Abstract 4955: Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients. (2013)

Abstract Pegylated recombinant human hyaluronidase PH20 (PEGPH20) is an investigational therapeutic agent under clinical development for use alone or in combination with other cancer therapies for the treatment of patients with non-hematologic malignancies that may accumulate hyaluronan (HA), a glycosaminoglycan that is a significant component of the extracellular matrix of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, decreases tumor interstitial pressure, increases vascular area, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. As dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a clinically translatable MRI perfusion protocol, we used DCE-MRI imaging to evaluate the effects of PEGPH20 treatment on tumor vascular permeability, vascular surface area and/or blood flow. In mice, prostate cancer PC3 cells were implanted adjacent to the right tibial periosteum. When tumors reached ∼500 mg, animals were staged into vehicle or PEGPH20 (4.5 mg/kg) treatment groups. Utilizing gadopentetate dimeglumine (Gd-DTPA) as a contrast agent, pre-treatment baseline DCE scans of the tumors were acquired. Animals were subsequently IV dosed with test article and post-treatment scans were acquired at 24 h. Initial area under the curve (IAUC) and Ktrans were calculated voxel-by-voxel using a 2-compartment PK model. Although vehicle alone did not increase or decrease Ktrans or IAUC, PEGPH20 treatment increased Ktrans (1/sec) and IAUC (mmol.s) by 74% and 78.7%, respectively. Concurrent to preclinical studies, DCE-MRI imaging was conducted pre- and post- PEGPH20 in 9 patients in a Phase 1 dose-escalation, safety, tolerability, PK/PD study of PEGPH20 treatment in patients with advanced solid tumors. Patients were treated with 1.6, 3 or 5 μg/kg PEGPH20 1-2/weekly. Baseline, day 1, day 2-5 and end-of-cycle (EOC) scans were acquired (w/ Gd-DTPA) in 3 patients. Images were fit on a pixel-by-pixel basis to a 2-compartment, 3-parameter, PK model and Ktrans and extracellular volume (Ve) calculated. Results suggest an early and rapid increase in tumor perfusion in target lesions, compared to baseline (mean ΔKtrans = 428%; N=3; Day 2-5 scans), as well as an expansion of the extracellular space with a reduction of these parameters towards baseline by EOC (mean ΔKtrans = 28% above baseline). Taken together, these studies suggest that PEGPH20 increases vessel permeability, blood flow and/or vessel surface area in HA-rich solid tumors. Additional preclinical and clinical studies, complete with DCE-MRI imaging, are ongoing to further evaluate PEGPH20 in the treatment HA-rich malignancies. Citation Format: Curtis B. Thompson, Patrick McConville, Ron Korn, Jenifer Baranski, Meridith Baugher, Deanne Lister, Erin Trachet, Jacob Y. Hesterman, Jack Hoppin, Joy Zhu, Daniel C. Maneval. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4955. doi:10.1158/1538-7445.AM2013-4955