Background: Treatment of locally advanced pancreatic cancer (LAPC) remains a challenge, and novel therapy options for local treatment of disease beyond systemic therapy are needed. Recently published data of intra-arterial delivery of gemcitabine (IAG) for local disease control has shown this approach to be safe (J. Pancreatic Cancer 3(1) 58:65). Furthermore, in patients who have received prior radiation for LAPC, there seems to be an effect on the local microvasculature that enhances the clinical efficacy of IAG. TIGeR-PaC is a randomized Phase 3 trial designed to test if the combination of induction systemic chemotherapy plus radiation followed by IAG is superior to systemic chemotherapy plus radiation alone (NCT03257033). Methods: All subjects with biopsy proven, and imaging-confirmed LAPC (by the NCCN guidelines) will receive induction therapy with IV gemcitabine plus nab-paclitaxel, for approximately four months, during which time a course of radiation therapy will also be incorporated. Subjects without evidence of disease progression will then be randomized to receive either IAG (test group); or continue only IV gemcitabine plus nab-paclitaxel (control group). Subjects will receive the randomized treatments for up to 16 weeks or until progression. Non-progressing patients from both groups will then receive, at the discretion of the investigator, either a continuation of IV gemcitabine and nab-paclitaxel, or oral capecitabine until disease progression. The primary endpoint is progression free survival; secondary endpoints will include overall survival, neutropenia, quality of life, and neuropathy assessed over 2 years. Based on an assumed superiority of IAG therapy, which will lead to an increased PFS from 6 months (control group) up to 12 months (IAG group), with an alpha-error of 0.05 and a 90% power, 132 patients will be randomized; assuming a 30% dropout during the induction phase prior to randomization, 200 patients will be recruited. TIGeR-PaC will test the hypothesis that IAG local therapy, after induction systemic chemotherapy plus radiation in patients with LAPC is superior to systemic therapy plus radiation alone. Clinical trial information: NCT03257033