Background: PNs in NF1 are a major source of morbidity, causing disfigurement, functional impairment, and pain. Selumetinib is an oral inhibitor of MEK 1/2, which may mediate anti-tumor effects in PNs by inhibiting Ras signaling. Selumetinib is currently undergoing evaluation in adult cancers, pediatric brain tumors and NF1 related PNs. Our phase I trial of selumetinib for children with NF1 and inoperable PNs demonstrated unprecedented activity with objective responses (PN volume decrease ≥ 20% using volumetric MRI analysis) in > 50% of patients (pts) enrolled. However, we have observed slow PN regrowth in several patients who required dose reductions for toxicity. This suggests that a certain selumetinib tissue concentration may be required for target inhibition and anti-tumor activity. Methods: This study will evaluate 1) the objective response rate to selumetinib in pts ≥ 18 years old with NF1 and inoperable, growing or symptomatic PNs, 2) PN and dermal neurofibroma (DN) biopsies prior to and on treatment with selumetinib for mechanisms of response and resistance, 3) the potential clinical benefit of selumetinib with evaluations of PN related pain, quality of life, and function, and 4) steady state pharmacokinetics and pharmacodynamics (cytokines, bone marrow derived precursor cells, and peripheral blood immune subsets). Willingness to undergo PN biopsies is required for eligibility. Pts will receive selumetinib at the adult recommended dose of 75 mg every 12 hours on a continuous dosing schedule (1 cycle = 28 days). PN biopsies will be analyzed for pERK, pAKT, pMEK, tumor kinome and transcriptome, and immune infiltrate. In addition, we will analyze and compare pERK, pAKT in DN. Response will be evaluated with periodic volumetric MRI analysis. Patient-reported outcome and adherence evaluations will be conducted. With a Simon two-stage design targeting a 45% response rate (90% power), if ≥ 5/20 pts in stage 1 respond, enrollment will be expanded to 35 evaluable patients and if ≥ 12/35 patients respond, selumetinib will be considered active. This CTEP-sponsored single site open label phase II study (NCT02644512) is currently enrolling patients. Clinical trial information: NCT02644512