Pioneer Part 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib in Indolent Systemic Mastocytosis

Introduction: Systemic mastocytosis (SM) is a rare clonal mast cell (MC) neoplasm characterized by MC accumulation and is primarily driven by the KIT D816V mutation. The D816V mutation is located in the activation loop of the KIT receptor tyrosine kinase resulting in constitutive activation of the receptor, causing aberrant MC proliferation and hyperactivation. MC mediator release can lead to severe clinical manifestations including skin, gastrointestinal, neurocognitive, skeletal, and systemic symptoms. Indolent SM is the most common subtype of SM; abnormal activation of mast cells leads to debilitating symptoms, poor quality of life, and has life-threatening consequences such as anaphylaxis. Although symptomatic treatments are used to control symptom severity (eg, cromolyn sodium, antihistamines, leukotriene inhibitors, omalizumab), there are no approved disease-modifying therapies to reduce MC burden and activation. Avapritinib is a potent, selective tyrosine kinase inhibitor that targets the KIT D816V mutant. Avapritinib has shown good tolerability in toxicology and safety pharmacology studies when assessed at active doses.

PIONEER (NCT03731260) is an international, multicenter, randomized, double-blind, placebo‑controlled, phase 2 study investigating the safety and efficacy of avapritinib in patients with indolent SM and symptoms inadequately controlled by best supportive care (BSC). PIONEER Part 1 assessed the safety and pharmacokinetics of avapritinib and identified the recommended phase 2 dose of 25 mg once daily in 4-weekly cycles. PIONEER Part 2 will assess the safety and efficacy of 25 mg avapritinib once daily versus placebo with BSC in patients with indolent SM whose symptoms are not adequately controlled by BSC.

Study design and methods: PIONEER Part 2 will enroll approximately 204 patients with indolent SM who will be randomized 2:1 to avapritinib plus BSC (25 mg once daily; n=136) or matched placebo plus BSC (n=68), stratified by baseline serum tryptase level (<20 ng/mL vs ≥20 ng/mL). Key eligibility criteria include confirmed indolent SM by central review, including pathology review of bone marrow biopsy, moderate-to-severe symptoms per total symptom score (TSS) of the Indolent SM Symptom Assessment Form (ISM-SAF), failure to achieve symptom control for ≥1 baseline symptom measured by ISM-SAF with ≥2 therapies considered BSC, and Eastern Cooperative Oncology Group Performance Score (ECOG PS) 0–2. Key exclusion criteria include diagnosis with other World Health Organization SM subclassifications, and antineoplastic therapy <28 days before or tyrosine kinase inhibitor therapy <14 days before the ISM‑SAF eligibility TSS assessment. The primary endpoint is proportion of responders at the end of Week 24 (Cycle 7 Day 1), defined as ≥30% reduction in TSS from baseline compared with placebo. Key secondary endpoints, measured from baseline to Week 24, are proportion of patients with ≥50% reduction in serum tryptase, ≥50% reduction in peripheral blood KIT D816V allele fraction (or undetectable <0.02% for patients with detectable mutation at baseline), ≥50% reduction in bone marrow MCs (or no aggregates for patients with aggregates at baseline), and change in ISM-SAF TSS. Enrolling a total of 204 patients is predicted to provide >97% power to detect superiority of avapritinib compared with placebo using a 2-sample Fisher Exact test, with a 1-sided type I error rate of 0.025, for the primary endpoint at Week 24. PIONEER Part 2 will enroll patients at sites in the USA, Canada, and Europe. Patients who complete PIONEER Part 1 or Part 2 will be eligible to enter an open-label extension to evaluate long‑term safety and efficacy of avapritinib 25 mg once daily.