A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)

Systemic mastocytosis (SM) is characterized by excessive accumulation of mast cells in bone marrow and other extracutaneous tissues encompassing a spectrum of variants ranging from non-advanced to advanced disease (Shomali et al, 2018). Advanced systemic mastocytosis (AdvSM) is an aggressive and life-threatening form of SM with an overall survival from <6 months to ~3-4 years depending on subtype (Gotlib et al, 2018; NCCN Systemic Mastocytosis, Version 2.2019; Pardanani, 2019; Rossignol et al, 2019; Shomali et al, 2018). The three distinct subtypes of AdvSM include aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) (NCCN Systemic Mastocytosis, Version 2, 2019; Pardanani, 2019; Shomali et al, 2018).

The molecular pathogenesis of SM is driven by mutations in the KIT gene leading to ligand-independent proliferation of mast cells, with 95% of patients carrying the D816V mutation in exon 17 (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Bezuclastinib, an oral, highly selective tyrosine kinase inhibitor with potent activity against KIT D816V has shown preliminary clinical activity and a tolerable safety profile in a Ph 1/2 study of patients with advanced solid tumors including gastrointestinal stromal tumor (GIST). In that study, a reduction in KIT exon 17 mutational burden was observed in subjects treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018).

Other agents targeting the KIT D816V mutations have shown activity in the treatment of AdvSM; however, toxicities such as cognitive impairment, intracranial hemorrhage, and edema may limit dosing and appropriateness of these therapies. Besides targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Additionally, minimal brain penetration has been observed with bezuclastinib, and no CNS toxicities have been identified in preclinical studies.

This is a multi-center, Phase 2, open-label, 2-part clinical study to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of bezuclastinib in subjects with AdvSM. This study will enroll subjects who meet WHO diagnostic criteria for AdvSM, have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria, and have a baseline serum tryptase of ≥20 ng/mL. The diagnosis of AdvSM and evidence of measurable disease will be confirmed by an Eligibility Committee prior to enrollment.

This study will enroll approximately 140 patients. Part 1 will consist of a dose optimization period to determine the optimal dose of bezuclastinib for subjects with AdvSM. Subjects will be randomized into one of four dose cohorts (50, 100, or 200 mg twice daily, or 400 mg once daily) in a 1:1:1:1 manner. A planned interim analysis to assess safety, efficacy, and biomarker endpoints will occur when approximately half the planned number of Part 1 patients have been evaluated through at least 2 cycles of treatment. After all subjects in Part 1 complete at least two cycles, the optimal dose will be selected. Part 2 will enroll subjects at the selected dose level to determine efficacy of bezuclastinib and to further characterize safety, PK, and PD. The primary assessment of efficacy is overall response rate, defined as the percentage of subjects classified as confirmed responders (CR, CR with incomplete hematologic recovery [CRh], partial response [PR], and clinical improvement [CI]) according to modified IWG-MRT-ECNM response criteria as assessed by a Central Response Review Committee (CRRC).

Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM.

This study opened in June 2021.