Bezuclastinib for Systemic Mastocytosis
Recruiting in Palo Alto (17 mi)
+40 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Cogent Biosciences, Inc.
Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers
Disqualifiers: Cardiac disease, HIV, Hepatitis, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This is an open-label, two-part Phase 2 study investigating CGT9486 for the treatment of patients with Advanced Systemic Mastocytosis (AdvSM), including patients with Aggressive SM (ASM), SM with Associated Hematologic Neoplasm (SM-AHN), and Mast Cell Leukemia (MCL).
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.
What data supports the effectiveness of the drug Bezuclastinib for treating systemic mastocytosis?
While there is no direct data on Bezuclastinib, similar drugs like avapritinib, which target the same mutation (KITD816V) found in most systemic mastocytosis cases, have shown promising results. Avapritinib has demonstrated a 72% overall response rate in patients with advanced systemic mastocytosis, suggesting that targeting this mutation can be effective.
12345How is the drug Bezuclastinib different from other drugs for systemic mastocytosis?
Bezuclastinib is unique because it specifically targets the KIT D816V mutation, which is present in most patients with systemic mastocytosis, potentially offering a more targeted approach compared to other treatments like midostaurin and cladribine that have broader mechanisms of action.
26789Eligibility Criteria
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
+6 more
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.
+16 more
Trial Timeline
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: bezuclastinibExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hialeah, FloridaHialeah, FL
Stanford Cancer InstituteStanford, CA
City of Hope Comprehensive Cancer CenterDuarte, CA
Winship Cancer Institute - Emory UniversityAtlanta, GA
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Cogent Biosciences, Inc.Lead Sponsor
References
Novel approaches to treating advanced systemic mastocytosis. [2020]Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V. Midostaurin, a broad spectrum TKI with activity against KITD816V, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.
MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. [2020]To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.
Mastocytosis: pathology, genetics, and current options for therapy. [2019]Mast cell disorders are defined by an abnormal accumulation of tissue mast cells (MCs) in one or more organ systems. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Cutaneous mastocytosis (CM) is a benign disease of the skin and may regress spontaneously. Systemic mastocytosis (SM) is a persistent disease in which a somatic c-kit mutation at codon 816 is usually detectable in MCs and their progenitors. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. The WHO discriminates five categories of SM: indolent SM (ISM), aggressive SM (ASM), SM with associated clonal hematological non-MC-lineage disease (AHNMD), and mast cell leukemia (MCL). The c-kit mutation D816V is quite common and may be found in all SM-categories. In SM-AHNMD, additional genetic abnormalities have been reported, whereas no additional defects are yet known for ASM or MCL. Patients with ISM and CM are treated with "mediator-targeting" drugs, whereas patients with ASM or MCL are candidates for cytoreductive therapy. The use of "Kit-targeting" tyrosine kinase inhibitors such as STI571 (Imatinib, Gleevec), has also been suggested. However, the D816V mutation of c-kit is associated with relative resistance against STI571. Therefore, these patients require alternative targeted drugs or new drug-combinations. In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established. Examples include the use of STI571 in patients with SM plus hypereosinophilic syndrome (SM-HES) and the FIPL1/PDGFRA fusion gene target, or chemotherapy for eradication of AML in patients with SM-AML.
Advanced systemic mastocytosis-Revised classification, new drugs and how we treat. [2023]Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.
Rapid Responses to Avapritinib (BLU-285) in Mastocytosis. [2019]In a phase I trial of avapritinib (formerly BLU-285), which targets D816V mutant KIT, for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control. The overall response rate was 72%, and 56% of patients experienced a complete or partial response. No patients discontinued treatment due to adverse events, most of which were mild to moderate in nature.
The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease. [2022]KIT D816V is present in a majority of patients with systemic mastocytosis (SM). We determined the KIT D816V allele burden by quantitative real-time PCR in bone marrow and peripheral blood of 105 patients with mastocytosis. KIT D816V was detected in 92/105 patients (88%). Significant differences in the median allele burden were observed between disease subgroups: cutaneous mastocytosis (0.042%), indolent SM (0.285%), smoldering SM (5.991%), aggressive SM (9.346%), and SM with associated hematologic non-mast cell lineage disease (3.761%) (P
Real-World Efficacy of Midostaurin in Aggressive Systemic Mastocytosis. [2021]In April 2017 midostaurin was approved by the US Food and Drug Administration for the treatment of patients with aggressive systemic mastocytosis (ASM). So far, very limited real world data on its efficacy is available. Thirteen patients aged from 48 to 79 years, who received midostaurin in the early access program, were included in the study. Midostaurin was used both in first (n = 5) and subsequent lines of treatment (n = 8). The median duration of exposure was 9 months. Most patients (77%, n = 10) had a clinical improvement already as soon as the second month of therapy. Objective response was noted in 4 (50%) of eight evaluated patients. Among responders, we observed a decrease in serum tryptase level (median 74.14%) and bone marrow infiltration by mast cells (median 50%) in the sixth month of treatment. In one case, in the 10th month of treatment, allogenic stem cell transplantation was performed, achieving complete remission. Five patients died, three due to progression of disease, one in the course of secondary acute myeloid leukemia and one due to reasons not related to mastocytosis. Treatment is ongoing in seven patients. We found that midostaurin therapy is beneficial to patients with ASM.
Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. [2022]We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment-emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.
The Efficacy of Cladribine (2-CdA) in Advanced Systemic Mastocytosis. [2020]Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33-67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM; n = 7) and SM with an associated hematological neoplasm (SM-AHN; n = 2). The "C" findings were as follows: (1) absolute neutrophil count (ANC) < 1 × 109/l (n = 1) and/or hemoglobin level < 10 g/dl (n = 4) and/or platelet count < 100 × 109/l (n = 4); (2) hepatomegaly with ascites (n = 4); (3) skeletal involvement (n = 2); (4) palpable splenomegaly with hypersplenism (n = 3) and (5) malabsorption with weight loss (n = 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35-60). Median number of cycles was 6 (range 1-7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2-11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete.