300 Background: PEGPH20 (PEG), a PEGylated recombinant human hyaluronidase, has anti-tumor activity as a single agent and in combination with chemotherapy in preclinical models. A Phase 1b study of PEG + Gem (P+G) in patients (pts) with advanced PDA showed good anti-tumor activity, particularly in pts with HA^high tumors (ECCO 2013). In this study, we investigated pharmacodynamic (PD) markers including plasma(soluble) HA (sHA), dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and ¹⁸Fluorodeoxyglucose positron emission tomography (PET/CT) to explore additional correlates for PEG activity. Methods: 28 pts with stage IV PDA were treated with PEG at 1, 1.6, or 3µg/kg IV twice weekly for Wks 1-4 and Wks 5-7, followed by 1 wk rest, plus Gem at 1000 mg/m2 IV once weekly for Wks 1-7, then 1 wk rest. Thereafter, P+G was given once weekly for 3 wks in 4-wk cycles. Serial plasma samples were collected and analyzed in a quantitative assay for PEG and sHA. Exploratory imaging by DCE-MRI was performed on selection pts at baseline, 8hr, 24hr and end of cycle 1, PET/CT was performed at baseline and at the end of each cycle. Results: PEG pharmacokinetics was well-characterized by a 2-compartment PK model, peak plasma concentration increased in a dose-proportional manner after a single or repeat administration of PEG. Dose- and time-dependent increases in sHA were observed within 2-3 days after 1.0, 1.6, or 3.0 µg/kg of PEG administration. The median peak concentrations were 3,736; 48,150; and 74,950ng/mL, respectively, and increased with increasing doses. sHA reached steady state approximately 1 wk after repeated PEG administration, consistent with the expected hyaluronidase activity of PEG. Exploratory analysis with DCE-MRI from 6 pts showed an early increase (24hrs) in tumor perfusion (Ktrans) in target lesions. PET/CT from 5 pts showed an average reduction in the maximum standardized uptake value (SUVmax) of 37% at EOC1, and partial metabolic responses using EORTC criteria were achieved in 4 of 5 pts. These results suggest that P+G has measurable biological activity in metastatic PDA Conclusions: Plasma sHA concentration, DCE-MRI and PET/CT are PD markers for evaluation of P+G activity.