Background: Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and folinic acid (LV), called the NAPOLI regimen, improves survival in advanced pancreatic cancer patients who failed gemcitabine-based chemotherapy (Wang-Gillam A et al. 2016). Capecitabine is an oral anti-cancer agent as the prodrug of 5-FU. Capecitabine has proven its efficacy in gastrointestinal cancers like stomach cancer, colon cancer, or pancreatic cancer. Replacing continuous 5-FU infusions with oral capecitabine with equivalent efficacy has been tested and is now widely used. However, in pancreatic cancer, replacing continuous infusion of 5-FU with an oral drug has not yet been tested. Therefore, this trial is being conducted with the aim of improving patient convenience while maintaining efficacy, when the continuous infusion of 5-FU/LV in NAPOLI (nal-IRI/5-FU/LV) regimen are replaced with oral capecitabine. This study is a two-arm, open-label, multicenter, randomized phase 2 trial to assess whether capecitabine plus nal-IRI combination treatment (NaliCap) is non-inferior to NAPOLI regimen in gemcitabine-pretreated patients with advanced pancreatic cancer. Methods: Eligible patients have histologically confirmed pancreatic adenocarcinoma who have failed to gemcitabine-based chemotherapy. This trial is composed of two parts: safety lead-in-part and randomization part. NaliCap regimen consists of administration of capecitabine twice daily for day 1-14 and intravenous administration of nal-IRI for day 1 every 3weeks. To figure out recommended phase 2 dose of the NaliCap combination regimen, the safety lead-in-part is being conducted as a 3+3 design. In the randomization part, patients will be assigned to NAPOLI or NaliCap in a 1:1 ratio. The planned enrollment is 184 patients in the randomization part. Patients allocated to the NaliCap group will receive recommended phase 2 dose of NaliCap determined through the safety lead-in-part. Patients allocated with the NAPOLI group will receive nal-IRI 70mg/m² intravenously day 1, LV 400mg/m² IV day 1, and continuous 5-FU 2400mg/m² infusion over 48hours every 2weeks. Response assessments are performed every 6 weeks using the RECIST criteria version 1.1 (every 2 cycles in the NaliCap group and every 3 cycles in the NAPOLI group). The primary endpoint is progression-free survival, with a non-inferior margin of the hazard ratio of 1.4. Key secondary endpoints are overall response rate, disease control rate, overall survival, safety, and quality of life. This study is prospectively registered at ClinicalTrials.gov, NCT04371224. Clinical trial information: NCT04371224.