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Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours
Jeffrey R Infante1, Ronald L Korn2, Lee S Rosen3
1Early Development Oncology, Janssen Research & Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
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.
Insights
PEGPH20 degrades tumor hyaluronan, enhancing cancer therapy access. This study found PEGPH20 feasible in advanced cancers, showing preliminary anti-tumor activity and supporting further evaluation.
Area of Science:
- Oncology
- Pharmacology
- Tumor Microenvironment
Background:
- Hyaluronan accumulation in tumor stroma correlates with poor prognosis in preclinical cancer models.
- PEGPH20 is an investigational enzyme designed to degrade hyaluronan, potentially improving drug delivery to tumors.
- The study aimed to evaluate the safety and preliminary anti-tumor effects of PEGPH20 in patients with advanced solid tumors.
Purpose of the Study:
- To assess the safety profile of PEGPH20 in patients with advanced solid tumors.
- To evaluate the preliminary anti-tumor activity of PEGPH20.
- To determine the maximum tolerated dose (MTD) of PEGPH20.
Main Methods:
- Two clinical trials (HALO-109-101 and HALO-109-102) involving patients with advanced solid tumors.
- Intravenous administration of PEGPH20 at various doses and schedules.
- Dexamethasone co-administration in HALO-109-102.
- Assessment of dose-limiting toxicities, plasma and tumor hyaluronan levels, and exploratory imaging.
Main Results:
- The maximum tolerated dose of PEGPH20 was determined to be 3.0 μg/kg twice weekly, with dose-limiting toxicities including myalgia, arthralgia, and muscle spasms.
- PEGPH20 administration led to a dose-dependent increase in plasma hyaluronan.
- A reduction in tumor hyaluronan levels was observed in most patients with available biopsies, alongside changes in tumor perfusion and metabolic activity.
Conclusions:
- PEGPH20 at 3.0 μg/kg twice weekly is a feasible regimen for patients with advanced cancers.
- Exploratory analyses suggest potential anti-tumor activity, supporting further clinical investigation of PEGPH20 in solid tumors.
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