Background: PN, which develop in 25-40% of individuals with NF1, are typically diagnosed and exhibit the fastest growth in young children. They can be associated with substantial morbidity including disfigurement, pain and loss of function. There are no effective medical treatments for PN. Selumetinib, an oral MEK1/2 inhibitor, may mediate anti-tumor effects in PN by inhibition of Ras signaling. A recently completed phase I study of selumetinib in children with NF1 and inoperable PN showed promising results with confirmed partial responses ( ≥ 20% decrease in PN volume by volumetric MRI analysis) in > 50% of patients, which were associated with clinical improvement in some patients. Methods: The objectives of this study are to determine the confirmed partial and complete response rate to selumetinib in patients with PN related morbidity (stratum 1, primary endpoint) and without significant PN related morbidity (stratum 2, secondary endpoint), and to prospectively evaluate its effect on PN related pain, quality of life (QOL), appearance, and PN related functional impairment (stratum 1). Additionally, the pharmacokinetics and pharmacodynamics (ERK phosphorylation in peripheral blood mononuclear cells, cytokines) of selumetinib will be evaluated. Patients 2-18 years old with NF1 and inoperable PN are eligible and will be assigned to stratum 1 or 2 depending on the presence of PN related morbidity (disfigurement, pain, functional impairment: motor, airway, bowel/bladder, vision, other) at enrollment. Selumetinib is administered at the recommended pediatric dose of 25 mg/m²/dose PO BID on a continuous dosing schedule for 28-day cycles. Changes in PN size will be assessed after every 4 cycles using MRI with centralized volumetric analysis. Prospective, standardized evaluations of pain, QOL, photography of visible PN, and PN related function will be performed at baseline and then after every 4 cycles. Medication adherence will be assessed throughout. Fifty patients will be enrolled on stratum 1 (target response rate 36%, null response rate 15%). This CTEP sponsored multi-site phase II study (NCT02407405) has enrolled 21 patients to date. Clinical trial information: NCT02407405