(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis

Official title

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

Overview

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

• Drug bezuclastinib
  Bezuclastinib is administered as tablets to be taken orally, continuously in 28-day cycles.

Primary outcome measures

• Part I: Identify clinically active and tolerable exposures of bezuclastinib in patients with AdvSM [Time frame: 18 months]
• Part II: - Determine efficacy of bezuclastinib as measured by mIWG Objective Response Rate (ORR) - Confirm the exposure-response relationship of bezuclastinib [Time frame: 18 months]

Secondary outcome measures (11)

• Pure Pathologic Response (PPR) [Time frame: 18 months]
• Safety of CGT9486 as assessed by incidence of Adverse Events (AEs) [Time frame: 18 months]
• To determine the effects of bezuclastinib on mutation allele burden. [Time frame: 18 months]
• To determine the effects of bezuclastinib on serum tryptase. [Time frame: 18 months]
• To assess the pharmacokinetics of bezuclastinib in subjects with AdvSM. [Time frame: 18 months]
• Change from baseline in histopathologic findings in blood and bone marrow [Time frame: 18 months]
• Change in spleen and liver volume by imaging [Time frame: 18 months]
• Duration of Response (DOR) [Time frame: 18 months]
• Time to Response (TTR) [Time frame: 18 months]
• Progression Free Survival (PFS) [Time frame: 18 Months]
• Overall Survival (OS) [Time frame: 18 months]

Eligibility criteria

Key Inclusion Criteria for Main Study:

• Diagnosed with one of the following advanced mastocytosis diagnoses by Eligibility Committee

• Aggressive Systemic Mastocytosis (ASM)
• Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN)
• Mast Cell Leukemia (MCL)
• Measurable disease according to modified IWG-MRT-ECNM criteria. (A subset of patients inevaluble per mIWG-MRT-ECNM will be included in the study).
• ECOG (0 to 3)
• Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits

Key Exclusion Criteria for Main Study:

• Persistent toxicity from previous therapy for AdvSM that has not resolved to ≤ Grade 1
• Associated hematologic neoplasm requiring immediate antineoplastic therapy
• Clinically significant cardiac disease
• 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
• Seropositive for human immunodeficiency virus (HIV) 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody
• History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study
• Diagnosed with or treated for malignancy other than the disease under study within the prior 3 years before enrollment
• 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
• Received hematopoietic growth factor support within 14 days before the first dose of study drug
• Received strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives, whichever is longer, before the first dose of study drug
• Need for treatment with high dose steroids

Key Inclusion Criteria for Substudy Population:

Rollover Cohort

• Demonstrate AHN progression requiring immediate AHN-directed therapy while receiving bezuclastinib
• Demonstrated clinical benefit from bezuclastinib therapy
• Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits

High-Risk Cohort

• Receiving or indicated for AHN-directed therapy.
• Diagnosed with one of the following pathologic diagnoses of SM-AHN:

• Myelodysplastic syndrome (MDS) that is high- or very high-risk
• Accelerated phase myeloproliferative neoplasm (MPN)
• MDS with excessive blasts in bone marrow or peripheral blood
• Chronic myelomonocytic leukemia-2 (CMML-2)
• Have clinically acceptable local laboratory screening results (clinical chemistry, hematology) within certain limits.

Key Exclusion Criteria for Substudy Population:

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 14 centers

• University of Alabama at Birmingham (UAB) Hospital — Birmingham
• Mayo Clinic Arizona — Phoenix
• City of Hope Comprehensive Cancer Center — Duarte
• UCLA Medical Center — Los Angeles
• Stanford Cancer Institute — Stanford
• Galiz Research — Hialeah
• Winship Cancer Institute - Emory University — Atlanta
• Rush University Medical Center — Chicago
• … and 6 more centers

Germany · 4 centers

• University Hospital Aachen — Aachen
• Universitätsklinikum Freiburg — Freiburg im Breisgau
• UKSH Campus Lubeck — Lübeck
• Universitätsklinikum Mannheim — Mannheim

Italy · 4 centers

• IRCCS Azienda Ospedaliero Universitaria di Bologna — Bologna
• Azienda Ospedaliero Universitaria Careggi — Florence
• AOU San Giovanni di Dio e Ruggi dAragonia — Salerno
• Azienda Ospidaleira Universitaria Integrata Verona — Verona

Australia · 3 centers

• Nepean Hospital — Kingswood
• Gold Coast University Hospital — Southport
• Peter MacCallum Cancer Centre — Melbourne N.

France · 3 centers

• Necker-Enfants Malades Hospital — Paris
• Centre Hospitalier Universitaire (CHU) de Poitiers — Poitiers
• Centre Hospitalier Universitaire (CHU) de Toulouse — Toulouse

Spain · 3 centers

• Hospital Universitario Vall d'Hebron — Barcelona
• Institut Català d'Oncologia - Hospital Duran i Reynals — Barcelona
• Hospital Universitario Ramón y Cajal — Madrid

United Kingdom · 3 centers

• Guy's Hospital - NHS Foundation Trust — London
• Leeds Teaching Hospitals NHS Trust — Leeds
• University College London Hospital - NHS Foundation Trust — London

Canada · 2 centers

• University of Alberta Hospital — Edmonton
• St. Michael's Hospital - Unity Health Toronto — Toronto

Austria · 1 center

• AKH Wien, Universitatsklinikum — Vienna

Belgium · 1 center

• CHU de Liege — Liège

Netherlands · 1 center

• University Medical Center Groningen — Groningen

Norway · 1 center

• Oslo University Hospital — Oslo

Poland · 1 center

• Public University Hospital No. 1 in Lublin — Lublin

Switzerland · 1 center

• Universitätsspital Basel — Basel

Identifiers

NCT: NCT04996875 · CGT9486-20-201 · 2024-511407-42-00 · 2021-001010-10

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