William Gwin, MD, Assistant Professor at the University of Washington School of Medicine and breast cancer specialist at Seattle Cancer Care Alliance, talks about the HER2 positive breast cancer trial.
Talk a little bit about your trial.
Dr. Gwin: We are looking at taking an agent that has been used in patients with breast cancer that is heard to be positive, but it is metastatic. We are combining it with a new therapy called Alpha T. Alpha T is a derivative of vitamin D. As you know, vitamin D has been studied in breast cancer and other tumors but has not shown the anti-cancer efficacy we had hoped. Interestingly, these derivatives, like Alpha T do show some cytotoxic activity. It is remarkably interesting, and we are excited about combining it with our standard therapies.
What exactly does Alpha T do to cancer cells?
Dr. Gwin: It seems to work in a couple different ways. It has this direct cytotoxic effect that is mediated by creating reactive oxygen species within the tumor cells themselves. That leads to apoptosis, which is essentially a cell death for the tumor cells. Interestingly, that was the initial mechanism that was felt to be the driver for the anti-cancer activity. The group that had been developing this therapy, sort of investigated it further. They found that it does have an immune modulatory effect, which is remarkably interesting to us. So, this immunomodulatory effect seems to be very reliant on the presence and activation of CD4 and CD8 T cells. So, it seems to activate CD4 and CD8 t cells, which are critical for mediating and going after cancer cells from an immune standpoint. That has us interested and we are thinking about the mechanism of action. Now why that is important is we are looking at her two positive breast cancer which is the type of breast cancer that we know is immunogenic. It has an especially important role in how the immune system responds to it. So, looking at therapies that can boost an immune response and anti-cancer immune response is critical to targeting and treating this type of cancer.
How does this new combination that you are looking at compare to current treatments?
Dr. Gwin: If you think about other therapies that are out there right now for her two positive breast cancers, we have a lot of incredibly good therapies. Even in the past year, we have had the approval of two new agents, particularly in the metastatic her two positive breast cancer population. So, we do have a lot of agents at our disposal. We do not have as much his agents that really manipulate the immune system and we know the immune system is particularly important in her two driven breast cancers and that’s where alpha T comes in. Alpha T’s an oral agent so it is well tolerated, and we hope it can complement the activity of party present and approved her two directed therapies in this population.
What stage in the trial process are you in?
Dr. Gwin: Right now, there are two different studies going on about the Alpha T agent. There is another study that is a single agent phase one dose escalation trial and that is ongoing. Because of our interest in looking at the immune components and whether it can act in partnership with the already existing her 2 directed therapies we have started this study as well. So, this is also a dose escalation phase one study. Right now, we are in the process of screening, recruiting, and enrolling patients who have just started. We are excited about the potential this agent has both in her two positive breast cancer, and in other breast cancer subtypes that are in different stages of breast cancer. Right now, we are looking at just stage four but if we see the activity we anticipate seeing, we will certainly look at this in earlier stages of disease and other tumor types within breast cancer.
How many patients are you looking to recruit for the trial and what are the eligibility criteria?
Dr. Gwin: There are going to be patients who have metastatic or stage for her two positive breast cancer. Right now, we are looking at patients who have had a disease that has not been responsive or started to grow with standard therapies. So, it is the patients who have gone through treatment and the disease continues to grow, and then they need other agents. Those are the main criteria. We also have other criteria that deals with labs and so forth. But in general, it is an open enrollment regarding eligibility.
For the patients is there a higher possibility that the apathy and the combination of drugs would work for them?
Dr. Gwin: Another interesting thing we know about her two positive breast cancer is that as patients develop her 2 positive or her 2 driven breast cancers, there’s an interesting loss of T cells that are very specific for the protein her 2. So, if you take folks who have other types of breast cancer and look at their T cells, the immune cells that target cancer, they still have T cells that recognize her 2. The patients with her 2 driven or positive breast cancer, they start losing the T cells and they lose that immunologic response. Our hope is that by using trastuzumab, which is the standard monoclonal antibody for her – targeting her two in conjunction with Alpha T, we can boost and drive the T cells that target her two and restore that immune response against her two so that not only are we targeting this mechanism or tumor as kind of the direct cytotoxic effects of alpha T, but we are also bringing the immune system into the fight.
How long are you expecting to follow the women to see at what stage it is going to be effective?
Dr. Gwin: We hope to see benefit within the first two to three months with regards to this therapy. Certainly, we will follow patients if it is effective and continue the patients on it so long as it is effective. Part of the purpose of this trial is to look at the safety of several doses. We have standard cut points and time frames that once a patient has not shown significant side effects at a certain dose for a certain period, then we will move to the next higher dose. Through that we are trying to find out what is the safest and most clinically effective, as well as the immunologic level of the alpha T.
What quality of life impact will this have for women who have been diagnosed with her two positive breast cancer and have tried treatments, but they are just not working for them?
Dr. Gwin: One of the real challenges that we must think about with any therapy that we are using is the side effects, and the toxicity that these therapies bring with them. This therapy in and of itself seems to be quite well tolerated. Again, we are still in the early phase with regards to evaluating, but the side effects seem quite manageable. It is also not an I.V. medicine but a pill that they would take at home. The interesting thing is it does seem to have similar effects to chemotherapy, but without the side effects. So these folks may have had a lot of chemotherapy in the past with a lot of side effects and we hope this provides a new avenue of therapy that provides that anti-cancer effect and anti-cancer immune response, without the long term side effects that we see with a lot of our standard agents.
So, right now you are starting off with a single oral dose?
Dr. Gwin: Yes. The way it is dosed, it is based on weight and we have four different dose levels. We are starting at point six milligrams per meter squared, which is our standard dosing, and then we will increase it from there. It is taken as a pill and how many milligrams you take is based on the individual. But it is taken daily for 14 days and then you take two weeks off. Then you start over.
How can a woman who wants to take part in the trial find more information?
Dr. Gwin: We are working through the Cancer Vaccine Institute here at the University of Washington. So, one way is to go to the University of Washington Cancer Vaccine Institute website and there you will find a direct link to contacting us, as well as looking at this trial and other trials that we are offering.
Anything I did not ask you that you feel people should know?
Dr. Gwin: We hope through this trial we will learn more about alpha T and its direct anticancer activity as well as its immunologic activity. We are also exploring how we can utilize this therapy and other tumor types, particularly triple negative breast cancer, which is another immunologic active tumor type. So, what we are looking at is can we combine this agent in a subsequent study with more immune directed therapies such as checkpoint blockade? That is an area that we are actively looking to develop in a clinical trial protocol.
How many women do you have currently enrolled?
Dr. Gwin: Right now, we are still in the screening phase. We have several folks coming in for screening in the next couple of weeks, but no one yet. We plan to enroll twenty-four patients. Again, it is four core cohorts and up to six patients per cohort.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Cvitrial@Medicine.Washington.edu
1-866-932-8588
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
