Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs quality of life. In other gastrointestinal cancer, infuser pomp free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. We previously conducted the phase Ⅰ study for assessing the safety and determining the recommended dose of OX-IRIS regimen. Methods: To evaluate efficacy and safety of OX-IRIS, HGCSG1803 study staeted as a multicenter, non-randomized, single arm, prospective, phase II study in December 2019. The patients with untreated metastatic or relapsed pancreatic cancer are eligible for this study. OX-IRIS is administered as follows; a 30-min intravenous infusion (IV) of antiemetic, a 2-h IV of oxaliplatin at 85 mg/m², a 1.5-h IV of irinotecan at 150 mg/m² on day 1 and day 15 of each 4-week cycle, and S-1 (40 mg/m²) was taken orally twice daily, from after dinner on day 1 to after breakfast on day 15, followed by a 14-day rest, and to be repeated every 2 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint is response rate, and the secondary endpoints are overall survival, progression-free survival, safety, and dose intensity for each drug. A total of 40 cases are planned for registration from 18 institutions in Japan within 2.5 years. Clinical trial information: jRCTs011190008.