Background: The Hh pathway is overexpressed in PDA tumors. Pre-clinically, Hh inhibitors have demonstrated a reduction in pancreatic cancer stem cells (pCSC) and stroma. Vismodegib, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with Gemcitabine chemotherapy. Methods: Pts with untreated, metastatic PDA were treated with Gemcitabine (1000 mg/m²) + nab-P (125 mg/m²) on days 1, 8 and 15 of 28 days cycle. Vismodegib (150mg PO daily) was started on the second cycle. All drugs were continued until disease progression or unacceptable toxicities. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate (RR), and toxicity. Pre and post treatment tumor biopsies were obtained from primary or metastatic lesions. Results: 59 patients have been enrolled at 3 sites. Median age 60 (range 42-86); ECOG PS 0/1: 23 (40%)/ 34 (60%); male/female 32 (54%)/ 27 (46%). Estimated median PFS and OS in ITT population was 5.5 and 10 mo respectively (95% CI: 5.2-5.9 / 7.3-11). Of the 49 pts evaluable for response to date, 1 (2%) had CR, 20 (41%) had PR, 21 (43%) had SD and 7 (14%) had PD. Common Gr ≥3 toxicities: neutropenia 37.5% (n=21), anemia 21.4% (n=12), neuropathy 16.1% (n=9) and fatigue 9.4% (n=5). All patients with partial response had response within the primary pancreatic tumor. CA19-9 declines of >70% occurred in 57% of patients with measurable levels. Conclusions: Addition of Vismodegib to Gemcitabine/nab-P is well tolerated in patients with untreated PDA. This trial is ongoing to complete 80 patients. Blood and tumor tissue biomarker analyses for stem cells, Hh signaling and stromal activity are ongoing and will be reported in ASCO GI 2014. Clinical trial information: NCT01088815.