Philip Highlights Promise of Devimistat in Pancreatic Cancer

Pancreatic cancer has fallen behind other tumor types in terms of the emergence of novel treatment options, explained Philip A. Philip, MD, PhD, FRCP; however, devimistat (CPI-613) is delivering new hope in the pancreatic paradigm.

A prospective, multicenter, open label, randomized phase 3 study (NCT03504423) is evaluating devimistat plus modified FOLFIRINOX compared with standard FOLFIRINOX alone in patients with metastatic adenocarcinoma of the pancreas.

“We will have some results, but it will be some time for the study to be complete, for the data to be analyzed, and to come up with an idea of how to present the data. The FDA is involved in the whole process,” said Philip. “We are very excited, and the bottom line is that we have an interesting compound and interesting concept. Hopefully, we will see something new that will help our patients with pancreatic adenocarcinoma.”

In an interview with OncLive, Phillip, professor of medicine, Wayne State University School of Medicine, and clinical professor of oncology at Barbara Ann Karmanos Cancer Institute, discussed challenges in pancreatic cancer and the emergence of devimistat in the treatment paradigm.

OncLive: Please provide an overview of the current treatment paradigm in pancreatic cancer.

Philip: Pancreatic cancer has been behind all other cancers when it comes to early detection. What we found is that we need to have better drugs for this disease because the majority of the patients are beyond curative without surgery or radiation treatment. They have metastatic disease and cells that already traveled beyond the primary tumor. You can cut the tumor out and even if you are successful in doing that the patients have a recurrence. Basically, we need some good systemic treatments for pancreatic cancer.

Up to this point, the drugs that have been tested and used in this disease have only been traditional cytotoxic drugs. This includes ones that are approved by the FDA, such as gemcitabine, and when we used these drugs the benefit is modest. It is marginal in some patients and modest in others and very few patients can really benefit but, then again, it does not help them in the long run. Part of this is due to the adverse events (AEs) because there are drugs that are cytotoxic drugs and kill the cancer cells, but they also hurt the normal cells, hence, the AEs. The benefit versus AEs has not been that good with these treatments.

If you look at what we have done over the last 10, 15, 20 years, it is to test new drugs. One thing that has become really important in oncology over the last 20 years is the concept of targeted therapies, personalized treatment, and biological agents. Regarding trying to make advances in the treatments that are based on molecular biology is what we learned more about over the last 30 to 40 years. Unfortunately, for pancreatic cancer that did not work. We did a lot of clinical trials testing 1 drug after another targeting this molecule then moving to the next and all of these studies were negative except for 1 or 2 exceptions. For example, PARP inhibitors, [which target BRCA]. Again, the benefit from [these agents is] limited and not a major breakthrough. We need to think of something which can affect more people who have pancreatic cancer rather than focusing on these genetic mutations that did not work well.

We are moving to the next phase, which is what can we do that can help patients in general. Immunotherapy could be a good candidate for that but, unfortunately, immunotherapy also did not work in this disease. So far the studies using drugs that have worked in other cancers, such as melanoma and lung cancer, when applied to pancreatic cancer, did not work. That is the nature of the disease itself, it does not lend itself for immunotherapy. We have a problem but then again we hopefully have developed our thinking and strategies to overcome this problem by moving into areas that have not been tested before. Here is where cancer metabolism comes into play.

What activity has been shown by the emerging agent devimistat?

The most important thing to remember is that devimistat is a novel drug, first in class, which targets metabolism and is the leading drug in metabolic pancreatic cancer. That is something that makes us very enthusiastic about the use of this drug. In fact, we have early results that were done about 2 years ago in a limited number of patients, approximately 19, and, surprisingly, adding the drug and not causing much-added toxicity with FOLFIRINOX resulted in significant benefit for the patients. The benefit was seen by looking at the degree of shrinkage of the tumor, how long the patient remained in remission, and also, in terms of prolonging survival. That was a pilot trial but, certainly, it gave us some results that were very interesting which means that the next thing is to try and develop the drug further.

