PEGPH20 as a Potential Breakthrough in Pancreatic Adenocarcinoma

Margaret A. Tempero, MD

Margaret A. Tempero, MD

The upcoming HALO 301 is the first-ever biomarker-driven trial in pancreatic adenocarcinoma, and could potentially change the treatment paradigm for the disease.

In an interview withTargeted Oncology, Margaret A. Tempero, MD, director, Pancreas Center, University of California, San Francisco, discusses the start of enrollment for the HALO 301 trial, the importance of a biomarker-driven trial in pancreatic adenocarcinoma, and how tumor microenvironments play a huge role in the disease.

HALO 301 is a placebo-controlled trial testing if the addition of PEGPH20 to gemcitabine and albumin bound paclitaxel confers an advantage in treatment for patients. The primary endpoint is progression-free survival and the co-primary endpoint is overall survival.

TARGETED ONCOLOGY:Can you give an overview of the HALO study?

Tempero:

I'm excited to talk about PEGPH20, which is a pegylated hyaluronidase. It was developed with the intent of actually making the stroma in pancreatic adenocarcinoma more permeable to agents, such as drugs. In preclinical models, this agent really has an impressive effect on the interstitial fluid pressure in the tumor microenvironment. As that pressure declines, it's clear that more drugs can get in to the part of interest, which is the epithelial component of the tumor.

When all of that knowledge was evolving, it was of tremendous clinical interest to take this into clinical trials for patients with pancreatic adenocarcinoma. Probably the most important finding from the trials to date has been in the HALO 202 trial, in which it was pretty clear, at least in a subset analysis and arguably this was a retrospective subset analysis, so the information has to be taken with some caution, that in the patients who had a high amount of hyaluronidase in their tumors, they seemed to get a very impressive benefit with the addition of PEGPH20.

So these results, while not definitive, are extraordinarily provocative and will really lay the foundation for HALO 301. HALO 301 is a placebo-controlled trial in which we're testing whether the addition of PEGPH20 to gemcitabine and albumin bound paclitaxel confers an advantage in treatment. The primary endpoint is progression free survival with a co-primary endpoint of overall survival. I'm thrilled to be involved with this trial because I think it will be the first, if it's successful and we definitely hope it will be, trial that is a biomarker-driven trial in pancreatic adenocarcinoma. This is going to be a landmark study.

TARGETED ONCOLOGY:What can you share right now about enrollment and when you expect to have a readout?

Tempero:

Enrollment is just started, and I believe abut 17 patients have been screened, and of the ones that have been screened, 3 have been enrolled. So we have a long way to go, but we've identified 200 cites globally who are very excited about participating in this trial, and as with all trials, you start out a little bit slow and then the enrollment kicks up over time. So I think we should complete enrollment within 2 years if not earlier than that, and I'm going to do my very best to encourage clinicians to participate in the trial and patients to participate in the trial.

TARGETED ONCOLOGY:So this being the first biomarker-driven trial, what do you think are some of the challenges with biomarker development in this field?

Tempero:

For one thing, we don't have very many effective therapies, and this is not a cancer that has been amenable to many of the targeted agents that we use so nicely in other diseases. This is a RAS-driven tumor, and when RAS is in charge, there's not much else that can get in the way. We don't have an agent that can target RAS.

So that's one issue, and the other issue is the fact that tissue is very scarce in this disease. I'm very excited now that we have other ways of looking at DNA, such as circulating cell-free DNA, that we might be able to get a lot more information. There probably are a small subset, we think it's around 7% or less, that have actionable mutations such as a DNA repair defect that we can do something about with some of the exciting agents that are so easily used in other diseases.

TARGETED ONCOLOGY:What do you envision the treatment paradigm looking like within the next 10 years?

Tempero:

Tempero: I hope that we're going to figure out how to reprogram the immunobiology in the tumor microenvironment. Right now it's a very tumor-supporting environment, and we need to change that to a tumor-inhibiting environment. We firmly believe that if we can get CD8 T cells into the tumor microenvironment, and then use checkpoint inhibitors, we think that we can get the same type of immune response that is being seen in so many other cancers right now.

So a lot of emphasis is on that very strategy. PEGPH20, by the way, may be an important part of that strategy, because we know from pre-clinical studies that when you address the tumor microenvironment with PEGPH20, you are making changes in the infiltrating immune cells. So we're trying to learn more about that so we can build on that information and really take advantage of some of these new agents that are available.