Background: BBI608 is an orally-administered first-in-class cancer stemness inhibitor. By targeting Stat3, BBI608 blocks cancer stem cell (CSC) self-renewal and survival through suppressing stemness pathways, including Stat3, β-catenin as well as immune checkpoint gene expression. Potent anti-tumor and anti-metastatic activity was observed in preclinical models, with marked synergy between BBI608 and paclitaxel. Moreover, cancer stemness genes, such as Stat3 and β-catenin, two poor prognostic biomarkers in many cancer types, predict sensitivity to BBI608. Encouraging anticancer activity in refractory gastric and GEJ adenocarcinoma was observed in a phase Ib (Stephenson et al, ASCO 2014 abstr) and a subsequent phase II study including 39 gastric or GEJ adenocarcinoma pts. On the basis of these data, a phase III trial is being conducted in North America, South America, Europe, Australia, and Asia. Methods: This study (ClinicalTrials.gov NCT02178956) will assess the efficacy of BBI608+paclitaxel vs PBO+paclitaxel in pts with pre-treated, advanced gastric and GEJ adenocarcinoma (target n=680). Pts must have failed one prior line of therapy containing a fluoropyrimidine/platinum doublet for unresectable disease. Pts are randomized in a 1:1 ratio to receive BBI608 480 mg or PBO twice daily continuously plus paclitaxel 80 mg/m² IV, weekly, for 3 of every 4 weeks. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival (OS) in the general study population; secondary endpoints include progression free survival (PFS), OS and PFS in a predefined biomarker (β-catenin)-positive sub-population, objective response rate, disease control rate, and safety. In addition, blood, plasma, and archival tissue will be assessed for pharmacokinetic and biomarker analyses and quality of life will be measured. As of January 2015, 28 pts were randomized and recruitment is ongoing. Clinical trial information: NCT02178956