Background: Targeting the RAS–RAF–MEK–ERK pathway may be useful in the treatment of PC, as 75–90% of PCs have KRAS mutation. BAY is an orally bioavailable, potent, allosteric MEK 1/2 inhibitor that showed single-agent activity, and synergistic activity with GEM, in ectopic, orthotopic, syngenic and patient-derived xenograft PC models. Methods: The phase I part aimed to determine the maximum tolerated dose (MTD) of BAY in combination with GEM, and the pharmacokinetics of BAY and GEM. 3+3 study design was used. After informed consent, eligible patients with advanced PC received GEM 1000 mg/m² (30-min, once-weekly IV infusion for 7 out of 8 weeks in cycle 1 [C1], and 3 out of 4 weeks in subsequent cycles) and oral BAY 30 mg BID (dose level 1 [DL1]) or 50 mg BID (DL2). No escalation beyond DL2 was planned. MTD was the highest dose at which maximum 1 out of 6 evaluable patients displayed dose-limiting toxicities (DLT) during C1. Results: As of 6 Jan 2012, 17 patients were enrolled and treated (10 at DL1, 7 at DL2). DL1 cohort has completed; DL2 evaluation is ongoing. At DL1, DLTs occurred in 1/6 evaluable patients: a patient with extensive liver metastasis developed chemotherapy-associated steatohepatitis (CASH) and died of hepatic failure. Rare CASH cases have been reported to be associated with GEM alone, but co-involvement of BAY currently cannot be ruled out. To date, 3 patients have completed C1 at DL2 without DLTs. DL2 completion is expected in March 2012. BAY+GEM showed a manageable tolerability profile. The most frequent treatment-related grade 3–4 adverse event (AE) at any DL was neutropenia (n=6). The most frequent clinically relevant BAY-related AE was acneiform rash (n=11), which was mostly grade 1–2 (one case grade 3) and manageable. BAY+GEM showed evidence of clinical efficacy: partial responses were seen in 4/10 patients at DL1 and 1/3 patients at DL2. No pharmacokinetic interaction between BAY and GEM was seen at DL1. Conclusions: In patients with advanced PC, BAY 30 mg BID in combination with GEM had a manageable safety profile, with acneiform rash as the clinically most relevant toxicity attributable to BAY.