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Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today we will be discussing cancer clinical trials. My guest today is a good friend and colleague, Dr. Peter Martin. Dr. Martin is a Hematologist and Medical Oncologist at Weill Cornell Medicine and New York Presbyterian Hospital. He is a Service Chief of the Weill Cornell Lymphoma Program. In addition to his expertise in caring for people with lymphoma, Dr. Martin has been deeply involved with researching and developing better treatments in order to integrate more effective and targeted therapies into clinical care for patients with cancer. He is really somebody who is an expert in the design and conduct of clinical trials in cancer. And it's really great to have you here, Peter, today to talk to us a little bit about this area of research and this field and how it impacts patients.

So, I want to start by asking you, why you got involved in clinical research. Doctors take care of patients and specialize in specific areas, but what about the idea of research and clinical research involving patients, drew you to this field?

Dr. Peter Martin (Guest): Well, first of all, John, thanks for having me here. With respect to the research, it's an interesting question. I think everybody to some degree is curious. And especially in medicine, we're all curious people, we make observations and ask ourselves, you know, why did this happen? What could we have done to make things work better? And I think in particular, the thing about research that I enjoy the most is, we get to ask the question and then we get to try to refine the question and figure out how it is we can answer that question.

And sometimes those questions start out as seeming somewhat mundane. Sometimes they're a little bit more ambitious. But it's always exciting to take our clinical experience and say, I wonder if we could have been better or I wonder why this happened. And then to turn that into a research question and to try to answer it and to know that somewhere down the line this question could really help somebody.

Host: So, we're focusing today on clinical research and people are familiar with research in general, and often people think about laboratory research, but what makes clinical research different and what is the definition? And what's special about this subset of research?

Dr. Martin: People that work in labs, thank goodness they do that. And it's been really remarkable to watch how fast scientific research has advanced over the past decade. It seems to move a lot more quickly than clinical research to some extent. All of us that work with patients on a day-to-day basis, are really focused on developing research questions that have in some form, an ability to inform our ability to take care of patients; either improve the quality of their care, the quality of their life and improve outcomes, reduce side effects. So, it's ultimately all focused on a measurable endpoint that can be experienced by a person in real life, in a relatively short timeframe.

I think fundamentally that the best laboratory researchers also do that, but they're also obliged to follow science wherever it takes them. And that might be down various different esoteric paths. Whereas I think we're more obliged to really focus on how is this going to impact the person that I'm seeing in clinic tomorrow.

Host: So, we're going to focus much of our time on a concept of clinical trials, but before we get there, there's a lot of knowledge that informs patient care that is clinical research, but not a clinical trial. And some of your higher impact studies have been research about patients, but not on, you know, a formal trial. So, maybe first before we define a trial and get into the details of that, what are some of the other ways that studying aspects of patients and what happens with them can impact patient outcome that doesn't involve kind of an intervention with a patient or a clinical trial in the classical sense?

Dr. Martin: We think about clinical research that really falls into two sort of subtypes. One is an interventional type of research, and those are really the clinical trials that we'll get to. And then some of it is more observational. And observational research, the best observational research is designed around research questions that would be hard to answer through an intervention, and they can be very, very meaningful types of research questions. For example, a very topical thing right now is around healthcare disparities. It would be very challenging to research healthcare disparities in an interventional clinical trial, but in observational research, we can, try to learn about why it is that things are happening. And to try to get to understand some of those things that then could be changed upon or, or intervened upon so that we could improve outcomes. So, some of the research, for example, that we've done in the past was to look at the management of mantle cell lymphoma. And during the 1990s and early 2000's, there was sort of a tendency to manage people with increasing intensity, despite the fact that many clinicians around the world, recognized that not everybody with mantle cell lymphoma has a clinical course that is identical. And so we asked that question how did people do when they're not managed intensively and found that many of them do, in fact startlingly well, and so now there are clinical trials that are measuring that as an intervention.

Whereas, 15, 20 years ago that might've felt almost unethical. Another observational study that was worked on recently, are looking at this "real world evidence" which is a loaded term because it implies that nobody else exists in the real world, which is also not true.

Clinical trials do happen in the real world, but real-world evidence gets to the observational data outside of interventional clinical trials. How are people actually managed in the clinic? And so we looked using a Flat Iron data set, which is a data set extracted from electronic medical records; 80% of patients in these medical records were treated in community sites which is important because 80% of people with cancer in the United States are managed in the community, not in academic centers. And we found that not everybody was managed in the way that you might have expected based on clinical trial data. Over the past 20 years, we've seen tremendous improvements in outcomes in mantle cell lymphoma in clinical trials.

