Pegylated Recombinant Human Hyaluronidase Ph20 (Pegph20) Enhances Nab-Paclitaxel Plus Gemcitabine Efficacy In Human Pancreatic Cancer Xenografts

Hyaluronan (HA) over-accumulation in the extracellular matrix (ECM) of many solid tumors is associated with tumor progression and poor prognosis. Accordingly, an HA-degrading enzyme, PEGPH20, is being developed to deplete tumor-associated HA in the ECM. In preclinical animal models, enzymatic removal of ECM HA with PEGPH20 is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. As pancreatic ductal adenocarcinoma (PDA) has been identified as a cancer type that accumulates high levels of HA, and the combination of albumin-bound paclitaxel (nab-paclitaxel, NAB) and gemcitabine (GEM) has been shown to improve survival in patients with metastatic pancreatic cancer (Von Hoff 2013), preclinical studies were conducted using human PDA xenograft models to investigate whether PEGPH20 enhanced the anti-tumor activity of NAB and GEM. In brief, nude mice were inoculated with human BxPC3 PDA cells, or with HA-high BxPC3/HAS3 cells, a cell line engineered to over-express HA, adjacent to the right tibial periosteum. Tumor growth was monitored via ultrasonography. When tumors reached ~350 mm 3 , mice were staged into 8 treatment groups: (1) vehicle control; (2) PEGPH20 alone, 4.5 mg/kg; (3) NAB alone, 10 mg/kg; (4) GEM alone, 180 mg/kg; (5) NAB plus PEGPH20; (6) GEM plus PEGPH20; (7) NAB plus GEM; and (8) NAB plus GEM plus PEGPH20. Vehicle, PEGPH20 and/or NAB was administered intravenously starting on study day 0, and then dosed twice weekly for four weeks. GEM was administered intraperitoneally starting on study day 1 and then dosed weekly for three weeks. Histology of tumors confirmed HA removal in all PEGPH20 treated groups. In the parental BxPC3 model, the addition of PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 15% (81% vs. 66%, respectively) and extended median survival time (MST) by u003e31% (68d vs. 52d, respectively); whereas in the HA-high BxPC3/HAS3 model, PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 34% (104% vs. 70%) and extended MST by u003e125% (72d vs. 32d, respectively). As Jacobetz et al. (2013) have shown that PEGPH20 treatment increases the intratumoral delivery of GEM in genetically engineered mouse PDA models; we evaluated whether PEGPH20 also improves intratumoral accumulation of paclitaxel in the BxPC3/HAS3 model vs. NAB alone. The co-administration of PEGPH20 with NAB increased intratumoral paclitaxel accumulation by u003e43% one hour following a single administration. Further, PEGPH20 enhanced NAB plus GEM mediated reduction in the PDA serum biomarkers CA19-9 and CEA in both models. As KRAS mutations occur in 90% of non neuro-endocrine pancreatic tumors (Thomas 2007), and BxPC3 cells are KRAS WT, we repeated these studies in KRAS mutant/HA-low AsPC1 xenografts, and engineered KRAS mutant/HA-high AsPC1/HAS3 PDA xenografts. Mice were inoculated and tumor growth was monitored as described above. Animals were then staged into 8 groups and then dosed when tumors reached ~350 mm 3 . The PEGPH20 dose in these studies was reduced to 37.5 μg/kg to approximate dosing in ongoing clinical trials (NCT01839487). As predicted by tumor HA level, the addition of PEGPH20 did not increase the anti-tumor efficacy or survival in the HA-low parental AsPC1 model. In the HA-high AsPC1/HAS3 model, the addition of PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 25% (78% vs. 53%, respectively) and extended MST by u003e31% (74d vs. 48d, respectively). Taken together, the data suggest that PEGPH20-mediated HA removal significantly increases the anti-tumor efficacy of NAB plus GEM in HA-high mouse models of PDA. Clinical trials are currently ongoing to evaluate PEGPH20 plus NAB plus GEM in stage IV patients with metastatic pancreatic cancer (NCT01839487). Citation Format: Ryan J. Osgood, James F. Skipper, Jessica A. Cowell, Yanling Chen, Li Zhu, Michael E. Bledsoe, Susan J. Zimmerman, David W. Kang, H. Michael Shepard, Daniel C. Maneval, Curtis B. Thompson. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances nab-paclitaxel plus gemcitabine efficacy in human pancreatic cancer xenografts. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B86.