Clinical trial NCT04996875: (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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Advanced Systemic Mastocytosis (AdvSM)
SM With an Associated Hematologic Neoplasm (SM-AHN)
Mast Cell Leukemia (MCL)
Aggressive Systemic Mastocytosis (ASM)
Keywords: Mastocytosis
Systemic Mastocytosis
Advanced Mastocytosis
Aggressive Mastocytosis
Hematologic Neoplasms
Mast Cell
Mast Cell Leukemia
Soft Tissue Neoplasms
Neoplasms by site
Skin Diseases
Immune Complex Diseases
Immune System Diseases
Hypersensitivity
Hematologic Diseases
Leukemia
Myeloid Leukemia
Acute Myeloid Leukemia
SM with Associated Hematologic Neoplasm
AdvSM
ASM
SM-AHN
MCL
Neoplasm
D816V
KIT D816V
AML
bezuclastinib
CGT9486
CGT
PLX
Connective Tissue Neoplasms
Urticaria Pigmentosa
High-risk myelodysplastic syndrome
Chronic myelomonocytic leukemia
Myeloproliferative neoplasm
High-risk myeloid neoplasm
High-risk MDS
MPN
High-risk MPN
Accelerated phase MPN
CMML
Lead sponsor: Cogent Biosciences, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-09
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: There are two parts to this study, including Part I, Dose Optimization, and Part II Expansion. Part II is separated into two stages.
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Part I: Identify clinically active and tolerable exposures of bezuclastinib in patients with AdvSM
timeFrame: 18 months
measure: Part II: - Determine efficacy of bezuclastinib as measured by mIWG Objective Response Rate (ORR) - Confirm the exposure-response relationship of bezuclastinib
timeFrame: 18 months
Secondary outcomes:
measure: Pure Pathologic Response (PPR)
timeFrame: 18 months
measure: Safety of CGT9486 as assessed by incidence of Adverse Events (AEs)
timeFrame: 18 months
measure: To determine the effects of bezuclastinib on mutation allele burden.
timeFrame: 18 months
measure: To determine the effects of bezuclastinib on serum tryptase.
timeFrame: 18 months
measure: To assess the pharmacokinetics of bezuclastinib in subjects with AdvSM.
timeFrame: 18 months
measure: Change from baseline in histopathologic findings in blood and bone marrow
timeFrame: 18 months
measure: Change in spleen and liver volume by imaging
timeFrame: 18 months
measure: Duration of Response (DOR)
timeFrame: 18 months
measure: Time to Response (TTR)
timeFrame: 18 months
measure: Progression Free Survival (PFS)
timeFrame: 18 Months
measure: Overall Survival (OS)
timeFrame: 18 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (UAB) Hospital
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Hialeah
country: United States
facility: Galiz Research
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute - Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Charleston
country: United States
facility: MUSC Health University Medical Center
state: South Carolina
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute - University of Utah Health
state: Utah
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Melbourne N.
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Vienna
country: Austria
facility: AKH Wien, Universitatsklinikum
city: Liège
country: Belgium
facility: CHU de Liege
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: St. Michael's Hospital - Unity Health Toronto
state: Ontario
city: Paris
country: France
facility: Necker-Enfants Malades Hospital
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire (CHU) de Poitiers
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire (CHU) de Toulouse
city: Aachen
country: Germany
facility: University Hospital Aachen
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Lubeck
country: Germany
facility: UKSH Campus Lubeck
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero Universitaria di Bologna
city: Florence
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggi dAragonia
city: Verona
country: Italy
facility: Azienda Ospidaleira Universitaria Integrata Verona
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Lublin
country: Poland
facility: Public University Hospital No. 1 in Lublin
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: University College London Hospital - NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's Hospital - NHS Foundation Trust
Study officials:
affiliation: Cogent Biosciences, Inc.
name: Rachael Easton, MD, Ph.D.
role: STUDY_DIRECTOR
References: