Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Abstract

Background: Systemic mastocytosis (SM) is characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. NonAdvSM is characterized by the lack of mast cell-related organ damage (e.g., C-findings) and other features of advanced SM such as associated hematologic neoplasms. NonAdvSM includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). ISM affects nearly 85% of the general SM population and is characterized by symptoms related to mast cell degranulation/mediator release. SSM is characterized by higher mast cell burden in the absence of organ damage or an associated hematologic neoplasm. There are currently no approved therapies for the treatment of the underlying causes of ISM or SSM, and anti-mediator therapies are used for symptom control with variable efficacy and tolerability due to disease heterogeneity. In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17; therefore, agents targeting this mutated kinase have been used to treat advanced SM variants. However, off-target activity of these agents may lead to toxicities that limit dosing and thus efficacy in this population. Therefore, an unmet need remains for safe and effective treatments for patients with NonAdvSM. Bezuclastinib inhibits KIT D816V mutations with high potency and specificity while avoiding other kinases with potential off-target liabilities such as PDGFRα, PDGFRβ, VEGFR2, and CSF1R. Bezuclastinib has demonstrated minimal brain penetration and no central nervous system toxicities were observed in preclinical studies. In an ongoing Phase 2 study (Apex) of patients with AdvSM, early data indicate that bezuclastinib was generally well tolerated and is associated with a meaningful reductions in serum tryptase levels, bone marrow mast cell burden, and KIT D816V variant allele fraction. Additionally, bezuclastinib was safely administered in a completed phase 1/2 clinical study in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST), in which activating KIT mutations are found in a majority of patients. In that study, bezuclastinib led to a reduction in KIT exon 17 mutational burden, which was associated with a reduction in tumor burden. These results support the investigation of bezuclastinib as a potential therapy in GIST as well as AdvSM and NonAdvSM. Study Design and Methods: The Summit study (NCT05186753) is a multi-center, Phase 2, double-blind, placebo-controlled, 3-part clinical trial to evaluate the safety, efficacy, and biomarker correlates (e.g., bone marrow mast cell burden, serum tryptase level, and KIT D816V mutation burden) of bezuclastinib in patients with NonAdvSM. Patients diagnosed with ISM or SSM who have inadequate control of their symptoms despite treatment with at least 2 anti-mediator therapies will be included in this trial. Multiple patient-reported outcome measures (PROMs) will be used to follow symptom scores while on treatment. Part 1 of the study will assess the safety profile of bezuclastinib and will determine the recommended dose for Part 2 through the assessment of changes from baseline of a disease specific PROM. Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo through the evaluation of the PROMs and changes in clinical activity markers such as serum tryptase, bone marrow mast cell burden, and KIT D816V mutation allele burden. All patients will continue to receive their baseline anti-mediator treatments throughout the trial. Serial photographic evaluation will assist in the determination of changes of disease in the skin. Part 3 allows patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, to participate in a long-term extension study and receive open label bezuclastinib. Conclusions: There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.