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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??g?kg-1) or once every 3 weeks (0.5-1.5??g?kg-1). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0??g?kg-1), with dexamethasone predose and postdose. RESULTS:Dose-limiting toxicities included grade ?3 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0??g?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??g?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.

SUBMITTER: Infante JR 

PROVIDER: S-EPMC5785735 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours.

Infante Jeffrey R JR   Korn Ronald L RL   Rosen Lee S LS   LoRusso Patricia P   Dychter Samuel S SS   Zhu Joy J   Maneval Daniel C DC   Jiang Ping P   Shepard H Michael HM   Frost Gregory G   Von Hoff Daniel D DD   Borad Mitesh J MJ   Ramanathan Ramesh K RK  

British journal of cancer 20170926 2


<h4>Background</h4>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.<h4>Methods</h4>In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 μg kg<sup>-1</sup>) or once every 3 weeks (0.5-1.5 μg kg<sup>-1</sup>). In  ...[more]

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