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.

Authors

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Kimberly Mayumi Komatsubara

Columbia University Medical Center, New York, NY

Kimberly Mayumi Komatsubara , Alexander Noor Shoushtari , Sapna Pradyuman Patel , Parisa Momtaz , Shahnaz Singh-Kandah , Amanda Carter , Suzanne Cain , Lauren Taiclet , Sarah DeNoble , Tiffany Negri , Danielle Lacey , Grazia Ambrosini , Shing Mirn Lee , Gary K. Schwartz , Richard D. Carvajal

Organizations

Columbia University Medical Center, New York, NY, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, The University of Texas MD Anderson Cancer Center, Houston, TX, New York-Presbyterian Hospital, Columbia University School of Medicine, New York, NY

Research Funding

Other

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

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Abstract Details

Meeting

2017 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Melanoma/Skin Cancers

Track

Melanoma/Skin Cancers

Sub Track

Advanced/Metastatic Disease

Clinical Trial Registration Number

NCT02768766

Citation

J Clin Oncol 35, 2017 (suppl; abstr TPS9597)

DOI

10.1200/JCO.2017.35.15_suppl.TPS9597

Abstract #

TPS9597

Poster Bd #

202a

Abstract Disclosures