Background: Patients (pts) with pancreatic cancer suffer from multiple symptoms related to the tumor itself or induced by chemotherapy (ctx). The available supportive therapy is still not able to relief all symptoms caused by the cancer itself or by the antineoplastic therapy. Additionally, anorexia and weight loss often result in increased morbidity and mortality in this population as well as in psycho-social burden and suffering. These are unmet needs in pancreatic cancer pts. Dronabinol has shown beneficial effects observed in cancer pts. However, evidence from randomized, placebo controlled trials in the use of cannabinoids for the treatment of cancer related anorexia-cachexia syndrome are lacking. Aim of this phase III trial is to investigate the efficacy and safety of dronabinol (orally administered tetrahydrocannabinol (THC)) as adjuvant, individually titrated therapy to first-line standard chemotherapy in pts with metastatic pancreas cancer for improvement of ctx- and tumor-related symptoms. Methods: Locally advanced or metastatic pancreas cancer pts from Austria and Germany with age of ≥18 yrs tolerating FOLFIRINOX or gemcitabine/nab-paclitaxel based ctx are eligible for enrolment. Exclusion criteria are use of dronabinol, cannabis-based medicine with THC or marihuana or relevant psychiatric disorders. The study duration for each patient will be a maximum of 18 wks treatment. Eligible pts are randomized 1:1 for treatment with dronabinol oral solution (2.5%) or placebo oral solution stratified by underlying ctx. The primary endpoint variable is the standardized area under the curve of the EORTC QLQ-C30 symptom summary score over the on-treatment period. Secondary endpoints include: other quality of life parameters, changes in Glasgow Prognostic Score, mean time to critical weight-loss (5%), ctx dose intensity over the treatment of 18 wks, adverse events/reactions, PFS and OS. Changes from baseline for bioelectrical impedance analysis parameters (e.g. fat-free mass, total body water, fat mass and phase angle) and handgrip strength will be evaluated. Estimating a difference of 20% in the primary endpoint between the treatment groups with a power of 80% and an expected standard deviation of 30 a total sample size of 74 assuming a balanced design is required. A total sample size of 104 pts is needed with expected drop-out rate of 30 pts. Enrolment started in 2019 and continues until 2024. The DIsCOvER trial is the first randomized, placebo-controlled phase III trial that investigates the impact of individually dosed dronabinol in cancer pts (Registration: NCT03984214). Clinical trial information: NCT03984214.