And to be honest, it's a little discouraging that not everybody in the country, is getting to share in that success. And then that begs the question, why is it that some people are not being managed in the ways that you might expect based on clinical trials? Is it because we've designed regimens that are too complicated? Is that we've got issues with access to healthcare? Is that we've got issues with educating physicians who are outside of academic medical centers?

And those are all things that can be studied and intervened upon in the future. So, observational research can be a really important component I think of improving healthcare and more, immediately designing other studies that can have those kinds of meaningful impacts.

Host: That leads us to what is a clinical trial. when you talk to a patient and you say I'd like you to consider participating in a clinical trial, or if someone reads information, a news story about the result of a clinical trial, what does that mean as far as how that research was conducted? How does that work?

Dr. Martin: Clinical trials mean a whole bunch of things to different people. You know, it depends on the hat they're wearing, right? From the perspective of an ethics review board, it might be a little bit different than the perspective of somebody who designed the clinical trial. And that might be different than the perspective of somebody who's treating a patient on a clinical trial or from the perspective of a patient or caregiver who's involved in a clinical trial. So, from the true research perspective, clinical trials are designed to answer a question. The question might be, is this treatment or regimen safe? What dose can we administer? Or what doses can we administer? Is it effective? How well does it work? How well does it work compared to some other kinds of therapy? So those are research questions. I think from the perspective of those of us who are really treating patients, and from the perspective of people who are participating in clinical trials, that the goal is to find a treatment that makes the most sense at that time.

There's a little bit of a balance that has to be struck sometimes between answering the question that needs to be answered and also doing our absolute best to ensure that the person who's participating in the clinical trial, has the optimum chance of benefiting from that, and the least chance of having any significant risk. And that's where the whole process of an informed consent comes in.

Host: But it's really an active process, right? I mean, someone comes to a patient or an individual and says, you're in this situation, we're studying this situation. We would like to, in many cases give you a treatment or perform a procedure and then we're going to see how that worked. We may be comparing it to something else, but the idea is it's an active process, as opposed to looking at your medical record and compiling data after you were treated. It's typically a prospective sort of exercise that a patient typically actively says, yes, I'd like to be part of this. Right?

Dr. Martin: Right, right. So, that's getting at the point of a clinical trial versus observational research is, we identify an issue. We say we would like to intervene in this way, for example, a new treatment or a procedure or device. And we think that this is what we expect to learn from your participation, and this is what you may expect to gain. This is what you may expect to experience. And the goal at the end of that clinical trial, is to then be able to answer that question. It's definitely prospective, not retrospective based on information that existed previously.

Host: So, why don't you tell us a little bit about the different phases of clinical trials? I mean, people hear phase one clinical trial, and that sounds early and phase three sounds like the one you want to be on, but in fact, that may or may not be the case. And then there's phase four, which are, I would say less common, but probably most people haven't even heard of. What are generally, in a nutshell, the key aims? And I think we would both agree that if someone's considering participating in a trial, they need to really understand what the goal of the trial is and the alternatives and the benefits and the risks.

Dr. Martin: Typically we have phase one, phase two and phase three trials. Then there are occasionally combinations phase 1/2 or 2/3 and phase one B and other strange nomenclature that start to get confusing even for those of us who live in this world 365 days a year. But broadly speaking, the research question in a phase one trial is, can we administer this regimen, treatment, individual drug or regimen, safely? And at what dose?

And that might be you know, a single drug where the dose of a single drug is escalated over time, or it might be a regimen where one part of the regimen is fixed and an experimental therapy is added to it and the dose is escalated, or it might be two treatments where the doses in both is escalated over time. But ultimately the goal is to demonstrate that in fact, you can do this in a safe way and move on to the next step, which would be phase two. And there, the question really is to define does this work? Is it active or in the clinical world, we say efficacious? And the term efficacious means in the research setting, is this, producing beneficial results. Phase two trials are typically a little bit larger than phase one trials, because we want to define, not only does it work, but how well does it work? And that requires a little bit more precision. You get a flavor, from phase one trials of what the expected safety profile is from that treatment. Once you know that a treatment is both safe and efficacious, or at least has a therapeutic index, meaning it's more effective, or its effectiveness can justify the expected side effect profile; then we move on to phase three. And in phase three trials, the question is, is this experimental regimen more or less or similarly effective compared to some other standard treatment?

