Background: G can sensitize pancreatic cancer (PC) to radiotherapy (RT). However, this approach requires lower doses of G and thus delays aggressive systemic treatment, which may lead to distant failure. In preclinical models, hyperfractionated low-dose RT sensitizes PC cells to G and erlotinib. We thus initiated a Phase I trial combining hyperfractionated low-dose RT combined with full dose G and a tyrosine kinase inhibitor, E, in the treatment of patients with advanced PC. Methods: Patients (pts) with locally advanced or metastatic PC confined to the abdomen and an ECOG performance status (PS) of 0-1, who had received 0-1 prior regimens (without G or E) and no prior RT were enrolled to successive cohorts in a 3+3 design. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4 hours on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Dosing cohorts were as follows (G in mg per m², E in mg, XRT/fraction in cGy): 1 (1,000, 100, 40), 2 (1,000, 100, 50), 3 (1,000, 100, 60), 4 (1,000, 150, 60). Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: A total of 27 pts, (median age 64 yrs and 15 male), were enrolled between 11/24/08 and 4/12/12. 17 patients had a PS of 1. The majority of patients were stage IV. Seven pts were enrolled in dose level 1, with 1 pt experiencing a DLT of grade 3 ileus, 3 pts enrolled each in dose levels 2-4 without DLT and 11 pts enrolled in the expanded portion of level 4. Best response by RECIST in 24 evaluable pts and was as follows: partial response 8, stable disease 15 and progressive disease 1. One pt initially found to be unresectable at surgery was subsequently resected with only minimal microscopic residual disease. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Conclusions: This phase I study combining low-dose hyperfractionated RT as a sensitizer to full dose G plus E was well tolerated with the majority of pts experiencing either a partial response or stable disease. This represents a novel strategy worthy of further investigation in pts with advanced PC. Clinical trial information: NCT00761345.