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

A Multi-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of The Safety and Efficacy of CGT9486 in Subjects With Nonadvanced Systemic Mastocytosis

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 Overview

• Status: Active, not recruiting
• Conditions: Mastocytosis; Mastocytosis, Systemic; SSM; Mastocytosis, Indolent; Smoldering Systemic Mastocytosis; ISM; BMM; Bone Marrow Mastocytosis
• Intervention / Treatment: Drug: Placebo Tablets; Drug: Bezuclastinib Tablets (Formulation A); Drug: Bezuclastinib Tablets (Formulation B)

• Study Type: Interventional
• Enrollment (Estimated): 237
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
• Belgium
  • Edegem, Belgium, 2650
    • Antwerp University Hospital (UZA)
  • La Louvière, Belgium
    • Chu Tivoli
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 2R3
      • University of Alberta
  • Ontario
    • Toronto, Ontario, Canada
      • St. Michael's Hospital
• Czechia
  • Prague, Czechia
    • Fakultni nemocnice Kralovske Vinohrady
• France
  • Paris, France, 75013
    • AP-HP- Hopital Pitie-Salpetriere
  • Toulouse, France, 31400
    • CHU de Toulouse - Hôpital Larrey
• Germany
  • Aachen, Germany, 52074
    • Universitaetsklinikum Aachen, AoeR
  • Berlin, Germany, 12203
    • Charité Universitätsmedizin Berlin
  • Hamburg, Germany
    • Universitaetsklinikum Hamburg-Eppendorf
  • Kiel, Germany
    • Universitätsklinikum Schleswig-Holstein
  • Mannheim, Germany, 68167
    • University Medical Centre Mannheim
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland, D08 NHY1
    • St. James's Hospital
• Italy
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola
  • Catania, Italy
    • AOU Policlinico Rodolico San Marco
  • Florence, Italy
    • Azienda Ospedaliero-Universitaria Careggi
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Ravenna, Italy
    • AUSL della Romagna-Ospedale S.Maria delle Croci
• Netherlands
  • Groningen, Netherlands, 9713
    • University Medical Center Groningen
  • Rotterdam, Netherlands
    • Erasmus Rotterdam
• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital
• Poland
  • Gdansk, Poland
    • Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii
  • Lublin, Poland
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 - Klinika Hematoonkologii i Transplantacji Szpiku
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain
    • Institut Català d'Oncologia - L'Hospitalet
  • Madrid, Spain, 28046
    • Hospital Universitario Ramon y Cajal
  • Toledo, Spain
    • Instituto de Estudios de Mastocitosis de Castilla La Mancha-Hospital Virgen del Valle
• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guy's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Scottsdale, Arizona, United States, 85258
      • One of a Kind Clinical Research Center
  • California
    • La Jolla, California, United States, 92037
      • Modena Allergy and Asthma Clinical
  • Florida
    • Clearwater, Florida, United States, 33756
      • Innovative Research of West Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Walter Reed National Military Medical Center
    • Glenn Dale, Maryland, United States, 20769
      • Allervie Clinical Research
    • Wheaton, Maryland, United States, 20902
      • Institute for Asthma and Allergy
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University at St. Louis
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Dartmouth Hitchcock Medical Center
  • North Carolina
    • Raleigh, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Tennessee
    • Nashville, Tennessee, United States, 37235
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75231
      • AIR Care
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • West Valley City, Utah, United States, 84119
      • Metrodora Institute of Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: (Part 2) Placebo + BSC	Drug: Placebo Tablets; Placebo will be administered orally, once daily continuously for 28-day cycles
Experimental: (Part 1a) Bezuclastinib Dose 1 + BSC	Drug: Bezuclastinib Tablets (Formulation A); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Experimental: (Part 1a) Bezuclastinib Dose 2 + BSC	Drug: Bezuclastinib Tablets (Formulation A); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Placebo Comparator: (Part 1a) Placebo + BSC	Drug: Placebo Tablets; Placebo will be administered orally, once daily continuously for 28-day cycles
Experimental: (Part 1b) Bezuclastinib Dose 1 + BSC	Drug: Bezuclastinib Tablets (Formulation B); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Experimental: (Part 1b) Bezuclastinib Dose 2 + BSC	Drug: Bezuclastinib Tablets (Formulation B); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Placebo Comparator: (Part 1b) Placebo + BSC	Drug: Placebo Tablets; Placebo will be administered orally, once daily continuously for 28-day cycles
Experimental: (Part 2) Bezuclastinib Selected Dose + BSC	Drug: Bezuclastinib Tablets (Formulation B); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Experimental: (Part 3) Bezuclastinib + BSC	Drug: Bezuclastinib Tablets (Formulation A); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486; Drug: Bezuclastinib Tablets (Formulation B); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486
Experimental: (Prior Therapy Sub-study) Bezuclastinib	Drug: Bezuclastinib Tablets (Formulation B); Bezuclastinib will be administered orally, once daily continuously for 28-day cycles; Other Names: CGT9486; PLX9486

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months
Part 2: Efficacy of bezuclastinib at the selected dose versus placebo	Mean absolute change on the Mastocytosis Symptom Severity Daily Diary (MS2D2)	24 Weeks
Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events	CTCAE v5	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	24 weeks
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	CTCAE v5	Up to 24 weeks
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	Plasma concentrations of CGT9846	3 months
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	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.	Up to 5 years
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	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	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		Up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Substudy: Efficacy of bezuclastinib at selected dose in subjects whose symptoms are not adequately controlled by avapritinib	Mean absolute change on the Mastocytosis Symptom Severity Daily Diary (MS2D2)	Up to 2 years

Collaborators and Investigators

• Sponsor: Cogent Biosciences, Inc.
• Investigators: Study Director: Rachael Easton, MD, PhD, Cogent Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2022
• Primary Completion (Actual): May 22, 2025
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: November 19, 2021
• First Submitted That Met QC Criteria: January 8, 2022
• First Posted (Actual): January 11, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hypersensitivity; Immune System Diseases; Hematologic Diseases; ISM; SSM; CGT9486; Bezuclastinib; PLX9486; Systemic Mastocytosis; Immune Complex Diseases; D816V; KIT D816V; CGT; PLX; NonAdvSM; Nonadvanced Systemic Mastocytosis; Indolent Systemic Mastocytosis; Smoldering Systemic Mastocytosis; BMM; Bone Marrow Mastocytosis
• Additional Relevant MeSH Terms: Mast Cell Activation Disorders; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Hemic and Lymphatic Diseases; Hypersensitivity; Hematologic Diseases; Immune System Diseases; Mastocytosis; Mastocytosis, Systemic; Immune Complex Diseases
• Other Study ID Numbers: CGT9486-21-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No