Background: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest form of cancer with a 5-year survival of less than 5% for patients with metastatic disease. Despite improvements over the past years, with the introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel, the majority has disease progression within 6 months after start of first line treatment. The NAPOLI trial was the first phase III study showing that patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy benefitted from second line treatment. Patients received liposomal irinotecan (nal-IRI) either as a single agent or in combination with 5-fluorouracil/leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with both nal-IRI and 5-FU/LV experienced a median overall survival (mOS) of 6.1 months versus 4.2 months for the 5-FU/LV group. Recently, two Japanese studies (GEST and JASPAC 01) reported on the use of S-1 in patients with PDAC. In patients with locally advanced or metastatic PDAC, S-1 was non-inferior compared to gemcitabine in terms of mOS (8.8 months for gemcitabine versus 9.7 months for S-1). In the adjuvant setting, S-1 showed superior mOS compared to gemcitabine, 46.5 and 25.5 months respectively, HR for mortality of S-1 compared with gemcitabine was 0.57 (95% CI 0.44–0.72). In view of these results, the objective of this NAPAN study is to compare the progression free survival (PFS) of nal-IRI plus S-1, with nal-IRI plus 5-FU/LV in a Western study population for second line treatment of PDAC. Methods: This is a multi-center, open label, randomized phase II trial. Patients ≥ 18 years of age with histologically or cytologically confirmed PDAC, previously treated with gemcitabine (-based) therapy, or progression within 6 months of adjuvant gemcitabine-based treatment are eligible. After a safety run-in of the nal-IRI plus S-1 regimen, patients will be randomized between nal-IRI plus S-1 and nal-IRI plus 5-FU/LV. Primary endpoint of the run-in phase is to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of nal-IRI when co-administered with fixed dose S-1. The primary endpoint of the phase II part is to determine the efficacy of the treatment arms in terms of PFS. Secondary endpoints include OS, response rate according to RECIST 1.1, adverse events according to CTC version 5.0 and Quality of life. Until now 2 of the planned 120 patients have been enrolled. Clinical trial information: NCT03986294.