So, for example, we have been working with Leondro Cerchietti and Ari Melnick, who are both physicians working in the lab now for a couple of decades and they've been studying epigenetics or the way genes are turned on or off. And one concept that they felt was interesting, was that certain genes that make cancer cells sensitive to chemotherapy, could be turned off inappropriately, so that cancer cells are then resistant to chemotherapy.

And through a couple of clinical trials we designed, phase one trials, we looked at a medication called CC-486, an oral medication that affects the way genes are turned on or off. And we first tested different doses of that medication in combination with R-CHOP. So, that was a phase one trial. R-CHOP is a standard treatment for people with diffuse large B cell lymphoma.

The idea is that potentially by adding this other medication, we can make the chemotherapy work better. So it's a phase one trial, but in that phase one trial, everybody is still receiving the standard of care treatment R-CHOP for diffuse large B cell lymphoma and the experimental treatment was escalating doses of the other medication, CC-486. And indeed, in that trial, we found that, we could administer CC-486 safely with R-CHOP and in fact, in a fairly large number of patients, we found that it appeared to work quite well, and that data has subsequently been used to justify other clinical trials including a phase two clinical trial and separate lymphoma peripheral T-cell lymphoma, run by Dr. Jia Ruan, here at Cornell. And now is in two national randomized trials in older patients with diffuse large B cell lymphoma receiving R-CHOP and in patients with peripheral T-cell lymphoma receiving CHOP.

So, that's sort of an example of how treatment might go through phase one into phase two or three, or randomized setting. And of course there are many other examples that are similar to that, sometimes involving perhaps treatments that are not yet approved, or even proven to be effective. And I think most of the time that people are thinking of phase one trials, they're thinking of these new drugs that are first in human, but I think probably the majority of clinical trials that are performed in oncology, there is already some sort of active treatment and the goal is to try to make it work better.

Host: So, what is the role of placebo in oncology trials and cancer trials, in particular? I would think that that's an issue for many patients or at least a concern for some patients that they don't want a placebo, if they're concerned about their cancer.

Dr. Martin: Yeah. And placebo is defined as an intervention that is not expected to have a significant either benefit or risk and it's performed essentially with the intention of blinding study participants and investigators from knowing whether the participant is receiving the active therapy or not. Because it's understood that sometimes people can experience something either good or bad if they know they're receiving the specific treatment. So, in oncology, there aren't a lot of scenarios where you would say, we're going to give somebody a placebo treatment and nothing else. There are a few examples of that, historically, but it's not very common. But there are plenty of examples of people who might be receiving a standard treatment. And the research question might be if I add drug X to a standard treatment, does it work better than the standard treatment alone? And in those circumstances, the appropriate thing to do, or the best way to answer that question would be to give everybody to standard treatment and then participants would receive either drug X or placebo. And at the end of the clinical trial, then you look and see what were the benefits in both arms and what were the risks? And in that circumstance, the placebo didn't likely impact things either good or bad, but they did allow the study to be conducted in a way that blinded participants and investigators from which drug they were receiving. So I know placeboes are sort of a taboo subject in research, but it's worth noting that in oncology it's really uncommon for placeboes to be used alone, without any other sort of active therapy. This is where ethics review boards really are important. When we propose a study, we first have to justify it in front of our peers.

And, they have to agree that it's scientifically sound. From there, they take it to a bigger group of peers and they think, this is a good idea and feasible. And, from there we go to the ethics review boards, or IRBs. And IRBs are made up of multiple individuals, many of whom aren't necessarily experts in the field. And they allow us to have that perspective of a diverse group of people, many of whom are researchers, but not all of them are researchers and they can say, can you define what a patient might expect to experience? Is there a potential for benefit? Is there a potential for risk and it doesn't mean that you can't do a study that has very limited potential for benefits, but they do want to make sure that the potential for risk is not overwhelming and they also want to make sure that patients are very much aware of the risks and benefits that might arrive from their participation in the study. So if there is a study, we're very careful to discuss all of those potential risks and benefits with people, especially if there's a placebo involved.

Host: So, I want to ask you, and we'll get to the good part of clinical trials in a second, beyond what you've discussed already, but there are some potential downsides. And so just in a nutshell, what are the potential downsides when someone thinks about participating, that they should either ask about or consider.

