiltration, suggesting that midostaurin effectively targets the underlying disease mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Efficacy of Midostaurin in Aggressive Systemic Mastocytosis. Szudy-Szczyrek, A., Bachanek-Mitura, O., Gromek, T., et al.[2021]

In a retrospective analysis of 9 patients with advanced systemic mastocytosis (SM), treatment with cladribine (2-CdA) resulted in an overall response rate of 66%, with 100% response in patients with SM associated with hematological neoplasm (SM-AHN).

The median duration of response to 2-CdA was 1.98 years, indicating that while the treatment can be beneficial, the responses are often incomplete and further research is needed to find a curative option for SM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Cladribine (2-CdA) in Advanced Systemic Mastocytosis. Helbig, G., Koclęga, A., Gaweł, WB., et al.[2020]

Mast cell disorders, particularly systemic mastocytosis (SM), can vary greatly in severity and are often linked to a specific mutation (D816V) in the c-kit gene, which affects treatment options.

Patients with indolent forms of mastocytosis are typically treated with mediator-targeting drugs, while those with aggressive forms may require cytoreductive therapy or alternative targeted treatments due to resistance against common drugs like Imatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mastocytosis: pathology, genetics, and current options for therapy. Valent, P., Akin, C., Sperr, WR., et al.[2019]

In a phase I trial of avapritinib for advanced systemic mastocytosis, 72% of patients showed a positive response, with 56% achieving complete or partial responses, indicating strong efficacy.

The treatment was well-tolerated, with no patients stopping due to adverse events, which were mostly mild to moderate, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Responses to Avapritinib (BLU-285) in Mastocytosis. [2019]

Avapritinib is a promising new treatment for advanced systemic mastocytosis (AdvSM), specifically designed to target the KITD816V mutation, showing potent antineoplastic activity in early Phase 1 trials, especially in patients who did not respond to midostaurin.

While avapritinib has demonstrated rapid symptom relief and reductions in bone marrow mast cells and mutant allele burden, it also has potential side effects, including myelosuppression, periorbital edema, and cognitive impairment, highlighting the need for further research on its long-term efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel approaches to treating advanced systemic mastocytosis. Gilreath, JA., Tchertanov, L., Deininger, MW.[2020]

Citations

1. jacionline.org jacionline.org/article/S0091-6749(24)01812-8/fulltext

A Randomized, Double-Blind, Placebo Controlled Phase 2 ... Results. Eighteen patients in Part 1 received 100 mg bezuclastinib original/optimized (bezu-100) and 19 received placebo. At baseline, patients received 2 ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/659/530240/Apex-Part-1-Updated-Assessment-of-Bezuclastinib

Apex Part 1: Updated Assessment of Bezuclastinib (CGT9486 ... Herein we report updated safety and efficacy results from the fully enrolled Part 1 of the Apex trial. Methods: Apex is a randomized Phase 2 ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05186753

NCT05186753 | (Summit) A Study to Evaluate the Efficacy ... This is a multi-part, randomized, double-blind, placebo-controlled Phase 2 clinical study comparing the safety and efficacy of bezuclastinib (CGT9486) plus ...

4. cogentbio.com cogentbio.com/wp-content/uploads/AAAAI-2025-Summit.pdf

AAAAI-2025-Summit.pdf Efficacy and Safety Results of Adult Patients with NonAdvanced Systemic Mastocytosis Receiving Bezuclastinib 100 mg in the Ongoing Summit Trial: A ...

5. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper194551.html

A Randomized, Double-Blind, Placebo Controlled ... 4556 Updated Efficacy and Safety Results of Patients ... Trial of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis.

6. investors.cogentbio.com investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-positive-top-line-results-achieving

Press Release Details Patients treated with bezuclastinib showed a superior mean change in total symptom score at 24 weeks (-24.3 points vs. -15.4 points, -8.91 point placebo- ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9431291/

P1049: A PHASE 2 STUDY OF BEZUCLASTINIB (CGT9486 ... Bezuclastinib, an orally administered and highly selective TKI with potent activity against KIT D816V, may be a treatment option in AdvSM.