(Summit) 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

The primary objective of this study is to determine the recommended dose of oral **bezuclastinib** administered in subjects with Nonadvanced Systemic Mastocytosis (NonAdvSM). This is clinically relevant as it aims to establish an optimal dosing regimen that maximizes therapeutic efficacy while minimizing potential adverse effects, thereby improving patient outcomes in this population.

Secondary objectives include:

• Part 1: To characterize the safety and tolerability of bezuclastinib in subjects with NonAdvSM, which is crucial for understanding the risk-benefit profile of the treatment.
• Part 2: To evaluate the efficacy of bezuclastinib versus placebo by changes in serum tryptase in subjects with NonAdvSM, providing insights into the drug's potential to modulate disease biomarkers and improve clinical symptoms.

The clinical trial involves a total of **96 participants** diagnosed with **Nonadvanced Systemic Mastocytosis**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, including a diagnosis of indolent systemic mastocytosis, smoldering systemic mastocytosis, or bone marrow mastocytosis, as per the 2022 World Health Organization classification. Additionally, participants must exhibit moderate-to-severe symptoms and maintain a stable regimen of at least two antimediator therapies over a 14-day eligibility period. The trial includes individuals with an Eastern Cooperative Oncology Group Performance Status of 0 to 2. The study population is characterized by a diverse range of health statuses, and the trial does not exclude based on gender. Lifestyle considerations such as diet and physical activity are not specified, and the trial includes a vulnerable population. The selection process ensures a representative sample of individuals affected by the condition under investigation.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase 2 study to evaluate the safety and efficacy of CGT9486 in subjects with **Nonadvanced Systemic Mastocytosis**. The trial is structured into three parts, each with specific objectives: Part 1 aims to determine the recommended dose of oral bezuclastinib, Part 2 focuses on assessing the efficacy of bezuclastinib at the selected dose versus placebo, and Part 3 is dedicated to characterizing the safety and tolerability of the treatment. The trial is expected to run from April 2023 to June 2030, with a maximum treatment period of 104 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of indolent systemic mastocytosis, smoldering systemic mastocytosis, or bone marrow mastocytosis, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2. Following the screening, participants will be randomized to receive either CGT9486 or a placebo, administered orally in tablet form. The study includes regular follow-up visits to monitor safety, efficacy, and any adverse events, with primary endpoints focusing on safety assessments, pharmacokinetics, and symptom improvement. Secondary endpoints include changes in laboratory and electrocardiogram results and the proportion of subjects achieving a significant reduction in serum tryptase levels.

The expected length of participant involvement is up to 104 weeks, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of CGT9486 in managing Nonadvanced Systemic Mastocytosis, with the ultimate goal of improving patient outcomes through targeted treatment strategies.

The clinical trial involves the administration of **CGT9486**, a small molecule tyrosine kinase inhibitor targeting KIT, in tablet form. The active substance in CGT9486 is **3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide**, which is of chemical origin. The medication is provided by Cogent Biosciences Inc. and is administered orally. The maximum daily dose for one formulation is 150 mg, while another formulation allows for a maximum daily dose of 200 mg. The treatment period for both formulations is up to 104 weeks. Participant compliance with the dosing schedule is monitored throughout the study.

In addition to the experimental medication, a **placebo** matching CGT9486 is used in the study. The placebo is designed to mimic the appearance of the CGT9486 tablet but does not contain the active substance. The placebo is administered orally, following the same schedule as the active treatment, to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the efficacy and safety of CGT9486 by providing a comparator group within the study.

The efficacy of the investigational product, **bezuclastinib**, in the clinical trial will be assessed through a series of predefined endpoints. In Part 2 of the study, the primary efficacy endpoint is the mean absolute change from baseline in the MS2D2 score at Week 24. This score is a measure of symptom improvement in subjects with NonAdvanced Systemic Mastocytosis. Additionally, a secondary efficacy endpoint in Part 2 includes the proportion of subjects achieving at least a 50% reduction in serum tryptase levels, a biomarker associated with the disease. These efficacy parameters will be collected and analyzed at specified timepoints to evaluate the therapeutic impact of bezuclastinib compared to placebo. The trial is designed to ensure rigorous assessment of efficacy through validated scales and laboratory tests, providing a comprehensive evaluation of the treatment's potential benefits.