(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis

Phase 2Active Not RecruitingNCT05186753

Cogent Biosciences, Inc.237 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

237

Conditions

SSM Mastocytosis, Indolent Mastocytosis, Systemic Mastocytosis

Interventions

Bezuclastinib Tablets (Formulation A)DRUG

Bezuclastinib will be administered orally, once daily continuously for 28-day cycles

Bezuclastinib Tablets (Formulation B)DRUG

Bezuclastinib will be administered orally, once daily continuously for 28-day cycles

Placebo TabletsDRUG

Placebo will be administered orally, once daily continuously for 28-day cycles

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (69)

University of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic Arizona

Phoenix, Arizona, United States

One of a Kind Clinical Research Center

Scottsdale, Arizona, United States

Modena Allergy and Asthma Clinical

La Jolla, California, United States

University of California, Los Angeles (UCLA) - Medical Center

Los Angeles, California, United States

Outcomes

Primary Outcomes

Part 1: Determine recommended dose of bezuclastinib (CGT9486) in subjects with NonAdvSM

Selection of the recommended dose to be used in subsequent parts of the study.

Time frame: 3 months

Part 2: Efficacy of bezuclastinib at the selected dose versus placebo

Mean absolute change on the Mastocytosis Symptom Severity Daily Diary (MS2D2)

Time frame: 24 Weeks

Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events

CTCAE v5

Time frame: Up to 5 years

Secondary Outcomes

Part 2: Proportion of subjects who had at least 50% reduction in serum tryptase

Time frame: 24 weeks

Part 2: Proportion of subjects who had at least a 50% reduction in peripheral blood D816V allele fraction

Time frame: 24 weeks

Part 2: Determine responder rates of subjects treated with bezuclastinib at the selected dose versus placebo

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.

Time frame: 24 weeks

Part 2: Proportion of subjects who had at least 50% reduction in mast cell burden

Time frame: 24 weeks

Parts 1 & 2: Safety and tolerability of bezuclastinib as assessed by number of adverse events

CTCAE v5

Time frame: Up to 24 weeks

Parts 1, 2, & 3: Change and percent change in patient reported outcome (PRO) measures

Time frame: Up to 5 years

Parts 1 & 3: Change and percent change in serum tryptase

Time frame: Up to 12 months

Parts 1 & 3: Change and percent change in bone marrow mast cells

Time frame: Up to 18 months

Part 1: Assess the pharmacokinetics (PK) of bezuclastinib in subjects with NonAdvSM

Plasma concentrations of CGT9846

Time frame: 3 months

Part 2: Determine mean change from baseline in predetermined PRO sub-domain and individual item scores

Time frame: 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

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.

Time frame: Up to 5 years

Part 3: Change and percent change in the levels of KIT D816V mutation allele burden

Time frame: Up to 12 months

Part 3: To determine the efficacy of bezuclastinib at the selected dose

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

Time frame: Up to 2 years

Part 3: Usage of concomitant medications as rescue therapy for NonAdvSM and changes from baseline in rescue therapy and best supportive care medications regimen

Time frame: Up to 5 years