NFM-06. NF106: PHASE 2 TRIAL OF THE MEK INHIBITOR PD-0325901 IN ADOLESCENTS AND ADULTS WITH NF1-RELATED PLEXIFORM NEUROFIBROMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY

Abstract

Plexiform neurofibromas (PNs) can cause significant disfigurement, compression of vital structures, neurologic dysfunction, and pain. MEK pathway inhibition results in significant PN shrinkage in neurofibromatosis type 1 (NF1) mouse models of PN. We evaluated the efficacy of the MEK inhibitor, PD0325901, in adolescents (≥ 16 years of age) and adults with symptomatic or growing NF1-PN in a phase II open label study. The primary aim was to assess tumor response by cycle 12 using centrally read MRI, defined as at least 20% decrease in tumor volume from baseline. Subjects received PD-0325901 by mouth twice daily at 2 mg/m2/dose (maximum dose 4 mg bid). Each course was 4 weeks, and subjects received drug on a 3 week on / 1 week off schedule. NF106 enrolled 19 subjects (7M;12F) in two stages with a median age of 24 years (range 16-39 years). The mean PN volume was 797.8 mL. Eight subjects (42.1%; 95% CI: 20%, 67%) had a response. PD0325901 was well tolerated, with the most common dose limiting toxicity being acneiform rash in 3/19 patients (16%). Five subjects (26.3%) developed Grade 3 toxicities, mostly pain (4/19; 21%). No subjects developed Grade 4 or higher toxicities. Five subjects (26.3%) had a dose reduction for toxicity: one for Grade 3 abdominal and back pain, the others for intolerable Grade 1-2 nausea, rash, or fatigue. This study demonstrated that PD0325901 is well tolerated and results in PN shrinkage in 42% of adolescent and adult subjects with NF1-PN. Supported by DOD Award W81XWH-12-1-0155.