e16239 Background: In pancreatic ductal adenocarcinoma (PDAC) desmoplasia is a central feature of the tumor microenvironment. By targeting both tumor cells and tumor stoma, treatment efficacy can be increased. LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy in PDAC patients. Methods: The objective of phase I of the study was to established the maximum tolerated dose (MTD) of LDE225 co-administered with gemcitabine and nab-paclitaxel (ESMO 2017). The objective of phase II was to evaluate efficacy and safety of the treatment combination after prior fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX; ESMO 2019). Tumor response evaluation was performed using CT scan. Tumor microenvironment was assessed with functional MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast enhanced (DCE) MRI. Also, the predictive value of IVIM-DWI and DCE MRI parameters on overall survival (OS) using ROC curves was determined. Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 of a 4-week cycle. We combined the outcomes of the five patients of phase I that received 200mg LDE225 and had prior treatment with FOLFIRINOX (n = 25 patients in total) in phase II. Most patients had WHO performance status of 0-1 (93%) and 57% were male. Patients were treated with a median number of two cycles (IQR 2-6). Six therapy related grade 4 adverse events (AE) were observed: sepsis (2), neutropenia (2), elevated gamma GT (1) and thromboembolic event (1), and three grade 5 (sepsis, pneumonia and progressive disease). Most common grade 3 therapy related AEs were neutropenia (37%) and diarrhea (14.8%). Patients discontinued treatment because of progressive disease (22), bacterial infection (1), sepsis (1) and diminished quality of life (1). In 24 patients target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%) and 7 patients had progressive disease (29%). The median OS was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction can predict OS ( > 222 days) with 80% sensitivity and 85% specificity. Conclusions: This study shows that LDE225 in combination with gemcitabine and nab-paclitaxel is well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Functional MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline perfusion. Clinical trial information: NCT02358161.