(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis

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

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).

Study Overview

• Status: Recruiting
• Conditions: Advanced Systemic Mastocytosis (AdvSM); SM With an Associated Hematologic Neoplasm (SM-AHN); Mast Cell Leukemia (MCL); Aggressive Systemic Mastocytosis (ASM)
• Intervention / Treatment: Drug: bezuclastinib

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hina Jolin, PharmD; Phone Number: +1 (617) 945-5576; Email: ApexInfo@cogentbio.com

Study Locations

• Australia
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Recruiting
      • Nepean Hospital
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Recruiting
      • Gold Coast University Hospital
  • Victoria
    • Melbourne N., Victoria, Australia, 3051
      • Recruiting
      • Peter MacCallum Cancer Centre
• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • AKH Wien, Universitatsklinikum
• Belgium
  • Liège, Belgium, 4000
    • Recruiting
    • CHU de Liège
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • Recruiting
      • University of Alberta Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • St. Michael's Hospital - Unity Health Toronto
• France
  • Poitiers, France, 86000
    • Recruiting
    • Centre Hospitalier Universitaire (CHU) de Poitiers
  • Toulouse, France, 31300
    • Recruiting
    • Centre hospitalier universitaire (CHU) de Toulouse
• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • University Hospital Aachen
  • Freiburg, Germany, 79104
    • Recruiting
    • Universitätsklinikum Freiburg
  • Mannheim, Germany, 68167
    • Recruiting
    • Universitätsklinikum Mannheim
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero Universitaria di Bologna
• Netherlands
  • Groningen, Netherlands, 9713
    • Recruiting
    • University Medical Center Groningen
• Norway
  • Oslo, Norway, 0450
    • Recruiting
    • Oslo University Hospital
• Spain
  • Barcelona, Spain, 08908
    • Recruiting
    • Institut Català d'Oncologia - Hospital Duran i Reynals
  • Barcelona, Spain, 08740
    • Recruiting
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramón y Cajal
• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • Universitätsspital Basel
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • Recruiting
    • University College London Hospital - NHS Foundation Trust
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's Hospital - NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • University of Alabama at Birmingham (UAB) Hospital
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Arizona
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Medical Center
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
  • Florida
    • Hialeah, Florida, United States, 33016
      • Withdrawn
      • Galiz Research
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute - Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
  • New York
    • New York, New York, United States, 10032
      • Withdrawn
      • Columbia University Irving Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Cleveland Clinic Taussig Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • MUSC Health University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute - University of Utah Health

Participation Criteria

Eligibility Criteria

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

Description

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 Exclusion Criteria for Substudy Population:

1. Diagnosis of Philadelphia chromosome-positive malignancy
2. Diagnosis of acute myeloid leukemia (AML)
3. Appropriate for allogenic hematopoietic stem cell transplantation
4. Any contraindication to selected concomitant therapy
5. Rollover Cohort: Have not demonstrated acceptable tolerability of previous bezuclastinib therapy
6. High-Risk Cohort: Previously treated with investigational therapy for AdvSM
7. High-Risk Cohort: Previously treated with cytoreductive therapy and discontinued due to treatment-related toxicity
8. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: bezuclastinib	Drug: bezuclastinib; Bezuclastinib is administered as tablets to be taken orally, continuously in 28-day cycles.; Other Names: CGT9486; PLX9486

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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
Pure Pathologic Response (PPR)	Months	18 months
Change in spleen and liver volume by imaging	Percentage change	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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2021
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: July 22, 2021
• First Submitted That Met QC Criteria: August 6, 2021
• First Posted (Actual): August 9, 2021

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Hypersensitivity; Immune System Diseases; MPN; AML; Leukemia; Hematologic Diseases; MCL; Hematologic Neoplasms; Accelerated phase MPN; Neoplasm; Mastocytosis; Mast Cell; Skin Diseases; CMML; ASM; Chronic myelomonocytic leukemia; Neoplasms by site; Urticaria Pigmentosa; Myeloid Leukemia; CGT9486; Myeloproliferative neoplasm; Systemic Mastocytosis; Advanced Mastocytosis; Aggressive Mastocytosis; Mast Cell Leukemia; Soft Tissue Neoplasms; Immune Complex Diseases; SM with Associated Hematologic Neoplasm; AdvSM; SM-AHN; D816V; KIT D816V; bezuclastinib; CGT; PLX; Connective Tissue Neoplasms; High-risk myelodysplastic syndrome; High-risk myeloid neoplasm; High-risk MDS; High-risk MPN
• Additional Relevant MeSH Terms: Behavioral Symptoms; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Hematologic Diseases; Neoplasms, Connective Tissue; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mast Cell Activation Disorders; Aggression; Neoplasms; Hematologic Neoplasms; Leukemia; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell
• Other Study ID Numbers: CGT9486-20-201; 2021-001010-10 (EudraCT Number)

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