BMM, Bone Marrow Mastocytosis, ISM, Mastocytosis, Mastocytosis, Indolent, Mastocytosis, Systemic, Smoldering Systemic Mastocytosis, SSM
Conditions
Keywords
Systemic Mastocytosis, Immune Complex Diseases, Immune System Diseases, Hypersensitivity, Hematologic Diseases, NonAdvSM, D816V, KIT D816V, Bezuclastinib, CGT9486, CGT, PLX, Nonadvanced Systemic Mastocytosis, PLX9486, Indolent Systemic Mastocytosis, ISM, Smoldering Systemic Mastocytosis, BMM, Bone Marrow Mastocytosis, SSM
Brief summary
This is a multi-part, randomized, double-blind, placebo-controlled Phase 2 clinical study comparing the safety and efficacy of bezuclastinib (CGT9486) plus best supportive care (BSC) with placebo plus BSC in patients with nonadvanced systemic mastocytosis (NonAdvSM), including indolent systemic mastocytosis and smoldering systemic mastocytosis, whose symptoms are not adequately controlled by BSC. This study will be conducted in three parts. Patients in Parts 1a, 1b and 2 will receive bezuclastinib or placebo, and may roll over onto Part 3 to receive treatment with bezuclastinib. Additionally, a substudy of subjects will investigate the efficacy, safety, and tolerability of bezuclastinib in patients who are experiencing inadequate symptom control with avapritinib.
Interventions
DRUGBezuclastinib Tablets (Formulation A)
Bezuclastinib will be administered orally, once daily continuously for 28-day cycles
DRUGBezuclastinib Tablets (Formulation B)
Bezuclastinib will be administered orally, once daily continuously for 28-day cycles
DRUGPlacebo Tablets
Placebo will be administered orally, once daily continuously for 28-day cycles
Sponsors
Cogent Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
In Part 1a and 1b of the study, patients with NonAdvSM will be randomly assigned to 1 of 2 dose levels of bezuclastinib plus BSC, or to placebo plus BSC. Upon analysis of the Part 1 data, a dose will be selected for Part 2. In Part 2, patients with NonAdvSM will be randomly assigned to the selected dose of bezuclastinib plus BSC, or to placebo plus BSC. Patients who complete Part 1 or Part 2 may participate in Part 3 in which all patients will receive bezuclastinib plus BSC. Subjects participating in the substudy will receive open-label bezuclastinib plus BSC.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Diagnosed with 1 of the following diagnoses according to the 2016 World Health Organization (WHO) classification for systemic mastocytosis (SM): * Indolent systemic mastocytosis (ISM), * Bone marrow mastocytosis (BMM) * Smoldering systemic mastocytosis (SSM) 2. Moderate-to-severe symptoms based on a minimum total symptom scoew (TSS) of the Mastocytosis Activity Score (MAS) and after establishing a stable regimen of at least 2 antimediator therapies over a 14-day eligibility period 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2 4. For patients receiving corticosteroids, the dose must be ≤10 mg/day of prednisone or equivalent Key
Exclusion criteria
1. Persistent toxicity from previous therapy for NonAdvSM that has not resolved to ≤ Grade 1 2. Diagnosed with any of the following WHO SM classifications: bone marrow mastocytosis, advanced systemic mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia; or mast cell sarcoma 3. Diagnosed with mastocytosis of the skin without systemic involvement 4. Received prior treatment with any targeted KIT inhibitor with the exception of approved agents for the treatment of SM 5. Received prior cytoreductive therapy or investigational agent for \<14 days or 5 half- lives of the drug and for cladribine, interferon alpha, pegylated interferon, or antibody therapy \<28 days or 5 half-lives of the drug (whichever is longer), before starting screening assessments 6. Received radiotherapy or psoralen and ultraviolet A therapy \<14 days before starting screening assessments 7. Received any hematopoietic growth factor support \<14 days or 5 half lives of the drug before starting screening assessments 8. History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study 9. Need for treatment of corticosteroids at \>10 mg/day of prednisone or equivalent 10. Received strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives before the first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Determine recommended dose of bezuclastinib (CGT9486) in subjects with NonAdvSM | 3 months | Selection of the recommended dose to be used in subsequent parts of the study. |
| Part 2: Efficacy of bezuclastinib at the selected dose versus placebo | 24 Weeks | Mean absolute change on the Mastocytosis Symptom Severity Daily Diary (MS2D2) |
| Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events | Up to 5 years | CTCAE v5 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Proportion of subjects who had at least 50% reduction in serum tryptase | 24 weeks | — |
| Part 2: Proportion of subjects who had at least a 50% reduction in peripheral blood D816V allele fraction | 24 weeks | — |
| Part 2: Determine responder rates of subjects treated with bezuclastinib at the selected dose versus placebo | 24 weeks | Proportion of subjects with at least a 30% reduction of the total symptom score (TSS) on the MS2D2. Proportion of subjects with at least a 50% reduction of the total symptom score (TSS) on the MS2D2. |
| Part 2: Proportion of subjects who had at least 50% reduction in mast cell burden | 24 weeks | — |
| Parts 1 & 2: Safety and tolerability of bezuclastinib as assessed by number of adverse events | Up to 24 weeks | CTCAE v5 |
| Parts 1, 2, & 3: Change and percent change in patient reported outcome (PRO) measures | Up to 5 years | — |
| Parts 1 & 3: Change and percent change in serum tryptase | Up to 12 months | — |
| Parts 1 & 3: Change and percent change in bone marrow mast cells | Up to 18 months | — |
| Part 1: Assess the pharmacokinetics (PK) of bezuclastinib in subjects with NonAdvSM | 3 months | Plasma concentrations of CGT9846 |
| Part 2: Determine mean change from baseline in predetermined PRO sub-domain and individual item scores | 24 weeks | — |
| Parts 2 & 3: Determine change of the lead (most severe) symptom and lead (most severe) subdomain of the MS2D2 in subjects treated with bezuclastinib versus placebo | Up to 5 years | Change and percent change from baseline in the symptom score of the subject's most severe symptom. Change and percent change from baseline in the MS2D2 subdomain score of the subject's most severe subdomain. |
| Part 3: Change and percent change in the levels of KIT D816V mutation allele burden | Up to 12 months | — |
| Part 3: To determine the efficacy of bezuclastinib at the selected dose | Up to 2 years | Proportion of subjects with at least a 50% reduction in MS2D2 TSS from baseline at 1 year and 2 years from start of bezuclastinib Change and percent change from baseline in the MS2D2 TSS, subdomain, and individual item scores |
| Part 3: Usage of concomitant medications as rescue therapy for NonAdvSM and changes from baseline in rescue therapy and best supportive care medications regimen | Up to 5 years | — |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, United Kingdom, United States
Contacts
STUDY_DIRECTORRachael Easton, MD, PhD
Cogent Biosciences
Outcome results
None listed