What is the safety profile of this agent?

The thing is that there are not really specific unusual AEs with this drug. We see this drug combined with other biological agents and the AEs that we see in those patients are more or less the same AEs we see with chemotherapy and when combined with devimistat. Maybe there is fatigue and aches and pains patients might experience, but apart from that, we do not see much in the way of AEs that are unusual. In other words, it is very well tolerated and that is the most important thing for us when we develop drugs and add them to existing chemotherapy agents. They should not add more toxicity and we are not seeing any real added toxicity which makes it very appealing because it is very important for us to have a drug or drug combination that we see more benefit and not worsening of the toxicity. That balance is important to us especially in patients with pancreatic cancer.

What does the future of this agent look like?

The most important thing to remember is that this drug has a unique mode of action which is a new class of agents. The good thing is that we are seeing activity with this drug not only in pancreatic cancer but also with other types of cancer. As you know, there are several other trials that are currently ongoing. There is activity for the drug, but the question is how best to use it.

At this point in time, the focus of the major clinical trial that we have, which is a phase 3 trial, is based on patients with metastatic pancreatic cancer who have received prior treatment for metastatic disease. The way the drug is given is by combining it with FOLFIRINOX. However, there are other smaller trials being done, pilot trials, that are combining it with a different combination. For example, gemcitabine and nab-paclitaxel (Abraxane) are also being investigated. There are also investigators looking at using the drug neoadjuvantly which is attractive because there are patients who cannot be operated upon because the tumor is too big, or attached blood vessels. If you can shrink the tumor down that would be a good way of trying to improve the outcome of patients who cannot have surgery.

These are the initial ways of trying to develop the drug but as we go forward, we will have other things to look at. One of them will be biomarkers that identify patients that benefit [from treatment] more than others. Is there a way to try to combine this drug with other biological agents, even immunotherapy? The field is wide open. There is a lot of room for investigation and clinical trials. Hopefully, we will have good signals as we move into the completion of the phase 3 trial. We do not have any results now, but it is important for us to keep in mind that this is a new strategy and there is preclinical and experimental evidence that supports it. There is also activity in other tumor types which makes it an active agent.

Is there anything else from the phase 3 trial that you wanted to talk about?

The design of the trial is fairly straightforward in terms of it being a randomized trial. Patients know what they are getting so there is no placebo. The experimental arm will be FOLFIRINOX in a modified form plus devimistat and the control arm will be the straightforward regimen FOLFIRINOX as it was developed. This study had good and fast accrual. It gives you an indication that physicians were very interested in putting patients in this study. There are major investigators that are a part of the clinical trial and it is a global trial, including countries such as Europe and South Korea. Unfortunately, the recent pandemic slowed it down, but it will be completed.

Is there anything else you would like to highlight?

The bottom line is that we have a very interesting treatment strategy and a drug that is targeting an important part of the process that makes cancer survive, spread, and be resistant to other chemotherapies. It does this in a very well-studied and well-known manner. It targets 2 enzymes in the Krebs cycle in the mitochondria. By doing that it is shutting down one vital pathway for the cancer cells and the way they utilize glucose from the blood. They take the sugar and metabolize it from the molecules. This compound is working on those enzymes that are working on that pathway.

It is a targeted agent, but it does not target gene mutations which are important because we like to do genetic tests on patients. However, in pancreatic cancer, genetic mutations that will help us to choose a drug is less than 5%. It is rare to find genetic testing which helps to add a drug to a patient. We need to think out of the box and maybe continue looking at options for genetic testing and how we can help patients, but at the same time, we should think of other ways to help and treat patients and strategies that will capture a wider segment of the population. The study will hopefully provide that opportunity for us.

Reference

Study evaluating efficacy and safety of FFX versus combination of CPI-613 with mFFX in patients with metastatic adenocarcinoma of the pancreas. www.clinicaltrials.gov/ct2/show/NCT03504423. Updated April 21, 2020. Accessed May 20, 2020.