Background ETC-159 is a small molecule selectively inhibiting the O-acyltransferase PORCN (porcupine) that is required for the palmitoylation of all Wnts. Preclinical studies show anti-tumour effects when administered orally using different dosing schedules. In this first-in-human study we investigate safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) of ETC-159 in patients (pts) with advanced or metastatic solid tumours. Methods Pts with no other treatment options and adequate organ function are eligible. ETC-159 is administered orally, once every other day in a cycle of 28 days. Doses are escalated according to an ordinal continual reassessment method (oCRM) with a dose limiting toxicity (DLT) period of 28 days. PK and PD (Axin2mRNA levels) are assessed on day 1 and day 15 of cycle 1 and on day 1 of cycle 2. Response is assessed every 2 cycles using RECIST 1.1 Results This is the initial report of a Phase 1 open-label, multicentre study of ETC-159. As of 12 August 2016, 10 pts have been enrolled: 1mg (2pts), 2mg (2pts), 4mg (3 pts), 8mg (3pts); 70% were male, mean age (range) was 56 (40-68) yrs. Tumour types were colorectal cancer (9) and renal cancer (1). Eight pts discontinued due to disease progression. The most common adverse events (AEs _3 pts) were: Anorexia (4 pts, grade 1-2), Fatigue (3 pts, grade 1-2), Lethargy (3pts, grade 1-2), Constipation (3pts, grade 1-2). No treatment-related serious AEs or DLTs were observed. Dose escalation is ongoing at the 8mg dose. At 4mg (n¼2), PK on day 1 showed mean Cmax, AUC last, and T1/2 of: 123 ng/mL, 2540ng*hr/mL and 14 h, respectively. To date, no complete responses (CR) or partial responses (PR) were observed. One pt at 2mg and 1 pt at 4 mg remained in the study in stable disease for 6 cycles; the patient at 4mg is still ongoing (with 1 pt in cycle 1 at 8 mg). Axin2 levels, measured in hair follicles, showed reduction in 4 out of 7 pts treated at 1, 2 and 4mg of ETC-159. Conclusions ETC-159 as a single agent has been safe and well-tolerated. No CR or PR but disease stabilisation was observed. Target engagement was observed at all dose levels explored. Dose escalation is ongoing. Clinical trial indentification NCT02521844 Legal entity responsible for the study D3(Drug Discovery and Development), A*STAR, Singapore Funding D3(Drug Discovery and Development), A*STAR, Singapore Disclosure V. Teneggi, P. Yeo: Employment at D3, the sponsor of the study. V. Diermayr, K. Ethirajulu, D. Chen, A. Matter: Employment at D3, the sponsor of the study. S. Gan, S. Blanchard, R. Nellore: Employment at D3, sponsor of the study. D. Virshup, B. Madan: Holds IP rights in the ETC-159 project. All other authors have declared no conflicts of interest.