Advanced Systemic Mastocytosis (AdvSM), Aggressive Systemic Mastocytosis (ASM), Mast Cell Leukemia (MCL), SM With an Associated Hematologic Neoplasm (SM-AHN)
Conditions
Keywords
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
Brief summary
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).
Interventions
DRUGbezuclastinib
Bezuclastinib is administered as tablets to be taken orally, continuously in 28-day cycles.
Sponsors
Cogent Biosciences, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for Main Study: 1. Diagnosed with one of the following advanced mastocytosis diagnoses by Eligibility Committee 1. Aggressive Systemic Mastocytosis (ASM) 2. Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN) 3. Mast Cell Leukemia (MCL) 2. Measurable disease according to modified IWG-MRT-ECNM criteria. (A subset of patients inevaluble per mIWG-MRT-ECNM will be included in the study). 3. ECOG (0 to 3) 4. Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits Key
Exclusion criteria
for Main Study: 1. Persistent toxicity from previous therapy for AdvSM that has not resolved to ≤ Grade 1 2. Associated hematologic neoplasm requiring immediate antineoplastic therapy 3. Clinically significant cardiac disease 4. 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 5. Seropositive for human immunodeficiency virus (HIV) 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody 6. History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study 7. Diagnosed with or treated for malignancy other than the disease under study within the prior 3 years before enrollment 8. 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 9. Received hematopoietic growth factor support within 14 days before the first dose of study drug 10. Received strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives, whichever is longer, before the first dose of study drug 11. Need for treatment with high dose steroids Key Inclusion Criteria for Substudy Population: Rollover Cohort 1. Demonstrate AHN progression requiring immediate AHN-directed therapy while receiving bezuclastinib 2. Demonstrated clinical benefit from bezuclastinib therapy 3. Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits High-Risk Cohort 1. Receiving or indicated for AHN-directed therapy. 2. Diagnosed with one of the following pathologic diagnoses of SM-AHN: 1. Myelodysplastic syndrome (MDS) that is high- or very high-risk 2. Accelerated phase myeloproliferative neoplasm (MPN) 3. MDS with excessive blasts in bone marrow or peripheral blood 4. Chronic myelomonocytic leukemia-2 (CMML-2) 3. Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits. Key
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Pure Pathologic Response (PPR) | 18 months | Months |
| Safety of CGT9486 as assessed by incidence of Adverse Events (AEs) | 18 months | Incidence of AEs according to CTCAE version 5.0 or higher |
| To determine the effects of bezuclastinib on mutation allele burden. | 18 months | Percentage change in KIT D816V |
| To determine the effects of bezuclastinib on serum tryptase. | 18 months | Percentage change in Serum Tryptase |
| To assess the pharmacokinetics of bezuclastinib in subjects with AdvSM. | 18 months | Percentage change in plasma concentrations of bezuclastinib |
| Change from baseline in histopathologic findings in blood and bone marrow | 18 months | Percentage change in mast cell infiltration in the bone marrow and percentage change in eosinophilia and monocytosis in the blood |
| Change in spleen and liver volume by imaging | 18 months | Percentage change |
| Duration of Response (DOR) | 18 months | Months |
| Time to Response (TTR) | 18 months | Months |
| Progression Free Survival (PFS) | 18 Months | Months |
| Overall Survival (OS) | 18 months | Months |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom, United States
Contacts
CONTACTCogent Biosciences, Inc.
STUDY_DIRECTORRachael Easton, MD, Ph.D.
Cogent Biosciences, Inc.
Outcome results
None listed