Background: Even as the number of targeted agents increases, therapeutic options for PDAC patients remain limited by a lack of biomarkers that can predict the potential clinical benefit of single agents or combination therapeutic strategies. To address this challenge, we implemented the WOO-M trial to serve as a highly adaptable, biomarker discovery platform that enables a preliminary assessment of biological activity of one or more targeted agents in patients with metastatic (m) PDAC. By using paired pre- and on-treatment biopsies, we can assess the independent biological impact of targeted agent(s) that perturb key signaling pathways predicted to drive PDAC tumorigenesis and resistance to therapy in order to identify new combination therapy strategies. Methods: WOO-M is a multi-arm early phase I trial platform to obtain longitudinal tumor samples to assess the pharmacodynamic (PD) effects of one or more study agent(s) alone or in combination in patients with mPDAC. The trial uses a Master Protocol to describe overarching design and logistics, and sub-protocols separately describe each study arm with different agent(s) – alone or in combination. Participants are alternatingly assigned to an available study arm (max. 20 participants per arm). There are no limits to the number of prior therapies. Participants undergo a baseline tumor biopsy, then receive their assigned study agent(s) for a specified timeframe (not exceeding 30 days), and then undergo a repeat tumor biopsy before proceeding to receive therapy per standard of care or clinical trials. The paired biopsy material from each patient is analyzed using multiplex assays that provides spatially-resolved, single-cell strategies to assess the effects of targeted therapies on tumor cell state and heterogeneity. The primary study objective is to independently assess the PD feasibility of detecting a measurable change in tumor biology at post-treatment from baseline for participants within a study arm. WOO-M uses a 2-stage Bayesian efficacy monitoring approach with a futility-stopping rule for each study arm. In stage 1, if 6 or more of the first 10 participants of a study arm have a detectable change in tumor biology measurements post-treatment from baseline, then the study arm may enroll up to an additional 10 participants. A study arm stops enrolling if 5 or fewer of the first 10 participants do not have a measurable change in tumor biology. To date, 4 study arms are being evaluated: 1) poly (ADP-ribose) polymerase inhibitor (PARPi), olaparib (300 mg PO BID for 10 days), 2) MEK inhibitor (MEKi), cobimetinib (60 mg PO QD for 10 days), 3) ERK inhibitor, LY3214996 (400 mg PO QD for 10 days), and 4) PLK1 inhibitor, onvansertib (12 mg/m² PO QD for 10 days). Of 21 participants enrolled and treated to date, 8 received cobimetinib, and 13 received olaparib. Additional arms are in the process of opening at time of submission. Clinical trial information: NCT04005690