Dr. Martin: There are definitely some downsides, just like we're asking that question, and hoping that the person that's sitting in front of us is going to participate in this clinical trial, we're hoping that they're going to benefit from it, but we don't know the degree to which they might benefit or whether they'll benefit. There's a potential for side effects. Oftentimes we have a good idea already of what those side effects might be, but on some occasions we don't necessarily know. And so there may be unexpected side effects. Clinical trial protocols are very careful to protect patients. And so if we experience side effects, we have ways of dealing with those, or minimizing them, or even removing people from clinical trials, if we think the risk is outsized. There are also these sort of practical aspects related to clinical research that makes them frankly, inconvenient. They require more clinical visits, typically. There are often more study procedures, like blood draws or EKGs. People are not typically as mobile as they might be.

So for example, if somebody is receiving an oral therapy in a clinical trial, they might have to return to the office every month. Whereas outside of a clinical trial, the pharmacy might ship it to them wherever they are in the world. So, there are these both potential medical and then sort of practical downsides to participating in clinical trials. And those practical downsides can be very real. And over time can start to weigh on people if they've been participating in a clinical trial for several months or years.

Host: So, there are a lot of good things obviously, or we wouldn't be talking about this and clinical trials can make a very big difference, both for the field and for an individual patient. So, what are the potential upside to the good impact that clinical trials might have?

Dr. Martin: Yeah, first and foremost, as you say, there's a big benefit to this field. A clinical trial might have 500 people in it. But for example, diffuse large B-cell lymphoma happens to 30,000 people every year in the United States. That's the most common lymphoma worldwide. That relatively small clinical trial, if it changes the way diffuse large B cell lymphoma is managed, has an impact on literally tens of thousands or hundreds of thousands of people every year around the world.

That's a pretty remarkable thing that you can show benefit in a small number of people and extrapolate that to the entire world and hope to help humanity in that kind of way. I think that's what all of us hope for anytime we start on a larger, clinical trial. Obviously, to participate in a clinical trial, the goal from the participant's perspective and from my perspective when I'm talking to somebody about a clinical trial, that’s great if it helps everyone, but what I really want is for it to help this person in front of me. And very often clinical trials have that potential. Sometimes it's more clear cut than others.

For example, when you know that you have a treatment that has worked well in the past, and you're using it in a slightly different way, it's easier to define what the expected benefit would be. In some cases it might be, you know, we have this treatment, but we think that we can reduce the side effects by doing this, then benefit is pretty clear. Where we expect to get maybe a little bit more challenging, I think are in some of those first-in-human phase one clinical trials, where treatment doesn't have quite the same sort of history that most clinical trials bring with drugs that have already been very well studied or interventions that have been well studied. But even those first-in-human phase one clinical trials do succeed and we've had plenty of examples. I don't know why it is that lymphoma is like this, but lymphoma, is just one of the most satisfying areas to be researching, oftentimes because the treatments that we use work really well. And even in phase one clinical trials, oftentimes treatments that haven't been very well studied in the past can be used and are just remarkably active. And I can think of a number of cases, where people may be hadn't had a lot of other options and were treated in a clinical trial. And and because of that trial, did very well, and are still around and succeeding in life.

Host: On the flip side, we do have some trials and you know, I don't want to be a wet blanket, but there are some trials where things don't work out well or the difference or the benefit isn't seen or in some cases, the effects are worse than we would've expected.

So, you do have to be prepared for that. And obviously it's all, the context of the situation. Some people ask the question is a trial what you do as a last resort? How do you answer that question, Peter?

Dr. Martin: So, the answer is no clearly, it's no. Definitely scenarios where people may have already experienced all of the FDA approved treatments and off label treatments. And so there are scenarios, where somebody has run through the mix of everything that's around. And then you look for other kinds of treatments that might be available. But that doesn't make up the bulk of the research that we do, or that's done in the United States. And it's simply because there's always room for improvement. Right?

And the most obvious place that there's room for improvement is very early on. So, again, taking diffuse large B-cell lymphoma as an example, if the goal is to impact the maximum number of people, to improve life for the maximum number of people, it doesn't make a lot of sense to wait until those people have already experienced every single FDA approved therapy. What makes the most sense is to come up with a treatment that is scientifically rational, based on some clinical evidence that these treatments work and then to bring it right up to the very front. We know that R-CHOP works in diffuse large B-cell lymphoma. If we can make it work better, if we can make it less toxic; we can impact hundreds of thousands of people around the world. And so definitely not a last resort sort of thing.

