Background: Preclinical data have demonstrated interactions between the hedgehog (HH) and EGFR signaling pathways that contribute to pancreatic tumorigenesis. We have found that simultaneous targeting of both pathways resulted in synergistic antitumor activity in pancreatic tumor models. Additionally, HH inhibition has been shown to enhance uptake of gemcitabine in a murine model of pancreatic cancer. Based on these findings, a phase I trial was initiated to determine the maximally tolerated dose (MTD), toxicities and responses of the combination of GDC-0449, an orally administered HH pathway inhibitor and erlotinib (E), an EGFR tyrosine kinase inhibitor (cohort I), as well as the MTD of GDC-0449, E, and gemcitabine (GEM) (cohort II) in patients with unresectable solid tumors. Methods: The 3 + 3 phase I design was used for dose escalation in each group. Patients in cohort I received GDC-0449 at a fixed dose of 150 mg po and E 50, 75, 100, or 150 mg po daily at dose levels 1, 2, 3, and 4, respectively on each day of every 28-day cycle. Patients in cohort II received GDC-0449/E (150/75 mg po daily) combined with GEM 1,000 mg/m² dose level 1 or 750 mg/m² dose level -1 weekly x 7 with 1 week rest for cycle 1. All subsequent cycles, GEM was administered weekly for 3 of 4 weeks. Results: Fifteen patients were enrolled to cohort I and there was 1 DLT grade 4 rash observed at dose level 4. No other potential DLT was observed in five additional patients at this dose level. Accordingly, the MTD for cohort 1 was dose level 4 (GDC-0449 150 mg, E 150 mg). Fourteen patients were enrolled to cohort II and 3 DLTs (nausea, infection, visual disturbance) were observed in 2 of 3 evaluable patients at dose level 1. At dose level -1, two of five evaluable patients experienced DLT thrombocytopenia. The dosing schedule for this cohort is currently being revised. In cohort I, one patient being treated at dose level 1 had stable disease as best response for five cycles and another patient at dose level 2 had stable disease for 2 cycles. Conclusions: GDC-0449 and E, each at a dose of 150 mg po daily, is well tolerated and suitable for phase II evaluation. The definition of the MTD for the GDC-0449, E, and GEM combination is currently in progress. Supported by U01CA69912 and P50CA102701.