4529 Background: The Ras signaling pathway stands as a strategic target in pancreatic cancer. S-trans,trans-farnesylthiosalicyclic acid (FTS) inhibits Ras dependent cell growth by dislodging all of the isoforms of Ras from membrane binding sites. Here we studied the activity of this agent in patients with advanced pancreatic cancer. Methods: Patients with treatment naïve advanced peri-ampullary cancer were treated with gemcitabine (Gem) administered at standard dose and schedule + FTS administered orally at doses of 200–800 mg bid 21 days of a 28 day cycle. Patients were treated until progression or protocol defined DLT. Plasma samples were collected when FTS was administered alone (C1D7 or C1D22) and in combination (C1D15 or C1D8) to characterize FTS pharmacokinetics. Plasma samples were collected when Gem was administered alone (C1D1) and in combination (C1D15 or C1D8) to characterize Gem pharmacokinetics. PBMCs and tissue biopsies pre treatment and during cycle 1 were collected to characterize the effect of Gem + FTS on levels of activated Ras protein. Treatment efficacy was assessed every other cycle. Results: Thirteen patients (8 male, 5 female, ages 40 to 80, ECOG 0–1) are enrolled to date. The most common adverse events were neutropenia, anemia, abdominal cramping, elevated liver function tests and diarrhea. At the time of this analysis, the progression free survival for these 13 patients is 4.7 months with median survival of >10.8 months and 1 year survival of 50%. Conclusions: 1. Salirasib in combination with gemcitabine appears to be safe with no PK interaction. 2. Salirasib in combination with gemcitabine at doses to 800 mg b.i.d. did not reach conventional MTD, although dose related diarrhea suggests better tolerance at doses up to 600 mg b.i.d. 3. Salirasib at doses of 400 to 800 mg b.i.d. in combination with gemcitabine demonstrated a PFS, MS and 1 year survival of 4.7 months, >10.8 months and 50% respectively. 4. Salirasib mechanism of Ras inhibition is confirmed by reduction of tumor Ras in pancreatic cancer patients. 5. Salirasib warrants evaluation in a controlled study with gemcitabine in pancreatic cancer; doses of 600 or 400 mg b.i.d. are recommended. No significant financial relationships to disclose.