Background: Pancreatic cancer (PC) is the 3^rd deadliest cancer in the United State surpassing breast cancer in 2016, with the overall survival rate of - 9% for those newly diagnosed individuals. The notorious disease is set to become the 2^nd leading cause of death from cancer by 2020 in US (National Cancer Institute, NIH). FOLFIRINOX regimen is one of the standard 1^st-line treatments for PC patients with good performance status; however, there is currently no standard of care in 2^nd-line therapy after FOLFIRINOX failure. EndoTAG-1 is a novel formulation of cationic liposomes embedded with Paclitaxel, which specifically displays antivascular and antiangiogenic activities. By binding and internalizing at tumor endothelial cells after intravenous administration, the cytostatic activity of paclitaxel will be targeted to the activated tumor endothelial cells. Methods: Eligible patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FILFIRINOX treatment will be screened and randomized (1:1) into one of the two arms in the study (n=218). The primary endpoint of the study is overall survival (OS), with secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and quality of life (QoL). Arm A: EndoTAG-1 plus Gemcitabine: Patients will receive intravenous injection with EndoTAG-1 (22 mg/m²) twice weekly plus gemcitabine (1,000 mg/m²) once weekly for consecutively 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. Arm B: Gemcitabine: Patients will receive gemcitabine (1,000 mg/m²) once weekly for consecutive 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. The phase III trial began enrollment since November 2018. The trial will continue as planned from the last review in January 2020. Clinical trial information: NCT03126435.