@article{a6320cd3d3524277b4b6aa806737b712,
title = "Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours",
abstract = "Background:Hyaluronan accumulation in tumour stroma is associated with reduced survival in preclinical cancer models. PEGPH20 degrades hyaluronan to facilitate tumour access for cancer therapies. Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours.Methods:In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 μg kg -1) or once every 3 weeks (0.5-1.5 μg kg -1). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0 μg kg -1), with dexamethasone predose and postdose.Results:Dose-limiting toxicities included grade 3/43 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0 μg kg -1 twice weekly. Plasma hyaluronan increased in a dose-dependent manner, achieving steady state by Day 8 in multidose studies. A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies. Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity, consistent with observations in animal models.Conclusions:The tumour stroma has emerging importance in the development of cancer therapeutics. PEGPH20 3.0 μg kg -1 administered twice weekly is feasible in patients with advanced cancers; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours.",
author = "Infante, {Jeffrey R.} and Korn, {Ronald L.} and Rosen, {Lee S.} and Patricia Lorusso and Dychter, {Samuel S.} and Joy Zhu and Maneval, {Daniel C.} and Ping Jiang and Shepard, {H. Michael} and Gregory Frost and {Von Hoff}, {Daniel D.} and Borad, {Mitesh J.} and Ramanathan, {Ramesh K.}",
note = "Funding Information: JRI reports that his institution has received research funding from Halozyme Therapeutics, Inc. RLK reports being a shareholder of Imaging Endpoints Core Lab. DDVH reports receiving a research grant to his institution from Halozyme Therapeutics, Inc. and is a consultant for Imaging Endpoints. LSR reports receiving a research grant to his institution from Halozyme Therapeutics, Inc. for the conduct of these clinical trials. PLR is currently on the DSMC for the pivotal phase 3 clinical trial of PEGPH20 in pancreatic cancer, sponsored by Halozyme Therapeutics, Inc., SSD is a shareholder of stock at Halozyme Therapeutics, Inc. and full-time employee at Fate Therapeutics. SSD, JZ, and GF were employees of Halozyme Therapeutics, Inc. at the time this trial was conducted. GF is a shareholder of stock at Halozyme Therapeutics, Inc. DCM, PJ, and HMS were employees of Halozyme Therapeutics, Inc. at the time this manuscript was submitted. RKR reports receiving research funding from Merrimack Pharmaceuticals. The other authors declare no conflict of interest. Funding Information: We thank the PEGPH20 team at Halozyme Therapeutics, Inc. for providing the experimental agent and recognise Marie Printz, Barry Sugarman, and Paneer Selvam for the development of plasma-based assays for analysis of PEGPH20 and HA. We also thank Dr David Z. D{\textquoteright}Argenio for discussions and pharmacokinetic modeling expertise. Additionally, we thank Dr Patrick O{\textquoteright}Connor and Dr Terrance Rugg for their assistance with drafting and reviewing regulatory documents related to these trials. Financial support for medical editorial assistance was provided by Halozyme Therapeutics, Inc. We thank William Sinkins, PhD, for his medical editorial assistance with this manuscript.",
year = "2018",
month = jan,
day = "1",
doi = "10.1038/bjc.2017.327",
language = "English (US)",
volume = "118",
pages = "153--161",
journal = "British journal of cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "2",
}