PEGPH20 (pegvorhyaluronidase alfa), a novel formulation of a naturally occurring enzyme, is being investigated as a biomarker-driven treatment for patients with advanced pancreatic cancer.
Researchers are testing the drug, a PEGylated recombinant human hyaluronidase enzyme, in combination with standard-of-care gemcitabine and nab-paclitaxel (Abraxane) in patients with stage IV treatment-naïve pancreatic cancer whose tumors express high levels of hyaluronan (HA). PEGPH20 degrades HA, a carbohydrate that can build up in the tumor microenvironment and block the delivery of anticancer therapies.
The phase III, randomized, multicenter HALO-301 trial seeks to recruit 420 patients with advanced, metastatic pancreatic ductal adenocarcinoma, including patients with disease progression that occurs following resection 6 months or longer after their last therapy (NCT02715804).
“This is a biomarker-stratified trial because we learned from retrospective analyses that the patients who benefit most from this enzymatic strategy to degrade HA are those with the highest levels of HA in their tumors,” said Sunil R. Hingorani, MD, PhD, director of the Center for Accelerated Translation in Pancreas Cancer at the Fred Hutchinson Cancer Research Center in Seattle and a professor at the University of Washington School of Medicine.
The rationale for the HALO-301 trial was established in the phase II HALO- 202 study, which randomized 279 and treated 260 patients to PEGPH20 combined with gemcitabine and nab-paclitaxel versus the chemotherapy agents alone.
The median progression-free survival (PFS) difference in the 2 regimens was modest but statistically significant in favor of the PEGPH20 treatment arm (6.0 vs 5.3 months, respectively). In patients with HA-high tumors (n = 84), the median PFS benefit was significantly higher in the PEGPH20 arm at 9.2 months, compared with 5.2 months with chemotherapy alone.1
One of the main adverse effects (AEs) associated with PEGPH20 is the increased risk of thromboembolic and clotting events. In the HALO-202 study, the thromboembolic event rate was 43% in the PEGPH20 arm, compared with 25% in the chemotherapy arm.1
Other significant AEs of any grade in the PEGPH20 arm included peripheral edema (63%), muscle spasms (56%), neutropenia (34%), and myalgia (26%). Febrile neutropenia was rare and did not differ between the 2 arms.1
Although PEGPH20 has shown efficacy in this patient population, the HALO-301 trial will determine whether it is a feasible treatment option in combination with gemcitabine and nab-paclitaxel in the firstline metastatic setting.
Eligible patients will be randomized 2:1 to be treated with either PEGPH20 plus standard-of-care gemcitabine and nab-paclitaxel or the chemotherapeutic agents alone with a placebo. Investigators will be looking at PFS and overall survival as the primary endpoints, with overall response rate, duration of response, and safety as secondary endpoints.
The Ventana HA CDx Assay, a companion diagnostic developed by Ventana Medical Systems, will be used to conduct HA testing. The test is a recombinant HA binding probe designed to be used with the Ventana OptiView DAB IHC Detection Kit on formalin-fixed, paraffin-embedded pancreatic tumor samples.2
The assay was tested for its interreader precision by 3 pathologists who evaluated 100 tumor samples with varied HA expression levels. The evaluation showed agreement rates greater than 94%, which investigators said demonstrated the assay’s “high robustness and reproducibility.”2
All prospective participants will be tested for HA levels in their tumors. HA-high tumors are defined as having HA staining on greater than 50% of the tumor surface in the extracellular matrix; those with low levels (<50%) will be excluded. Additionally, participants must have an ECOG performance status of 0 or 1, as well as no evidence of deep vein thrombosis, pulmonary embolism, or any other known thromboembolic event.
WHO IS ELIGIBLE?
1. Hingorani SR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA). J Clin Oncol. 2017;35(suppl; abstr 4008). http://meetinglibrary.asco.org/record/ 144526/abstract.
2. Khelifa S, Pu J, Aldrich C, et al. Development of a companion diagnostic assay for tissue hyaluronan detection and treatment with PEGPH20 in metastatic pancreatic ductal adenocarcinoma patients. J Clin Oncol. 2016;34 (suppl; abstr e15749). http://meetinglibrary.asco. org/record/127997/abstract.