Abstract
10018 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 (...
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