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Novel Agents in Pancreatic Cancer

Insights From:Philip A. Philip, MD, Karmanos Cancer Center; Tanios Bekaii-Saab, MD, Mayo Clinic
Published: Wednesday, Sep 07, 2016


Transcript:

Tanios Bekaii-Saab, MD:
The PEGPH20 is an agent that essentially modifies the desmoplastic reaction on the tumor as it breaks through it in simple ways. And the thought is that if you break down that barrier, you will be able to enhance drug delivery. The reason why these tumors are hypovascular is because of the dense desmoplastic reaction around the tumor. So, if you actually break down that barrier, those vessels will pop up, will open up, and then you will get better delivery of chemotherapy, immune cells, and other healthy cells. The question is, at least in the first clinical trials, did PEGPH20 show any signs of promise? When you look at the unselected patient population, meaning that across the board everyone gets treated, there’s no improvement in outcome. However, when you go down to select those patients who express HA, hyaluronic acid at higher levels, those are the patients that seem to derive benefit from an approach that targets specifically that enzyme, or that protein.

At this point of time, at least from the early clinical work in patients whose tumor expressed with high levels of hyaluronic acid, PEGPH20 is added to standard chemotherapy, so gemcitabine/nab-paclitaxel. There is another study with FOLFIRINOX plus PEGPH20 that will hopefully show some benefit. The larger study is the one that’s selecting for patients—it started activating and selecting patients a couple months ago—and that study selects for the high levels of HA, and the agent PEGPH20 is combined to gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone. That’s a very interesting study, because it essentially selects those patients who are more likely to respond. So, hopefully, given the early promise of the early clinical results, this will hold on as we move forward in a large prospective manner.

Philip A. Philip, MD: JAK/STAT pathway is well known in hematological disorders. That has been targeted by certain drugs and the most well-known is ruxolitinib. And if we go back to that pathway, it’s also where the cytokines are working. The cytokines in some patients are released systemically, and they also contribute to the systemic effects of cancer. Pancreas cancer patients, they can get a lot of fatigue, weight loss, even fever, and other features like elevated white cell count and low albumin, which are features of having an infection. Sometimes they can be mistaken for an infection. So, there was a good thought behind bringing in ruxolitinib as a drug to be used in patients with pancreatic cancer. It may have an anticancer effect, but it can also support the patients by minimizing those symptoms. And the use of ruxolitinib, in some hematologic disorders, really gets a rapid symptomatic improvement. There was a pilot clinical trial to look into ruxolitinib when it was added to capecitabine in the second-line setting—so patients who failed frontline therapy, mainly gemcitabine-based treatment. That trial was interesting, because it showed benefit to patients who have elevated C-reactive protein. C-reactive protein is a measure of the systemic inflammatory immune status, which biologically made sense. Patients also gained weight on it, so it was really interesting. That went into a phase III trial, trying to look in a larger number of patients. That trial was stopped because there was no benefit seen with the drug. So, the JAK/STAT pathway is, now, not a strategy that is being pursued by anybody.

Tanios Bekaii-Saab, MD: Necuparanib is an agent that, essentially, is a heparinoid. It was built on the platform of low-molecular weight heparin to lose its anticoagulant activity, or most of it, and enhance its anticancer activity. Because, we’ve always known that low-molecular weight heparins have some baseline activity against cancer. The phase I study presented at ASCO in combination with gemcitabine plus nab-paclitaxel, and the earlier study with gemcitabine alone, showed some interesting results. The larger phase II randomized study with gemcitabine/nab-paclitaxel, plus/minus necuparanib, is on track to be completed in the fall. Therefore, we will have some preliminary results about this strategy added to chemotherapy versus chemotherapy alone, and whether it’s worthwhile to move to the phase III setting. But, again, if some of those earlier results hold on, there hopefully will be a path moving forward with this agent in pancreas cancer.

Transcript Edited for Clarity
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Transcript:

Tanios Bekaii-Saab, MD:
The PEGPH20 is an agent that essentially modifies the desmoplastic reaction on the tumor as it breaks through it in simple ways. And the thought is that if you break down that barrier, you will be able to enhance drug delivery. The reason why these tumors are hypovascular is because of the dense desmoplastic reaction around the tumor. So, if you actually break down that barrier, those vessels will pop up, will open up, and then you will get better delivery of chemotherapy, immune cells, and other healthy cells. The question is, at least in the first clinical trials, did PEGPH20 show any signs of promise? When you look at the unselected patient population, meaning that across the board everyone gets treated, there’s no improvement in outcome. However, when you go down to select those patients who express HA, hyaluronic acid at higher levels, those are the patients that seem to derive benefit from an approach that targets specifically that enzyme, or that protein.

At this point of time, at least from the early clinical work in patients whose tumor expressed with high levels of hyaluronic acid, PEGPH20 is added to standard chemotherapy, so gemcitabine/nab-paclitaxel. There is another study with FOLFIRINOX plus PEGPH20 that will hopefully show some benefit. The larger study is the one that’s selecting for patients—it started activating and selecting patients a couple months ago—and that study selects for the high levels of HA, and the agent PEGPH20 is combined to gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone. That’s a very interesting study, because it essentially selects those patients who are more likely to respond. So, hopefully, given the early promise of the early clinical results, this will hold on as we move forward in a large prospective manner.

Philip A. Philip, MD: JAK/STAT pathway is well known in hematological disorders. That has been targeted by certain drugs and the most well-known is ruxolitinib. And if we go back to that pathway, it’s also where the cytokines are working. The cytokines in some patients are released systemically, and they also contribute to the systemic effects of cancer. Pancreas cancer patients, they can get a lot of fatigue, weight loss, even fever, and other features like elevated white cell count and low albumin, which are features of having an infection. Sometimes they can be mistaken for an infection. So, there was a good thought behind bringing in ruxolitinib as a drug to be used in patients with pancreatic cancer. It may have an anticancer effect, but it can also support the patients by minimizing those symptoms. And the use of ruxolitinib, in some hematologic disorders, really gets a rapid symptomatic improvement. There was a pilot clinical trial to look into ruxolitinib when it was added to capecitabine in the second-line setting—so patients who failed frontline therapy, mainly gemcitabine-based treatment. That trial was interesting, because it showed benefit to patients who have elevated C-reactive protein. C-reactive protein is a measure of the systemic inflammatory immune status, which biologically made sense. Patients also gained weight on it, so it was really interesting. That went into a phase III trial, trying to look in a larger number of patients. That trial was stopped because there was no benefit seen with the drug. So, the JAK/STAT pathway is, now, not a strategy that is being pursued by anybody.

Tanios Bekaii-Saab, MD: Necuparanib is an agent that, essentially, is a heparinoid. It was built on the platform of low-molecular weight heparin to lose its anticoagulant activity, or most of it, and enhance its anticancer activity. Because, we’ve always known that low-molecular weight heparins have some baseline activity against cancer. The phase I study presented at ASCO in combination with gemcitabine plus nab-paclitaxel, and the earlier study with gemcitabine alone, showed some interesting results. The larger phase II randomized study with gemcitabine/nab-paclitaxel, plus/minus necuparanib, is on track to be completed in the fall. Therefore, we will have some preliminary results about this strategy added to chemotherapy versus chemotherapy alone, and whether it’s worthwhile to move to the phase III setting. But, again, if some of those earlier results hold on, there hopefully will be a path moving forward with this agent in pancreas cancer.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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