Clinical trial NCT05186753: (Summit) a Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients with Indolent or Smoldering Systemic Mastocytosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: SSM
Mastocytosis, Indolent
Mastocytosis, Systemic
Mastocytosis
ISM
BMM
Smoldering Systemic Mastocytosis
Bone Marrow Mastocytosis
Keywords: Systemic Mastocytosis
Immune Complex Diseases
Immune System Diseases
Hypersensitivity
Hematologic Diseases
NonAdvSM
D816V
KIT D816V
Bezuclastinib
CGT9486
CGT
PLX
Nonadvanced Systemic Mastocytosis
PLX9486
Indolent Systemic Mastocytosis
ISM
Smoldering Systemic Mastocytosis
BMM
Bone Marrow Mastocytosis
SSM
Lead sponsor: Cogent Biosciences, Inc.
Sponsor class: INDUSTRY
First posted: 2022-01-11
Enrollment: 207
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Part 1a and 1b of the study, patients with NonAdvSM will be randomly assigned to 1 of 2 dose levels of bezuclastinib plus BSC, or to placebo plus BSC. Upon analysis of the Part 1 data, a dose will be selected for Part 2. In Part 2, patients with NonAdvSM will be randomly assigned to the selected dose of bezuclastinib plus BSC, or to placebo plus BSC.

Patients who complete Part 1 or Part 2 may participate in Part 3 in which all patients will receive bezuclastinib plus BSC.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Determine recommended dose of bezuclastinib (CGT9486) in subjects with NonAdvSM
timeFrame: 3 months
measure: Part 2: Efficacy of bezuclastinib at the selected dose versus placebo
timeFrame: 24 Weeks
measure: Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events
timeFrame: Up to 5 years
Secondary outcomes:
measure: Part 2: Proportion of subjects who had at least 50% reduction in serum tryptase
timeFrame: 24 weeks
measure: Part 2: Proportion of subjects who had at least a 50% reduction in peripheral blood D816V allele fraction
timeFrame: 24 weeks
measure: Part 2: Determine responder rates of subjects treated with bezuclastinib at the selected dose versus placebo
timeFrame: 24 weeks
measure: Part 2: Proportion of subjects who had at least 50% reduction in mast cell burden
timeFrame: 24 weeks
measure: Parts 1 & 2: Safety and tolerability of bezuclastinib as assessed by number of adverse events
timeFrame: Up to 24 weeks
measure: Parts 1, 2, & 3: Change and percent change in patient reported outcome (PRO) measures
timeFrame: Up to 5 years
measure: Parts 1 & 3: Change and percent change in serum tryptase
timeFrame: Up to 12 months
measure: Parts 1 & 3: Change and percent change in bone marrow mast cells
timeFrame: Up to 18 months
measure: Part 1: Assess the pharmacokinetics (PK) of bezuclastinib in subjects with NonAdvSM
timeFrame: 3 months
measure: Part 2: Determine mean change from baseline in predetermined PRO sub-domain and individual item scores
timeFrame: 24 weeks
measure: 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
timeFrame: Up to 5 years
measure: Part 3: Change and percent change in the levels of KIT D816V mutation allele burden
timeFrame: Up to 12 months
measure: Part 3: To determine the efficacy of bezuclastinib at the selected dose
timeFrame: Up to 2 years
measure: Part 3: Usage of concomitant medications as rescue therapy for NonAdvSM and changes from baseline in rescue therapy and best supportive care medications regimen
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Scottsdale
country: United States
facility: One of a Kind Clinical Research Center
state: Arizona
city: La Jolla
country: United States
facility: Modena Allergy and Asthma Clinical
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles (UCLA) - Medical Center
state: California
city: Clearwater
country: United States
facility: Innovative Research of West Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Glenn Dale
country: United States
facility: Allervie Clinical Research
state: Maryland
city: Wheaton
country: United States
facility: Institute for Asthma and Allergy
state: Maryland
city: White Marsh
country: United States
facility: Chesapeake Research Center
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic- Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University at St. Louis
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Raleigh
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: AIR Care
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: West Valley City
country: United States
facility: Metrodora Institute of Technology
state: Utah
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Linz
country: Austria
facility: Kepler Universitaetsklinikum GmbH
city: Wien
country: Austria
facility: Medizinische Universitaet Wien
city: Edegem
country: Belgium
facility: Antwerp University Hospital (UZA)
city: La Louvière
country: Belgium
facility: CHU Tivoli
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University
state: Quebec
city: Praha 10
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
city: Marseille
country: France
facility: AP-HM - Hopital de la Timone
city: Paris
country: France
facility: AP-HP- Hopital Pitie-Salpetriere
city: Toulouse
country: France
facility: CHU de Toulouse - Hopital Larrey
city: Aachen
country: Germany
facility: Universitaetsklinikum Aachen, AoeR
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Mannheim
country: Germany
facility: University Medical Centre Mannheim
city: Athens
country: Greece
facility: Attikon University General Hospital Athens
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola
city: Catania
country: Italy
facility: AOU Policlinico Rodolico San Marco
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Ravenna
country: Italy
facility: AUSL della Romagna-Ospedale S.Maria delle Croci
city: Rome
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona-Ospedale Borgo Trento
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus Rotterdam
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne, Klinika Hematologii i Transplantologii
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 - Klinika Hematoonkologii i Transplantacji Szpiku
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - L'Hospitalet
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Toledo
country: Spain
facility: Instituto de Estudios de Mastocitosis de Castilla La Mancha-Hospital Virgen del Valle
city: Basel
country: Switzerland
facility: University Hospital Basel
city: London
country: United Kingdom
facility: Guy's Hospital
Study officials:
affiliation: Cogent Biosciences
name: Rachael Easton, MD, PhD
role: STUDY_DIRECTOR
References: