This study has been transitioned to CTIS with ID 2024-511407-42-00 check the CTIS register for the current data. Part 1: dose optimizationTo identify a clinically active and tolerable systemic exposure range of bezuclastinib in subjects with…
ID
Source
Brief title
Condition
- White blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
Safety assessments and dose modifications
Pharmacokinetics (PK) and pharmacodynamic assessments
Overall Response Rate (ORR)
Part 2 Stage 1
• Safety assessments and dose modifications
• PK and pharmacodynamic assessments
• Overall Response Rate (ORR)
Part 2 Stage 2
ORR
Secondary outcome
Incidence of AEs, SAEs, AEs leading to dose modifications, and changes from
baseline in laboratory results
Duration of response (DOR), defined as the date of the first documented
response (CR, CRh, PR, or CI) to date of first documented and confirmed disease
progression or death from any cause, whichever occurs first, based on modified
IWG-MRT-ECNM response criteria
Time to response (TTR), defined as the date of first dose of study drug to the
date of the first documented response (CR, CRh, PR, or CI) based on modified
IWG-MRT-ECNM response criteria
Progression-free survival (PFS), defined as the date of first dose of study
drug to the date of first documented confirmed disease progression or death
from any cause, whichever occurs first
Overall survival (OS), defined as the date of first dose of study drug to the
date of death from any cause
Pure Pathologic Response (PPR), including complete remission, complete
remission with partial recovery of peripheral blood, and partial remission
(Gotlib et al, 2020)
Changes in spleen and liver size assessed by magnetic resonance imaging (MRI)
Changes in the levels of serum tryptase
Changes in the levels of KIT D816V mutation allele burden in blood and bone
marrow
Change in pathologic findings in the blood and bone marrow including mast cell
infiltration, monocytosis, and eosinophilia
Plasma concentrations of bezuclastinib
Patient Global Impression of Change (PGIC) scale and change and percent change
from baseline in the following patient-reported outcome measures: Patient
Global Impression of Severity (PGIS) scale, Mastocytosis Quality of Life
Questionnaire (MC-QoL), and Mastocytosis Activity Score (MAS) where appropriate
translations are available (Siebenhaar et al, 2018; Siebenhaar et al, 2016)
Incidence of AEs, SAEs, AEs leading to dose modifications, and changes from
baseline in laboratory results
PPR, including complete remission, complete remission with partial hematologic
recovery, molecular complete remission, and partial remission
Background summary
Systemic mastocytosis (SM) encompasses a variety of mast cell disorders
characterized by accumulation and expansion of abnormal neoplastic mast cells
in various organs including the bone marrow, gastrointestinal tract, skin,
liver, and spleen (Shomali and Gotlib, 2018). Mast cells play a role in
immunoglobulin E-mediated immune responses, inflammation, and immune responses
to infection. Accumulation of abnormal mast cells can lead to hematologic and
non-hematologic organ damage. SM is characterized by mast cell infiltration of
1 or more extracutaneous organs with or without skin involvement (Shomali and
Gotlib, 2018) and encompasses a spectrum of diagnoses that can range from a
nonadvanced course to a more advanced course. AdvSM is an aggressive and
life-threatening form of the disease. The molecular pathogenesis of SM is
driven by activation of the KIT receptor. In 95% of cases, a KIT D816V mutation
in exon 17 can be identified (Garcia-Montero et al, 2006; Jara-Acevedo et al,
2015; Vaes et al, 2017).
CGT9486 is an inhibitor of KIT exon mutations with potent activity against KIT
exon 17 and 18 activation loop mutations. CGT9486 has been evaluated in a
completed Phase 1/2 study in patients with GIST as a monotherapy and in
combination with sunitinib. In addition, CGT9486 is being investigated in an
ongoing phase 3 study in GIST, and ongoing Phase 2 studies in AdvSM (EHA 2022)
and NonAdvSM. The results of this study are to be used to investigate CGT9486
for the treatment of AdvSM.
Study objective
This study has been transitioned to CTIS with ID 2024-511407-42-00 check the CTIS register for the current data.
Part 1: dose optimization
To identify a clinically active and tolerable systemic exposure range of
bezuclastinib in subjects with AdvSM
Part 2 Stage 1: Dose Confirmation
To confirm the optimal dose of bezuclastinib in subjects with AdvSM
Part 2 Stage 2: Expansion
To determine the efficacy of bezuclastinib at the selected optimal dose in
patients with AdvSM
Secondary (part 1 and part 2):
To characterize the safety and tolerability of bezuclastinib in patients with
AdvSM
To evaluate additional efficacy parameters with bezuclastinib inpatients with
AdvSM
To determine the effects of bezuclastinib on serum tryptase
To determine the effects of bezuclastinib on KIT D816V mutation allele burden
To evaluate histopathologic response in the blood and bone marrow
To assess the PK of bezuclastinib in patients with AdvSM
To assess patient-reported outcomes in patients with AdvSM
To explore the effect of bezuclastinib in subjects with AdvSM who are
nonevaluable based on the modified IWG-MRT-ECNM response criteria.
Study design
This is a 2-part study of the KIT inhibitor CGT9486 in patients with AdvSM.
Part 1 will consist of a dose optimization period to determine the optimal dose
for patients with AdvSM. Approximately 28 subjects will be randomized to 1 of 4
dose cohorts of bezuclastinib. Part 2 will be conducted with a 2-stage design:
Stage 1 will confirm the optimal dose of bezuclastinib, and Stage 2 will
consist of an expansion period. Stage 1 will enroll approximately 20 subjects
and Stage 2 will enroll approximately 75 subjects. Each 28-day period is 1
cycle.
Subjects will receive bezuclastinib at their assigned dose until confirmed
disease progression, intolerable toxicity, Investigator decision, withdrawal of
consent, or other protocol-specified reason for discontinuation of study drug.
Patient eligibility will be reviewed, and enrollment approved by an Eligibility
Committee (EC) during the Screening Period. In addition, disease response will
be adjudicated by the CRRC.
Intervention
In Part 1 of the study, approximately 28 subjects will be randomized to 1 of 4
dose cohorts of bezuclastinib Formulation A. Subjects will be randomized in a
1:1:1:1 manner.
Part 2 will be conducted with a 2-stage design: Stage 1 will confirm the
optimal dose of bezuclastinib Formulation B, and Stage 2 will consist of an
expansion period.
Study burden and risks
The potential benefits of the drug outweigh the expected risks. For the
risk/benefit assessment, please refer to the Clinical Trial Protocol (Section
1.4) and Investigator's Brochure.
Wyman Street 3rd floor 275
Waltham MA 02451
US
Wyman Street 3rd floor 275
Waltham MA 02451
US
Listed location countries
Age
Inclusion criteria
1. Diagnosed with 1 of the following advanced mastocytosis diagnoses by
Eligibility Committee
a. Aggressive Systemic Mastocytosis (ASM)
b. Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN)
c. 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.
Exclusion criteria
1. Persistent toxicity from previous therapy for Advanced Systemic Mastocytosis
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 also lack the 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 before the first dose of
study drug
11. Need for treatment with steroids
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511407-42-00 |
| EudraCT | EUCTR2021-001010-10-NL |
| ClinicalTrials.gov | NCT04996875 |
| CCMO | NL80629.056.22 |