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Dr. Alicia Morgans: Hi this is Alicia Morgans, a medical oncologist at Northwestern University where I specialize in GU oncology and I am delighted to have with me today, Dr. Mike Harrison who is an associate professor of medicine at the Duke Cancer Institute and a member of the Duke Prostate Cancer and Urologic Cancer Center. Thank you so much for coming to speak with us today Mike.

Dr. Michael Harrison: Thanks Alicia for having me. I'm excited to be here. 

Dr. Alicia Morgans: Great. I really wanted to hear about a study that you've worked on and have launched within the last year or so, the ASSET study, can you tell us a little bit about that?

Dr. Michael Harrison: Sure, I'd be happy to. The ASSET Study stands for Alternative Schedule Sunitinib with Exercise Testing.  It's a pilot study, but I should probably give you a little bit of background on this first. So, we're looking at the drug sunitinib which, as you know, as a VEGF receptor TKI that's been approved for metastatic kidney cancer for well over a decade, then more recently, it was approved for high-risk kidney cancer after radical nephrectomy.

The rationale for the study, though, is that one of the most common side effects with sunitinib is fatigue, which hasn't really been studied in a lot of depth and why people get fatigue.  Also, there are other cardiovascular toxicities, so things that are very common like hypertension and then less common like decreases in the left ventricular ejection fraction as well as frank, congestive heart failure, arterial thromboembolism, etc. We wanted to do a study where we looked at the phenomenology of fatigue using exercise physiology principles to kind of drill down on that. And furthermore, we wanted to do it in a randomized fashion where we looked at the standard schedule of Sutent, or sunitinib which as you know is the 4/2 schedule, four weeks on, two weeks off, and then also the more commonly used schedule, I think now, at least in practice, which is the two weeks on, one week off schedule or the 2/1 schedule.

The objective of the study is to look at changes in cardiopulmonary function in patients on each one of those schedules on the 4/2 schedule and the 2/1 schedule -will take a relatively small number of patients, it is a pilot study 30 patients and randomize them so 15 would go on to each arm and we were going to look at the primary endpoint of VO2 peak and we're looking at it over a short time period, the first 12 weeks. So basically, the change from baseline to 12 weeks.

And that's because from other larger studies like COMPARZ that looked at sunitinib and pazopanib we think things like the drop in quality of life really occur, you know right off the bat- pretty soon after starting the drug.

Dr. Alicia Morgans: Great. And I like that you're really looking at two different schedules, because at least in, in practice, it looks like there's a difference in tolerability with these two different schedules. Can you explain your primary endpoint, just a little bit just so that other clinicians and patients who might be interested really understand what it is you're looking at what is this the CO2?

Dr. Michael Harrison: Sure, that's a great question because that's, that's an endpoint we don't encounter as much in oncology, at least, is that VO2 peak or another way to say it is the peak oxygen consumption.

And so how is that measured?  It’s measured by a cardiopulmonary exercise test. So, the way to think of it is, it's a little bit like a stress test, so patients would be on either a treadmill or a bike, and they would have a gas exchange measurement device in their mouth, it's similar to actually a snorkel.  Basically, what we're looking at with the peak oxygen consumption is where we're kind of looking at how efficiently their body delivers the oxygen that they inhale to their muscles. So, it's really kind of an integrative process. If you think about oxygen going into the lungs pressing the capillary beds, you know, going into the bloodstream being pumped by the heart through the vasculature, and then being taken up by the muscle, so it integrates a lot of different processes.

If the VO2 peak is decreased versus what's predicted and that's actually known for men, women of different ages and according to their activity levels they're kind of normative and values if that's if that's decreased, than one of those or several of those systems must be compromised. So obviously, in this study were hypothesizing that it could be the heart or the vasculature most likely that are that are compromised based on the side effect profile.

So, what we're looking to do is, this is the first study of doing this type of exercise testing, the VO2 peak testing, in this population of metastatic kidney cancer patients. We're looking, number one, to just see how these patients compare against normative values patients with cancer and without cancer, and then we want to see how that declines or stays the same, or possibly even increases with the sunitinib.  We’re hypothesizing that it will decline and we have data from, for example, breast cancer patients, suggesting that it can be a significant decline in a short period of time. So, for example, just by aging alone, the VO2 peak can decrease by about 1% per year, but in breast cancer patients on chemotherapy, it can decrease by 10% and six months, which is equivalent in a way to aging a decade in six months.  We're essentially wanting to find that out and how the VO2 peak declines in our metastatic kidney cancer patients with this drug, sunitinib.

