Initial Results from Summit: An Ongoing, 3-Part, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)
Authors: Bose Prithviraj , Oh Stephen T. , Modena Brian , Hunter Anthony M. , Akin Cem , Castells Mariana , Manning Michael , Herrscher Richard , Siebenhaar Frank , DeAngelo Daniel J. , George Tracy I. , Exter Benjamin , Zhang Jenna , Pilla Amanda , Jolin Hina , Easton Rachael , Rein Lindsay A.M 
Published: December 2023

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. Nonadvanced SM (NonAdvSM) includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). NonAdvSM is often associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL).
In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preclinical studies demonstrate bezuclastinib inhibits KIT D816V with minimal brain penetration. Early results from Part 1 of a Phase 2 trial of patients with AdvSM demonstrate that bezuclastinib is well-tolerated and is associated with encouraging clinical activity. Bezuclastinib resulted in meaningful reductions in markers of disease burden including serum tryptase, bone marrow mast cell burden, and KIT D816V variant allele fraction (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). These results support the investigation of bezuclastinib as a potential therapy in NonAdvSM.
Study Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, 3-part clinical trial of bezuclastinib in patients with NonAdvSM, including ISM and SSM, who have inadequate control of symptoms despite treatment with best supportive care (BSC). Patient-reported outcome measures (PROMs), including mastocytosis activity score (MAS) and mastocytosis quality of life (MC-QoL), are being used to assess treatment impact on symptoms and HRQoL. Approximately 48 patients will be enrolled in Part 1 of the trial with 1:1:1 randomization to one of two doses of bezuclastinib (100 or 200 mg QD for Part 1a; 100 or 150 mg QD for Part 1b) or placebo. Here we report initial data from Part 1a of the Summit trial.
Results: Part 1a of Summit enrolled 20 patients; 18 patients had ISM and 2 patients had SSM. In Part 1a, a majority of patients were female (75%) and had an Eastern Cooperative Oncology Group Performance Status of 0-1 (90%) or 2 (10%). Mean age was 54. Patients utilized a median (range) of 3 (2 to 7) BSC medications, with 100% using H1 blockers, 95% using H2 blockers and 40% using leukotriene receptor antagonists. Enrolled patients had a median (range) serum tryptase of 74 (10 to 592) ng/mL and 85% of patients had a serum tryptase ≥20 ng/mL. 75% of patients were KIT D816V positive and median (range) KIT D816V variant allele fraction in whole blood was 0.5% (0 to 32). Median (range) percent bone marrow mast cell burden was 23% (1 to 80%). Utilizing MAS to assess baseline disease severity, a majority of patients self-reported severe disease with a median score of 43 (range 22-79). Patients also self-reported a mean score of 56+/- 19 on the MC-QOL, indicating moderate impact to their HRQoL.
Conclusions: The Summit trial evaluating safety and efficacy of bezuclastinib enrolled 20 patients in Part 1a. The patients enrolled in Part 1a of the Summit trial are generally representative of the population of patients with moderate to severe nonadvanced systemic mastocytosis based on number of supportive care medications, symptom severity, and disease impact on HRQoL. Initial safety and efficacy results from Part 1a of the 3-part, randomized, double-blind, placebo-controlled Summit trial will be presented.