Abstract: 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 ( & lt;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 & lt;28 days before or tyrosine kinase inhibitor therapy & lt;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 & lt;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 & gt;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. Disclosures Akin: Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding. Elberink:Novartis: Research Funding; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees. Gotlib:Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding. Sabato:Blueprint Medicines Corporation: Other: My institution received research funding. Hartmann:Allergopharma: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Deciphera: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Menarini: Honoraria, Other: reimbursement of travel expenses , Research Funding; Novartis: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Takeda: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Euroimmun: Honoraria, Other: reimbursement of travel expenses , Research Funding; Thermofisher: Other: reimbursement of travel expenses , Research Funding; ALK-ABello: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding. Broesby-Olsen:Thermo Fisher: Honoraria; Novartis: Honoraria; Blueprint Medicines Corporation: Honoraria, Other: study steering committee member. Castells:Annals of Allergy, Asthma & Immunology: Other: Editorial Board; Blueprint Medicines Corporation: Consultancy, Other: Clinical trials: Principle Investigator; UpToDate: Other: Author fee. Heaney:Partner Therapeutics: Consultancy; AbbVie: Consultancy; Sierra Oncology: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Research Funding; Deciphera: Research Funding; CTI Biopharma: Consultancy, Research Funding; BMS: Research Funding; Blueprint Medicines Corporation: Research Funding. George:Celgene: Consultancy; Deciphera: Other: consultancy, but has received no financial compensation for the past 12 months; Blueprint Medicines Corporation: Consultancy, Other: I have received no funding for this research. ARUP Laboratories, owned by the University of Utah, has received funding; Allakos: Consultancy. Siebenhaar:Hyphens: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Pediapharm: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Aralez: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; SunPharma: Other; Moxie: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Allakos: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Novartis: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Sanofi: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Glenmark: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Uriach: Other; Biocryst: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Blueprint Medicines Corporation: Honoraria, Research Funding. Radia:Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Education events. Triggiani:Deciphera: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Abbvie: Research Funding; Jazz: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Autolos: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Hew:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Roche:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company; Epizyme: Other: outside the submitted work. Maurer:Novartis: Honoraria, Other; Regeneron: Honoraria, Other; UCB: Honoraria, Other; ThirdHarmonicBio: Honoraria, Other; Sanofi: Honoraria, Other; Roche: Honoraria, Other; FAES: Honoraria, Other: institutional grant/research support; Dr. Pfleger: Honoraria, Other: institutional grant/research support; Blueprint Medicines Corporation: Honoraria, Other: institutional grant/research support; Bayer: Honoraria, Other: institutional grant/research support; AstraZeneca: Honoraria, Other: institutional grant/research support; Amgen: Honoraria, Other: institutional grant/research support; Allakos: Honoraria, Other: institutional grant/research support; Moxie: Honoraria, Other; Merckle Recordati: Honoraria, Other; Uriach: Honoraria, Other; CellDex: Honoraria, Other; GIInnovation: Honoraria, Other; Lilly: Honoraria, Other; Kyowa Kirin: Honoraria, Other; Innate Pharma: Honoraria, Other: institutional grant/research support; GSK: Honoraria, Other: institutional grant/research support; Genentech: Honoraria, Other: institutional grant/research support.

