Systemic mastocytosis (SM) is a mast-cell neoplasm found in the bone marrow and organs driven primarily by KIT D816V mutations. SM can progress to advanced SM (AdvSM), which can be divided into 3 subtypes: SM with an associated hematologic neoplasm, aggressive SM, and mast-cell leukemia. Previous phase 1 and phase 2 studies investigated bezuclastinib, a highly selective tyrosine kinase inhibitor against KIT D816V, in patients with advanced solid tumors. Results from various trials indicate bezuclastinib safely demonstrated clinical activity, including reductions in KIT D816V mutations and tumor burden. Other tyrosine kinase inhibitors have been shown to mitigate KIT D816V–mediated AdvSM disease; they are limited in this setting due to toxicities such as cognitive impairment, intracranial hemorrhage, and edema. The potential benefits of bezuclastinib include its high selectivity and little to no impact on other kinases, and minimal brain penetration and no toxicities in the brain and spinal cord. Despite its activity in solid tumors such as gastrointestinal stromal tumors and relatively low toxicity, bezuclastinib has not been sufficiently evaluated in AdvSM.
The study reported here is currently enrolling and seeks to examine safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of bezuclastinib in a cohort of 140 patients with AdvSM. The investigation will be divided into 2 parts: part 1 will determine optimal dose of bezuclastinib (50, 100, or 200 mg twice daily or 1 daily dose at 400 mg) after all patients have completed ≥2 treatment cycles; part 2 will enroll additional patients and evaluate the PD, PK, safety, and efficacy at the dose identified in part 1. Efficacy of bezuclastinib in AdvSM will primarily be determined by overall response rate, the percentage of subjects classified as confirmed responders, confirmed responders with incomplete hematologic recovery, partial response, and clinical improvement.
Results from this study are pending; however, the data will provide insight into the safety and potential clinical utility of bezuclastinib in patients with SM.
Source Gotlib J, George TI, Deininger MW, et al. A phase 2 study of bezuclastinib (CGT9486), an oral, selective, and potent KIT D816V inhibitor, in adult patients with advanced systemic mastocytosis. 2021 American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3636.
