Multi-center phase Ib study of intermittent dosing of the MEK inhibitor, selumetinib, in patients with advanced uveal melanoma not previously treated with a MEK inhibitor.

TPS9597 Background: Uveal melanoma (UM) is a rare subtype of melanoma with no effective therapy for advanced disease. UM is characterized by mutations in GNAQ and GNA11 leading to constitutive activation of the mitogen activated protein kinase (MAPK) pathway. We have previously shown that targeting the MAPK pathway though MEK inhibition with Selumetinib (AZD6244, ARRY-142886) using a continuous dosing schedule improved progression free survival (PFS) in a randomized Phase II study of Selumetininb versus chemotherapy in patients with metastatic UM; however, no PFS or overall survival (OS) benefit was observed in a subsequent randomized Phase III study of Selumetinib and chemotherapy versus chemotherapy alone. We hypothesize that an intermittent dosing schedule of Selumetinib may be more effective than continuous dosing by achieving higher dose levels, better drug tolerability, and more complete target inhibition. We propose a Phase Ib study of Selumetinib in UM using an intermittent dosing schedule. Methods: A total of 28 subjects will be enrolled using the time to event continual reassessment method (TITE-CRM). Key inclusion criteria include a diagnosis of advanced UM, measurable disease by RECIST v1.1, and no prior MEK inhibitor therapy. Eligible subjects will be treated with Selumetinib starting at a dose level of 125 mg orally twice a day, using a 3-days-on and 4-days-off per week schedule. The primary goal of this study is to estimate the maximum tolerated dose (MTD) of intermittently dosed Selumetinib. Secondary endpoints are response rate, PFS and OS. Responses will be evaluated every 8 weeks by a CT scan of the chest and CT or MRI of the abdomen/ pelvis using RECIST v1.1 criteria. Mandatory tumor biopsies will be obtained at baseline, cycle 1 day 3 (Selumetinib-on day), and between cycle 1 day 11-14 (Selumetinib-off day) in 20 subjects, and optionally at progression. Tumor tissue will be assessed for MAPK pathway inhibition and reactivation at each time point, as well as mechanisms of resistance. Recruitment is currently ongoing. Clinical trial information: NCT02768766.