Evaluation of Avapritinib (BLU-285) Efficacy and Safety in Indolent Systemic Mastocytosis: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

The primary objective of this study is to evaluate the safety and efficacy of **avapritinib**, a selective KIT mutation-targeted tyrosine kinase inhibitor, in patients with Indolent Systemic Mastocytosis (ISM) whose symptoms are inadequately controlled with standard therapy. Specifically, the study aims to determine the recommended Phase 2 dose (RP2D) of avapritinib in Part 1, assess the mean change in ISM-SAF Total Symptom Score (TSS) from baseline to C7D1 compared to placebo in Part 2, and evaluate the long-term safety and efficacy of avapritinib in ISM patients in Part 3. These objectives are clinically relevant as they address the need for effective treatment options for ISM, a condition characterized by the accumulation of mast cells in various tissues, leading to a range of symptoms that can significantly impact quality of life.

Secondary objectives include determining the proportion of avapritinib-treated patients with ISM who achieve: a ≥50% reduction in serum tryptase, a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable levels for those with a detectable mutation at baseline, a ≥50% or ≥30% reduction in ISM-SAF TSS, and a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at baseline. Additional secondary objectives involve assessing changes in measures of mast cell burden, best supportive care usage for systemic mastocytosis symptoms, other patient-reported outcomes, quality of life measures, and the safety and tolerability of avapritinib as assessed by adverse events, vital signs, electrocardiograms, and laboratory tests. The pharmacokinetics of avapritinib will also be evaluated in Parts 1 and 2.

The clinical trial involves a total of **137 participants** diagnosed with **Indolent Systemic Mastocytosis (ISM)**. The study population includes both male and female subjects, aged 18 years and older, with a confirmed diagnosis of systemic mastocytosis as per WHO diagnostic criteria. Participants were selected based on their moderate-to-severe symptoms, as indicated by a minimum mean Total Symptom Score (TSS) over a 14-day eligibility screening period. The trial includes individuals who have not achieved adequate symptom control with at least two symptomatic therapies, such as H1 and H2 blockers, proton-pump inhibitors, or corticosteroids, among others. Participants are required to have a stable dose of symptomatic therapies for at least 14 days prior to the eligibility assessment. The trial also considers individuals with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 to 2. The study population is characterized by a vulnerable group, reflecting the specific health challenges associated with ISM. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled Phase 2 study** to evaluate the safety and efficacy of **Avapritinib**, a selective KIT mutation-targeted tyrosine kinase inhibitor, in patients with **Indolent Systemic Mastocytosis (ISM)**. The trial is structured into three parts, with the primary objective of determining the recommended Phase 2 dose (RP2D) of Avapritinib in Part 1, assessing the mean change in ISM-SAF total symptom score (TSS) from baseline to C7D1 compared to placebo in Part 2, and evaluating the long-term safety and efficacy of Avapritinib in Part 3. The trial is expected to conclude by June 2027, with recruitment having commenced in February 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of systemic mastocytosis, and symptom severity. The inclusion criteria require patients to be 18 years or older, have moderate-to-severe symptoms, and have failed to achieve adequate symptom control with standard therapies. Follow-up visits will be conducted to monitor the participants' response to the treatment, assess safety, and collect data on secondary endpoints such as changes in mast cell burden and quality of life measures. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining health concerns are addressed.

The expected length of participant involvement varies depending on the part of the study they are enrolled in, with the potential for long-term follow-up in Part 3. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or failure to comply with study protocols. The trial will utilize **Avapritinib** in a film-coated tablet form, administered orally, with a maximum daily dose of 100 mg. The study will also include a placebo group to ensure the reliability of the results. Safety and tolerability will be assessed through adverse events, vital signs, electrocardiograms, and laboratory tests, with pharmacokinetics evaluated in Parts 1 and 2.

The clinical trial involves the administration of **Avapritinib**, a selective KIT mutation-targeted tyrosine kinase inhibitor, in the form of film-coated tablets. The active substance, avapritinib, is of chemical origin and is provided by Blueprint Medicines. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 100 mg, with the same amount being the maximum total dose. The treatment period is extensive, with a maximum treatment period set at 999,999 days, although the specific dosing schedule within this period is not detailed. The trial aims to evaluate the safety and efficacy of avapritinib in patients with indolent and smoldering systemic mastocytosis whose symptoms are inadequately controlled with standard therapy.

In addition to the experimental treatment, the study includes the use of **Avapritinib Placebo Tablets**. These placebo tablets are designed to match the experimental medication in appearance and administration route, which is oral. The placebo serves as a comparator to assess the efficacy of avapritinib by providing a control group for the double-blind, placebo-controlled study design. The placebo tablets do not contain the active substance and are used to ensure that any observed effects can be attributed to the active treatment rather than psychological or other non-specific effects.

The efficacy of Avapritinib in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint for Part 2 of the study is the mean change in the Indolent Systemic Mastocytosis Symptom Assessment Form Total Symptom Score (ISM-SAF TSS) from baseline to Cycle 7 Day 1 (C7D1), compared to placebo. This endpoint will help determine the effectiveness of Avapritinib in reducing symptoms associated with **Indolent Systemic Mastocytosis** (ISM).

Secondary endpoints include changes in measures of mast cell burden, such as serum tryptase levels, KIT D816V allele burden in blood, and bone marrow mast cells. Additionally, changes in best supportive care usage and quality of life assessments using tools like MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L will be evaluated. Safety and tolerability will be monitored through adverse events, vital signs, electrocardiograms, and laboratory tests. Pharmacokinetics of Avapritinib will also be assessed in Parts 1 and 2 of the study.