Perioperative stromal depletion by PEGPH20 in pancreatic ductal adenocarcinoma.

Abstract

TPS476 Background: Treatment with PEGylated recombinant human hyaluronidase (PEGPH20) depletes stromal HA in pancreatic tumors, resulting in increased intratumoral perfusion and improved drug delivery. This Phase 2 study evaluates the clinical, biologic, and radiographic effects of neoadjuvant PEGPH20, gemcitabine (GEM) and nab-paclitaxel (NAB) in patients (pts) with borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods: Therapy-naïve patients aged ≥ 18 years with histologically confirmed PDAC defined as borderline resectable by consensus national guidelines will be eligible. Pts must have ECOG PS of 0-1 and adequate renal, marrow and hepatic function. Co-primary endpoints include incidence of postoperative pancreatic fistula and pathologic complete response rate. The trial uses a 2-stage design. In Part 1 (n = 15), pretreatment endoscopic ultrasound-guided core biopsies and functional MRI (fMRI) will be obtained. After a 1-week run-in with PEGPH20 (3μg/kg on Days [D]1 and 4), pts will undergo repeat biopsy and fMRI. Pts will then receive PEGPH20 (3μg/kg), NAB (125 mg/m2) and GEM (1000mg/m2) on D1, 8 and 15 of a 28-day cycle. Enoxaparin (1mg/kg daily) and dexamethasone (8mg pre- and post- PEGPH20) will be administered prophylactically. CA 19-9 levels will be checked monthly. Restaging CT will be obtained at the end of Cycles 2 and 4, with repeat fMRI performed after Cycle 4. Pts who are judged to be appropriate operative candidates upon multidisciplinary tumor board review will go to surgery at that point. Tissue analyses will be performed on the serially collected tumor samples, including the resected pancreatic specimen, with a focus on HA expression and immune cell infiltrates. Upon recovery, pts will receive 2 adjuvant cycles of GEM and NAB. If the predefined safety threshold is met in Part 1, an additional 21 pts will be enrolled in Part 2, without the one-week PEGPH20 run-in or pre- and post-run-in biopsies. Assuming 25 of the 36 pts are evaluable (i.e., able to go to surgery), a post-operative fistula rate of 11% would be able to be estimated with 95% CI of 3.4%-23.1%. Study initiation has begun as of September 2015. Clinical Trial Information: NCT02487277 Clinical trial information: NCT02487277.