If anything, it's, it's almost the opposite. I think you can benefit a huge number of people by performing the right kind of clinical trial in the right setting as early as possible.

Host: I want to wrap up with just a comment on the issue of diversity in clinical trials and historically there have been different groups of patients defined in a number of different ways that have been underrepresented in clinical trials. Why is it important to get broader representation of different groups of patients in clinical trials? And I know this is an area that you're interested in.

Dr. Martin: Fundamentally it's an issue of justice and equality. I think when we work in medicine, we don't treat just one type of people or one type of person we don't say, okay, I will treat you up until age 65. And then after that, I can't help anymore.

And so clinical trials that preferentially enroll people up to a certain age, and then not beyond that, it sort of leaves those of us who are treating patients to say, well, that's great, but what do I do with all of the 70 year olds that I see in clinic every day? Their life is obviously still meaningful and valuable and I want to make their lives better too. So, we as society and I'll speak for myself as a researcher, it behooves us to perform observational research to figure out why some of these disparities exist. Why is it that we seem to do very well enrolling, educated white urbanites into clinical trials, but don't do that well with older patients or rural patients, or visible minorities or sexual orientation, may be another thing that may be overlooked, I don't think it's been well studied yet right now.

So, I think that if we're going to treat patients from our entire population, everyone that we see, we have to be able to generalize the results of clinical trials to those patients, and the clinical trial that is overwhelmingly involved in one subset of people, just doesn't help us. It doesn't inform us in a way that's meaningful.

You can chop that up so many different ways, but fundamentally, there's clearly room for improvement and fortunately, it's very clear, I think that everybody recognizes that need and it's encouraging to see how many people are really moving forward to try to make try to make that better.

Host: So, I was just going to ask you as kind of a last thought for people that may be considering a trial as part of their cancer care either now or in the future or for their loved one, what is your kind of key message for them to think about this area? The key thing that you, you would encourage them to consider as they at least explore this as an option?

Dr. Martin: I think another equally important question, maybe even more important question is the fact that most people are not presented with a clinical trial as an option, right; 5% or fewer adults with cancer participate in clinical trials and probably the most common reason why people do not participate in clinical trials is that they're not aware that it's an option for them. And so I think the first question, that every one of us needs to address is, why wasn't a clinical trial considered in this situation. If there is a potential for somebody to participate in research that has the potential to improve outcomes globally, for everyone and has the potential to improve their own outcomes, then why wouldn't we want to do that? So that's number one. Number two, I think from a personal perspective, if you're presented with a clinical trial, I think it's a hundred percent reasonable to ask your physician point blank, what do I have to gain from this? And what do I have to give up to be part of this? I think to try to deal very much in those specifics.

So, in particular, what are the expected side effects that I'm likely to experience? What are the expected issues, that are going to be inconvenient? What are the inconveniences that I'm going to have to experience? And then what is the probability that I might experience benefit? And then to weigh those in in some sort of an equation. But to that equation, I would definitely also add altruism. I think people that participate in clinical trials are quite literally heroes. You know, we go to all of the medical meetings and at the end of every single clinical trial presentation, investigators always say, I'd like to thank the participants in this clinical trial and it would be kind of nice if we created some sort of montage at the end of a national meeting to show that every time that that happens, because it happens at every single one and it's, it's too bad that the participants don't get to see that, but they are definitely appreciated. They're changing the lives of people globally through their simple act of participating.

Host: Well, Peter, I think that you've left us on really a great note to end on, and I would agree with you. I think people that participate in clinical trials are heroes. They're making a difference hopefully for themselves and others. And I also want to thank you and your colleagues who are doing the work behind this as well, which also is not easy, not as difficult as the patients go through, obviously, but often a long process as well.

So, thank you for joining us and sharing your wisdom in this area. Thanks again for all your hard work. I want to invite our audience to download, subscribe, rate, and review CancerCast on Apple podcasts, Google podcasts, Spotify, or online at weillcornell.org.

We also encourage you to write to us at This email address is being protected from spambots. You need JavaScript enabled to view it. with questions, comments, and topics you'd like to see us cover more in depth in the future. That's it for CancerCast, Conversations About New Developments in Medicine, Cancer Care and Research. I'm Dr. John Leonard. Thanks for tuning in.

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