Abstract B243: A phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors.
Authors: Bendell Johanna C. , Papadopoulos Kyriakos , Jones Suzanne F. , Barrett Emma , Guthrie Kari , Kass Carrie L. , Litwiler Kevin S. , Napier Cheryl , Patnaik Amita 
Published: June 2012

Abstract
Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival, and is often aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this completed Phase 1 dose-escalation study were to determine the maximum tolerated dose (MTD) and characterize the safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with advanced solid tumors. An expansion phase of the study is ongoing in order to further explore toxicity and PK in pts with biliary cancer and in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.
Methods: Pts were enrolled in successive cohorts using a 3 + 3 design and received MEK162 as a single oral dose on Day (D) 1 followed by twice daily (BID) dosing starting on D2. Safety was assessed by adverse events (AEs), clinical laboratory tests, physical exams, ECGs, ECHO/MUGA scans and ophthalmic exams. Plasma samples were used to assess PK. Levels of circulating cytokines and growth factors in serum and expression and/or phosphorylation status changes in relevant growth factor pathway proteins in skin were evaluated to assess PD. Mutation status of RAS, RAF and other relevant genes and expression and/or phosphorylation status of MEK pathway protein were assessed from archival tumor samples. Tumor response was assessed every 6 weeks.
Results: Nineteen pts of median age 57 years (range 33–79) were enrolled in 4 dose cohorts (30 [4], 45 [4], 60 [7] and 80 [4] mg BID). All pts had prior chemotherapy and were ECOG 0–1. Tumor types included colorectal (7), pancreatic (3), cholangiocarcinoma (2) and other (7). The most common treatment-related AEs were rash, diarrhea, nausea, vomiting and peripheral edema, and most were Grade (G) 1/2. G3/4 treatment-related AEs included G3 rash (2), G3 palmar-planter syndrome (1), G3 central serous-like retinopathy (1) and G3/4 creatine kinase elevation (1 each). Seventeen pts were evaluable for MTD determination (30 [4], 45 [3], 60 [7] and 80 [3] mg BID). All DLTs occurred at 80 mg BID (G3 rash and central serous-like retinopathy, 1 pt each); thus, the MTD was 60 mg BID. Of the 17 pts evaluable for response, 1 pt with NRAS-mutant cholangiocarcinoma achieved a PR, and SD was achieved in 9 pts. Of the 11 other evaluable pts with known mutational status, 2 were wild type on all loci tested, plus 5 KRAS, 1 NRAS, 1 BRAF, 1 PIK3Ca and 1 dual KRAS/PIK3Ca mutants. Exposure increased in a dose-proportional manner with good inter-pt variability (∼30% CV). Exposure by D15 averaged 36% &gt; corresponding D1 values indicating modest accumulation. The median t1/2 was ∼5 hr. Mean steady-state plasma concentrations were continuously maintained above the in vitro IC50 value for cell proliferation at all dose levels. In 7 paired skin biopsies from the 60 mg cohort, decreases in pERK and Ki67 were observed post-dose by immunohistochemistry. In serum, a decrease in TNFα was also observed across all dose cohorts.
Conclusions: MEK162 had an acceptable safety profile at doses up to the MTD of 60 mg BID and showed preliminary signs of clinical activity. MEK162 displayed desirable PK properties with dose-dependent exposures. MEK162-induced changes in PD markers of MEK activity suggest that MEK162 has target-related PD activity at multiple-dose levels at and below the MTD.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B243.