Background: 2-OHOA, is a synthetic hydroxylated lipid that activates sphingomyelin synthase (SGMS) and regulates the lipid content of cell membranes resulting in translocation of Ras to the cytoplasm and inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. 2-OHOA reduces tumor growth in xenograft mice models of prostate, leukemia, breast, colon, breast cancer, and GBM, and also crosses the blood brain barrier. This first-in-human trial was designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D), alongside the PK, PD and anti-tumor profile of 2-OHOA. Methods: Eligible pts with advanced solid tumors or grade (G) III/IV GBM received 2-OHOA as a PO suspension, BID in 21-d cycles using a ‘3+3’ dose escalation design. Adverse events (AE) were assessed by Common Terminology Criteria for AE v4; tumor response was assessed every 2 cycles using RECIST 1.1/RANO criteria. Results: 17 pts (median age 59 years; range 19-71; 7 GBM and 10 solid tumors) were treated at 5 dose levels: 250-, 500-, 1000, 2000 and 4000-mg BID. Treatment was well tolerated with toxicities limited to grade 1-2 nausea (n = 4), vomiting (n = 6) and diarrhea (n = 6). The PK profile was dose-proportional with no accumulation up to 2000mg BID; t1/2 = 4h. No effect of food was observed. One pt with GBM treated at 500mg BID has a confirmed and ongoing partial response and is currently at cycle (C) 23 of treatment; a 2nd GBM pt has SD after 2 cycles and continues on study. A 3rd pt with progressive mesothelioma demonstrated SD lasting to C15. Conclusions: 2-OHOA can be safely administered up to doses of 4000mg BID. Clinical benefit was observed in 3 patients including 1 PR in a pt with GBM. Dose escalation continues to determine a RP2D, followed by a RP2D expansion in patients with both solid tumors and grade III/IV GBM. Clinical trial information: NCT01792310