Pioneer: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.2950-2950
• Main Authors: Akin, Cem, Sabato, Vito, Gotlib, Jason, Castells, Mariana, Deininger, Michael W., Elberink, Hanneke Oude, Heaney, Mark L, van Daele, Paul, Radia, Deepti, Triggiani, Massimo, DeAngelo, Daniel J., Alvarez-Twose, Iván, Broesby-Olsen, Sigurd, George, Tracy I., Hartmann, Karin, Frank, Siebenhaar, Reiter, Andreas, Vadas, Peter, Bonadonna, Patrizia, Panse, Jens P., Staubach-Renz, Petra, Brockow, Knut, Thaci, Diamant, Lin, Hui-Min, Morrison, Andrew, Mar, Brenton, Maurer, Marcus
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-126035

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