Portal de Periódicos da CAPES

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

2017; Springer Nature; Volume: 118; Issue: 2 Linguagem: Inglês

10.1038/bjc.2017.327

1532-1827

Jeffrey R. Infante, Ronald L. Korn, Lee S. Rosen, Patricia LoRusso, Samuel S. Dychter, Joy Zhu, Daniel C. Maneval, Ping Jiang, H. Michael Shepard, G. J. Frost, Daniel D. Von Hoff, Mitesh J. Borad, Ramesh K. Ramanathan,

Glycosylation and Glycoproteins Research

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. 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. Dose-limiting toxicities included grade ⩾3 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. 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.