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Clinical Trial
. 2018 Jan;118(2):153-161.
doi: 10.1038/bjc.2017.327. Epub 2017 Sep 26.

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

Jeffrey R Infante  1 , Ronald L Korn  2 , Lee S Rosen  3 , Patricia LoRusso  4 , Samuel S Dychter  5 , Joy Zhu  6 , Daniel C Maneval  7 , Ping Jiang  7 , H Michael Shepard  7 , Gregory Frost  8 , Daniel D Von Hoff  9 , Mitesh J Borad  10 , Ramesh K Ramanathan  10
Affiliations
Clinical Trial

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

Jeffrey R Infante et al. Br J Cancer. 2018 Jan.

Erratum in

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 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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
PEGPH20 Plasma Pharmacokinetics and Pharmacodynamics. Mean (±s.e.m.) plasma concentration–time profiles for (A) PEGPH20 and (B) HA in Cycle 1. The majority of patients received PEGPH20 3.0 μg kg−1 twice weekly.
Figure 2
Figure 2
Effects of PEGPH20 on tumours. (A) HA levels in tumour tissue from baseline and post-PEGPH20 treatment (n=6). Decreases in HA levels were observed in five patients. Representative micrographs of HA and H&E (inset) staining demonstrated HA positivity at baseline (left) and 2 days after eight doses of PEGPH20 3 μg kg−1 (right) from one patient (bold line). (B) Median change in tumour perfusion (Ktrans) by DCE-MRI following multiple doses of PEGPH20 (n=11). (C) Change from baseline in plasma HA and tumour metabolic response (percentage of change in SUVmax) at the end of Cycle 1 (n=9); each set of bars represents a single patient. * Indicates patients with PMR by 18F-FDG-PET/CT imaging during treatment (n=6). Remaining patients had progressive (n=2) or stable (n=1) metabolic disease.
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