(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 2 Open-Label, Multicenter Clinical Study of the Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Profiles of CGT9486 as a Single Agent in Patients With Advanced Systemic Mastocytosis

Conditions
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Advanced Systemic Mastocytosis (AdvSM), SM With an Associated Hematologic Neoplasm (SM-AHN), Mast Cell Leukemia (MCL), Aggressive Systemic Mastocytosis (ASM)

Intervention / Treatment
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* Drug: bezuclastinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria for Main Study: Diagnosed with one of the following advanced mastocytosis diagnoses by Eligibility Committee Aggressive Systemic Mastocytosis (ASM) Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN) Mast Cell Leukemia (MCL) Measurable disease according to modified IWG-MRT-ECNM criteria. (A subset of patients inevaluble per mIWG-MRT-ECNM will be included in the study). ECOG (0 to 3) Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits Key Exclusion Criteria for Main Study: Persistent toxicity from previous therapy for AdvSM that has not resolved to ≤ Grade 1 Associated hematologic neoplasm requiring immediate antineoplastic therapy Clinically significant cardiac disease Known positivity for the FIP1L1 PDGFRA fusion. Patients with eosinophilia without detectable KIT D816V mutation must demonstrate lack of PDGFRA fusion mutation prior to enrollment Seropositive for human immunodeficiency virus (HIV) 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study Diagnosed with or treated for malignancy other than the disease under study within the prior 3 years before enrollment Received any cytoreductive therapy or any investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon, and any antibody therapy less than 28 days, before screening bone marrow biopsy Received hematopoietic growth factor support within 14 days before the first dose of study drug Received strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives, whichever is longer, before the first dose of study drug Need for treatment with high dose steroids Key Inclusion Criteria for Substudy Population: Rollover Cohort Demonstrate AHN progression requiring immediate AHN-directed therapy while receiving bezuclastinib Demonstrated clinical benefit from bezuclastinib therapy Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits High-Risk Cohort Receiving or indicated for AHN-directed therapy. Diagnosed with one of the following pathologic diagnoses of SM-AHN: Myelodysplastic syndrome (MDS) that is high- or very high-risk Accelerated phase myeloproliferative neoplasm (MPN) MDS with excessive blasts in bone marrow or peripheral blood Chronic myelomonocytic leukemia-2 (CMML-2) Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits. Key Exclusion Criteria for Substudy Population: Diagnosis of Philadelphia chromosome-positive malignancy Diagnosis of acute myeloid leukemia (AML) Appropriate for allogenic hematopoietic stem cell transplantation Any contraindication to selected concomitant therapy Rollover Cohort: Have not demonstrated acceptable tolerability of previous bezuclastinib therapy High-Risk Cohort: Previously treated with investigational therapy for AdvSM High-Risk Cohort: Previously treated with cytoreductive therapy and discontinued due to treatment-related toxicity High-Risk Cohort: Received any cytoreductive therapy or any investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon, and any antibody therapy less than 28 days, before screening or archival bone marrow biopsy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: There are two parts to this study, including Part I, Dose Optimization, and Part II Expansion. Part II is separated into two stages.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bezuclastinib<br> | Drug: bezuclastinib<br>* Bezuclastinib is administered as tablets to be taken orally, continuously in 28-day cycles.<br>* Other names: PLX9486;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Identify clinically active and tolerable exposures of bezuclastinib in patients with AdvSM |  | 18 months | 
| Part II: - Determine efficacy of bezuclastinib as measured by mIWG Objective Response Rate (ORR) - Confirm the exposure-response relationship of bezuclastinib |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pure Pathologic Response (PPR) | Months | 18 months | 
| Safety of CGT9486 as assessed by incidence of Adverse Events (AEs) | Incidence of AEs according to CTCAE version 5.0 or higher | 18 months | 
| To determine the effects of bezuclastinib on mutation allele burden. | Percentage change in KIT D816V | 18 months | 
| To determine the effects of bezuclastinib on serum tryptase. | Percentage change in Serum Tryptase | 18 months | 
| To assess the pharmacokinetics of bezuclastinib in subjects with AdvSM. | Percentage change in plasma concentrations of bezuclastinib | 18 months | 
| Change from baseline in histopathologic findings in blood and bone marrow | Percentage change in mast cell infiltration in the bone marrow and percentage change in eosinophilia and monocytosis in the blood | 18 months | 
| Change in spleen and liver volume by imaging | Percentage change | 18 months | 
| Change in Patient Global Impression of Severity (PGIS) scale | 0 -10 points (higher values represent worse symptom outcomes) | 18 months | 
| Change in Patient Global Impression of Change (PGIC) scale | 0 - 7 points (higher values represent better symptom outcomes) | 18 months | 
| Change in Mastocytosis Quality of Life Questionnaire (MC-QoL) | 0 - 100 (higher values represent better symptom outcomes) | 18 months | 
| Change in Mastocytosis Activity Score (MAS) | 0 - 252 (higher values represent worse symptom outcomes) | 18 months | 
| Duration of Response (DOR) | Months | 18 months | 
| Time to Response (TTR) | Months | 18 months | 
| Progression Free Survival (PFS) | Months | 18 Months | 
| Overall Survival (OS) | Months | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mastocytosis, Systemic Mastocytosis, Advanced Mastocytosis, Aggressive Mastocytosis, Hematologic Neoplasms, Mast Cell, Mast Cell Leukemia, Soft Tissue Neoplasms, Neoplasms by site, Skin Diseases, Immune Complex Diseases, Immune System Diseases, Hypersensitivity, Hematologic Diseases, Leukemia, Myeloid Leukemia, Acute Myeloid Leukemia, SM with Associated Hematologic Neoplasm, AdvSM, ASM, SM-AHN, MCL, Neoplasm, D816V, KIT D816V, AML, bezuclastinib, CGT9486, CGT, PLX, Connective Tissue Neoplasms, Urticaria Pigmentosa, High-risk myelodysplastic syndrome, Chronic myelomonocytic leukemia, Myeloproliferative neoplasm, High-risk myeloid neoplasm, High-risk MDS, MPN, High-risk MPN, Accelerated phase MPN, CMML