Abstract We assessed the safety, tolerability, PK, PD and efficacy of the PKC inhibitor LXS196 in patients with metastatic uveal melanoma (MUM). As of 30 Sep 2018, 68 patients received LXS196 at doses ranging from 100 to 1000 mg once daily (QD; 38 patients) and 200 to 400 mg twice daily (BID; 30 patients). All patients in the QD regimen had discontinued treatment due to progressive disease. Five patients in the BID regimen remain on study. LDH was > ULN in 38 patients (55.9%), and 60 patients (88.2%) had liver involvement. Dose limiting toxicities (DLTs) in cycle 1 were reported in 7 of 38 patients on the QD schedule and in 2 of 17 patients on the BID schedule who were evaluable for the dose determination. The most common DLT was hypotension, manageable with LXS196 interruption and dose reduction. The most frequent AEs (all grades, in ≥ 20% of patients) suspected to be related to LXS196 in patients across both dosing schedules (n = 68) included nausea (66.2%), diarrhea (45.6%), vomiting (30.9%), hypotension (22.1%), increased ALT (22.1%), and fatigue (20.6%). The majority of gastrointestinal and constitutional AEs were of low grade (grade 1 or 2). Grade 3 or 4 AEs suspected to be related to LXS196 were reported in 17 patients (25.0%), the most frequent being hypotension (8.8%). BID dosing was better tolerated than QD dosing with fewer grade 3 or 4 AEs reported (20% with BID vs 28.9% with QD dosing) and fewer drug-related SAEs (6.7% with BID vs 15.8% with QD). In this study, MTDs were determined at 500mg QD and 400 mg BID and the RDE was declared at 300mg BID. The most common AEs suspected to be related to LXS196 (any grade, in >15% of patients) at the RDE (n = 18) included nausea (77.8%), diarrhea (61.1%), vomiting (38.9%), increased ALT (27.8%), asthenia, dry skin and rash (22.2% each), hypotension, fatigue, increased AST, dermatitis acneiform, and peripheral edema (16.7% each). Clinical PK demonstrates rapid absorption of LXS196 with Tmax of ~1 hr post dose and consistent terminal T1/2 across different doses (~ 11 hr). Exposure at doses above 300 mg QD and 200 mg BID are in the efficacious range from preclinical projections. LXS196 results in reduction of pMARCKS and pPKC delta, evident of target engagement in on-treatment tumor biopsies. Overall, amongst 66 evaluable patients, per RECIST v1.1, 6 had a PR (2 in QD; 4 in BID) and 45 had SD as their best response. At the RDE, of 17 evaluable patients, 2 had confirmed PRs and 12 had SD as their best response (including 2 patients with > 30% tumor reduction/unconfirmed PRs). The median duration of exposure is 3.71 months (range; 1.81 - 15.28 months) and 4.6 months (range; 0.33 - 20.01 months) for patients in the QD and BID regimens, respectively. Of the 5 ongoing patients in the BID regimen, 2 maintain a PR (200 and 300 mg BID) and 3 have SD (all at 300 mg BID). All 5 patients have remained on study for > 13 months. These results suggest encouraging clinical activity of LXS196 as a single agent with manageable toxicity profile in patients with MUM. Citation Format: Ellen Kapiteijn, Matteo Carlino, Valentina Boni, Delphine Loirat, Frank Speetjens, John Park, Emiliano Calvo, Richard Carvajal, Marta Nyakas, Juan Gonzalez-Maffe, Xu Zhu, Ramu Thiruvamoor, Padmaja Yerramilli-Rao, Sophie Piperno-Neumann. A Phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT068.