Abstract: Background: The gain-of function mutation KIT D816V plays a central role in the pathogenesis of systemic mastocytosis (SM). Among subtypes of SM, indolent SM (ISM) is the most frequent and is associated with normal/near-normal life expectancy; smoldering SM (SSM) is a subtype with a relatively higher burden of mast cells and may be associated with an increased risk of progression to advanced mastocytosis. However, both ISM and SSM patients may experience severe symptoms associated with mast cell mediator release, such as pruritus, diarrhea, anaphylaxis, and bone pain, which can be severely debilitating and have a profoundly negative impact on quality of life. Symptomatic treatments (eg, antihistamines and corticosteroids) are used to control symptoms with varying degrees of efficacy; however, these treatments fail to impact mast cell burden, and approved cytoreductive therapies for ISM or SSM are still lacking. There is an urgent unmet need for other treatment options in patients with moderate-to-severe symptoms who do not adequately respond to symptomatic treatment. Avapritinib is a potent and selective investigational oral kinase inhibitor that targets KIT D816V and other KIT exon 17 mutations. Avapritinib has shown potent and selective in vivo activity against KIT D816V, robust growth inhibition in an in vivo mastocytoma model, and tolerability at active doses in toxicology and safety pharmacology studies. The 3-part, phase 2 PIONEER study is being conducted to identify the recommended phase 2 dose (RP2D) in ISM (part 1), to investigate efficacy of avapritinib vs placebo in patients with ISM and SSM (part 2), and to further characterize the safety and efficacy of long-term treatment with avapritinib (part 3). Study Design and Methods: PIONEER (NCT03731260) is an international, multicenter, randomized, double-blind, placebo-controlled phase 2 study of patients with ISM or SSM whose symptoms are not adequately controlled by best supportive care (BSC). For inclusion, patients must have moderate-to-severe symptoms per total symptoms score (TSS) on the ISM-Symptom Assessment Form (SAF) and have failed to achieve symptom control for ≥1 baseline symptom measured by ISM-SAF with ≥2 therapies considered BSC. BSC may include treatments such as H1 and H2 blockers, proton pump inhibitors, corticosteroids, and mast cell stabilizers. The ISM-SAF is being developed specifically to assess symptoms in patients with ISM and SSM, and final validation will be based on data from part 1 of this study. The study includes 3 parts (Figure). Part 1 aims to identify the RP2D. Patients with ISM will be randomized to three avapritinib doses (25 mg, 50 mg, or 100 mg once daily) or placebo + BSC, stratified by baseline serum tryptase level and the presence/absence of skin lesions. The primary endpoint is R2PD, determined by efficacy, safety, and pharmacokinetics at each dose level, with a primary criterion of maximum reduction in ISM-SAF TSS at week 12. Secondary endpoints include changes in measures of mast cell burden, changes in measures of skin lesions, quality of life, safety, and pharmacokinetics. Part 1 will include approximately 40 patients, with 10 patients per cohort (avapritinib 25, 50, and 100 mg once daily and placebo). Dose investigation will be done in parallel, for a duration of 12 weeks. In part 2, patients with ISM or SSM will be randomized to the avapritinib RP2D or placebo + BCS to evaluate the efficacy of avapritinib vs placebo in reducing symptoms of ISM and SSM. Patients will be stratified by the same factors as in part 1 as well as by diagnosis (ISM vs SSM). The primary endpoint is mean change in ISM-SAF TSS from baseline to week 12. Secondary endpoints are the same as those in part 1. In part 2, enrollment of 32 patients per group (64 total) will have 〉 90% power to detect superiority of avapritinib to placebo at reducing SM symptoms based on the difference in mean change in the ISM-SAF TSS at week 12 using a 2-sample t-test with a 1-sided type I error rate of 0.025. To account for possible missing data, 35 patients per group will be enrolled (72 total). Part 3 will evaluate long-term safety and efficacy of avapritinib in ISM and SSM in an open-label extension including patients who completed parts 1 or 2. The primary endpoint is long-term safety and efficacy, secondary objectives include change in TSS ISM-SAF and are similar to those evaluated in parts 1 and 2. Figure Disclosures Akin: University of Michigan: Employment; Michigan Allergy and Asthma Society: Membership on an entity's Board of Directors or advisory committees; ECNM: Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy, Research Funding; Up to Date: Patents & Royalties; LAD2 cell line: Patents & Royalties; Novartis: Consultancy; NIH: Patents & Royalties. Gotlib:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Humana: Honoraria; Incyte: Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heaney:Partner Therapeutics: Consultancy; Deciphera: Research Funding; Incyte: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Blueprint: Research Funding; Celgene: Research Funding; CTI: Research Funding; BMS: Research Funding; Constellation: Research Funding; Novartis: Consultancy; AbbVie: Consultancy. van Daele:Erasmus MC, Rotterdam: Employment; Novartis: Speakers Bureau. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. Triggiani:Novartis: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding. George:Blueprint Medicines: Consultancy; Deciphera: Consultancy; Novartis: Honoraria; Allakos: Consultancy. Hartmann:ALK-Abello: Consultancy; Bluepriont: Consultancy; Deciphera: Consultancy; Novartis: Consultancy; Euroimmun: Research Funding. Frank:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement. Panse:Roche: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Thaci:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medimmune: Honoraria; Boehringer Ingelheim: Consultancy; Morphosis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Galderma: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Speakers Bureau; DS-Biopharma: Consultancy, Honoraria; UCB: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Glaxo-Smith Kline: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria; Lilly: Consultancy, Honoraria, Speakers Bureau; Almiral: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Honoraria; Sandoz: Consultancy, Honoraria, Speakers Bureau; Regeneron: Consultancy, Honoraria; Medac: Consultancy, Honoraria, Speakers Bureau. Lin:Blueprint Medicines: Employment. Morrison:Blueprint Medicines: Employment. Mar:Blueprint Medicines: Employment. Maurer:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.