Abstract Background: Deregulation of the RAS/RAF/MEK/ERK signaling pathway has been implicated in diverse human tumors. GDC-0623 is an orally bioavailable inhibitor of MEK1/2 which has shown antitumor activity in preclinical models (Hatzivassiliou et al. 2013). Methods: An open-label Phase I dose-escalation study using a 3 + 3 design was initiated in patients with advanced solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0623. Patients were administered oral GDC-0623 as a QD or BID regimen on a 21-day on/7-day off dosing schedule in the fasted state (minimum 2 hour fast). In addition, two cohorts were enrolled to examine the effect of food (4 pts) and acidic beverage (3 pts) on GDC-0623 PK. Serial plasma samples for GDC-0623 PK analysis were collected over 24 hours following first dose and after 15 days of continuous dosing. Results: On the QD regimen, 45 pts enrolled in eight successive cohorts (7-160 mg). Dose-limiting toxicities (DLTs) were Grade 4 (G4) creatine phosphokinase (CPK) elevation (90 mg), transient G3 visual disturbance and the serious adverse event (SAE) of G3 dehydration both occurring in the same patient (120 mg), and G3 thrombocytopenia and G3 hyponatremia (160 mg). The maximum tolerated dose was 120 mg (QD cohort). Eight patients enrolled in a single cohort dosing at 45 mg BID. One patient had a DLT of G2 retinal pigment epithelial detachment. Further BID cohorts were not enrolled since the AE profiles between on 90 mg QD and 45 mg BID were comparable. The most frequent adverse events (AE) attributed by the investigator to be GDC-0623-related were rash, visual disturbance - including impaired or blurred vision - which was often associated with sub-retinal fluid, diarrhea, nausea and vomiting, fatigue, elevated CPK, peripheral edema, decreased appetite, headache and dizziness. Preliminarily, GDC-0623 showed dose-proportional PK over the dose range administered. GDC-0623 was rapidly absorbed and distributed, with a terminal half-life of 4-6 hours. Due to its short half-life, GDC-0623 had no accumulation at steady-state following daily oral dosing. Effect of food or acidic beverage on GDC-0623 PK was inconclusive given the inter-patient and intra-patient variability in GDC-0623 PK and very small sample size. One confirmed partial response was observed in a patient with KRAS wild type squamous cell vaginal carcinoma at the QD MTD. Six patients had stable disease ≥ 5 months. Conclusion: GDC-0623 is well-tolerated and showed dose-proportional and time-independent PK. Classic MEK-related AEs, including rash, gastrointestinal symptoms and visual disturbance occurred with similar frequency for QD and BID dosing regimens at the same total daily dose, suggesting comparable intensity of MEK target effect. Updated data will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B75. Citation Format: Anthony El-Khoueiry, Carla Kurkjian, Thomas Semrad, Luna Musib, Mary Gates, Steve Eppler, Ilsung Chang, Iris Chan, Isabelle Rooney, Johanna Bendell. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B75.