Background: Lack of functional neurofibromin in NF1 leads to dysregulated Ras and tumorigenesis. Selumetinib (AZD6244; ARRY-142886), an oral selective inhibitor of MEK1/2, may inhibit PN growth by blocking Ras signaling. Methods: We are conducting a phase 1 trial (NCT01362803) to determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of selumetinib in patients (pts) 3-18 years old with NF1 and inoperable PNs. The MTD is determined based on cycle (C) 1-3 toxicities. Selumetinib is administered BID on a continuous dosing schedule (1 C = 28 days) at dose level (DL) 1: 20 mg/m²/dose, and 2: 30 mg/m²/dose. Response evaluation with volumetric MRI analysis occurs after C 5, 10, and then after every 6 C (partial response [PR] = ≥20% decrease in the PN volume). Results: Eighteen pts (10 M:8 F, median age 12.9 years, range 5.3-18.5) with a median PN volume of 1204 mL (range 47-10,269 mL) have enrolled. DL2 exceeded the MTD with DLT in 2/6 pts: grade (gr) 3 creatine kinase (CK) elevation (n=1), and gr 3 decrease in left ventricular ejection fraction (n=1). DL1 was tolerated with DLT in 2/12 pts: gr 3 cellulitis (n=1), and grade 3 urticaria (n=1). The most frequent toxicities (all grades) are acneiform rash, asymptomatic CK elevation, nausea, vomiting, abdominal pain, diarrhea, and fatigue. All DLTs have been reversible. Preliminary median (range) selumetinib C1 day 1 PK parameters [DL1 (n=2), DL2 (n=5)] were: C_max DL1 513 ng/mL (487-539), DL2 841 ng/mL (576-1770); AUC_0-24hDL1 2068 (2046-2089) ngxh/mL, DL2 2702 (2088-6008) ngxh/mL; half-life DL1 7.7 h (6.8-8.5), DL2 7.6 h (5.4-9.8). Of 11 pts with ≥ 1 restaging MRI, all had a decrease in PN volume (median maximal decrease 24%, range 8-39), and 3/5 at DL1, and 3/6 at DL 2 had a PR. All pts remain on trial after a median of 9 C (range 4-30). Conclusions: In children with NF1 PNs selumetinib is tolerated at 20 mg/m²/dose BID on a continuous dosing schedule, approximately 50% of the adult recommended dose (75 mg BID). Preliminary activity is observed at DL1 and DL2. Enrollment is being expanded at 25 mg/m²/dose, the MTD in study PBTC-029 for pediatric low grade gliomas, and a phase II trial is in development. Clinical trial information: NCT01362803.