Background: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m² weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m² via 2-hr continuous IV (CIV) infusions given twice weekly for 3 weeks of a 4-week cycle (RIG+GEM) versus gemcitabine 1000mg/m² weekly for 3 weeks in a 4-week cycle (GEM). Results: A total of 160 patients were enrolled globally and randomly assigned to RIG+GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG+GEM group vs. 6% in the GEM group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median overall survival (OS), was 6.1 months for RIG+GEM versus 6.4 months for GEM (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median progression-free survival (PFS) was 3.4 months for both groups (HR = 0.96; 95% CI, 0.68-1.36). The partial response rate by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 was 19% versus 13% for RIG+GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of RIG+GEM failed to demonstrate an improvement in survival or response compared to GEM in metastatic pancreatic adenocarcinoma. Rigosertib had a similar safety profile to that observed in other trials of the IV formulation. Clinical trial information: NCT01360853