Dr. Alicia Morgans: Are you looking at anything besides the peak VO2 in the study?

Dr. Michael Harrison: Yes, we are.

You know, and so on that note, as I explained, there's a lot of different things that go into VO2 peak. So, we are doing correlative studies where we're looking at other parts of the system that might affect VO2 peak.

One thing we're doing is detailed echocardiograms both at rest and after the stress of the CPAP  test itself. And we're doing it in two dimensions, in three dimensions and also looking at novel parameters.   So basically, trying to tease out what the changes are on the heart because of the sunitinib or at least associated with the sunitinib treatment.

We're also measuring muscle strength and the changes in cross sectional area of the muscles over time.  Like I said earlier, that's one thing that can affect VO2 peak and there's some least retrospective evidence that patients do develop sarcopenia with drugs like sunitinib so we are looking at those endpoints, as well. We're not looking at vasculature. That would be one thing to look at it in the future.

Dr. Alicia Morgans: So, this is really fascinating because to me, these are the kind of results that not only help to really define the biology of the problem that we think we're seeing in our patients,

but might also then give us some understanding of how we might intervene to prevent this issue, or else provide some mechanism by which we can reverse or limit this issue. What are you and  the team at Duke planning to do with the data after you get through with this pilot?  Do you have plans for a follow up studies and for interventions potentially?

Dr. Michael Harrison: We do, yes. And you hit the nail on the head. We're actually planning as next steps to do intervention studies in this population.

Since this is the first study, we really don't know very much about how the VO2 peak will change. This trial will help us develop some baseline data and you know things like confidence intervals and standard deviations to build and plan bigger interventional studies.

So, if we do plan a larger trial of exercise intervention that would probably be in R21 or maybe DoD or Foundation funded type study.

Even though sunitinib now is becoming a little bit less used, I think the study will still be relevant, because, as you know, we're now seeing studies coming out of combination with immuno oncology drugs with these VEGF receptors TKIs, so I think we may learn something that would be useful to look at those combinations.

We are also doing a study that has not has not launched yet but is funded by BMS called INTENSE and that is actually looking at, it's a similar design, except it does have an exercise intervention arm, and that's patients who are being treated with ipilimumab and nivolumab for metastatic RCC also in the first line. So, we think, you know, the combination of these two trials will help inform us about how to develop further trials.

Dr. Alicia Morgans: Tell me a little bit about how the study’s going in terms of enrollment and then if a patient wants to be involved or clinician wants to send his or her patient to get involved, how does that happen?

Dr. Michael Harrison: Okay, sure. We have enrolled 7 out of the 30 patients who are about a quarter of the way along. We are looking for a second site to partner with us. That's been challenging, as you know, because the landscape has recently changed, so if there any clinicians out there, reach out to me. 

If patients are interested, they can go on our Duke Prostate Cancer and Urologic Cancer Center website and under the research tab, they can find this trial and who to contact.

It is a trial that's only 12 weeks long, so there are probably four or five visits within that timeframe, which is fairly standard of care for sunitinib.  So that's, how patients would be followed.

We are grateful for funding for the study from Pfizer, and I also have a couple of collaborators who are key. I have a cardio-oncologist who is a cardiologist Dr. Michael Curry and then David Bartlett an exercise immunologist, who is partnering with me on this study.

Dr. Alicia Morgans: I want to commend you and the team at Duke. You guys are always thinking about not just making or helping patients to live longer, but thinking about how do we help patients live better and I really commend you, these are not easy studies to do but they really answer important questions for our patients,  who live a lot of their lives outside of clinic and need to be able to function and to have their best life outside of clinics. Thank you for doing this. Do you have any final thoughts or closing thoughts for the listeners?

Dr. Michael Harrison: Thanks, Alicia, first of all, that means a lot. I think like you said, we are interested now that patients with metastatic kidney cancer are living longer, and especially the patients who might get sunitinib who you know, more likely to be favorable risk. We're definitely wanting to think about helping them live better and potentially stave off some of these after effects that may occur from our treatments. But as far as final thoughts, I would say there are a lot of great programs out there for patients. There's the Live Strong at the YMCA, programs Silver Sneakers, and I think a lot of academic institutions have cancer rehabilitation program.

I would say if there are patients out there, look to get involved with these types of trials, but even if it's not feasible, please ask your oncologist, or your other providers and have them help you be directed to these type of exercise programs because it can really make a world of difference in my experience.

Dr. Alicia Morgans: Absolutely.

Well, thank you so much for your time and thank you for sharing your expertise today.

Dr. Michael Harrison: Thank you, Alicia, appreciate it.