Clinical Trials: Finding the Right One for Your Patient and Overcoming Enrollment Barriers

Erin Kopp

Hi, Adrianne. I’m glad we get to talk about graft-vs.-host disease again. I’d love to talk with you about clinical trials and the role they play in the care your patients with chronic GVHD receive.

Adrianne Maurer

I’m lucky enough to work at a research institution at Fred Hutchinson, so clinical trials are always at the forefront of our mind. But even if you’re at a non-research facility or a community provider, one of the first recommendations in the NCCN guidelines for managing chronic GVHD  is to consider a clinical trial.¹ As our population ages, the mainstay of treatment is steroids. We know steroids come with many toxicities and complications, so we're trying to find new ways to avoid them, or at the very least, minimize the time that patients are spending on steroids. So clinical trials are a very important way for us to start exploring some of those alternatives.

Erin Kopp

It's such an important point because any APP who’s been in this area for any length of time has stories about when we didn't have anything evidence-based to help us decide what was next, especially when it came to second-line therapy after corticosteroids. Even today, I see patients coming in with multiple agents, and we have to figure out what's working and what's not working. But now we're developing and have access to more evidence. Like you, I work at a research institution. We’re very blessed with a number of clinical trial options for our patients at City of Hope.

Let’s review the relevance of clinical trials in today's practice, not only the results of past trials but also looking to the future. For instance, what are the gaps? And what do you do when you don't have any clinical trials for a patient? Usually, the first step is to say, "All right, well I can't do that, so let me do this instead." I also want to discuss some of the barriers at the institutions with clinical trials, and which barriers are patient- and provider-driven.

First, let’s talk about where we've gotten so far with some of these clinical trials. We have the AGAVE-201 trial, which led to the release of axatilimab, the newest agent in the market. And then there is ruxolitinib from the REACH trials. It’s really nice to be able to tell a patient the science behind the agent I’m prescribing for them so we can understand and know what to expect with it.

Adrianne Maurer

Yes, absolutely. One of my mentors used to tell me that treating GVHD, chronic GVHD particularly, is an art, not a science. And it was really like a lock and key mechanism, just picking an agent and hoping that it might open that lock, but 8 or 9 times out of 10, that first agent we try isn’t the right one.

I want to mention the ROCKstar study, which brought forth belumosudil. Now it's being used in second-, third-, even fourth-line treatment, but there are current clinical trials open examining it in frontline use as opposed to steroids.²

There's a study we're doing at Fred Hutch right now that compares belumosudil to a placebo in early-stage chronic GVHD that you otherwise wouldn't treat.³ So, think isolated oral GVHD or maybe ocular GVHD, where you're just going to treat topically. The goal here is to try to prevent that GVHD from progressing any further by using one of those aggressive and successful agents right out of the gate so potentially we can prevent the use of prednisone. We've done a lot of work looking at what additional agents could be used in highly refractory GVHD. But what's so unique about this study is that we're looking at something more upfront as opposed to what happens down the road when we can't continue to treat.

Erin Kopp

That's such a good point; instead of catching things later in the game, we can work on catching them earlier. And one study builds upon another, right? So, when you see the efficacy in one area, then you can say, "Well, I understand this. I understand the mechanism of action. We see the results, so how can we apply it in a different area?"

Morbidity and mortality for chronic GVHD can be underestimated in the frontline setting. When you hear something is acute, you're on alert, right? I think, "I must fix or prevent it right now because the sequela and the ramifications are so significant."

When we add the word “chronic,” that can lead to a sense of complacency where we might think about doing steroids for 4 weeks and that'll be okay, that the patient won’t have any major concerns. However, that's not always the case. The concept of putting these agents to the test, because we are part of the science field, the art will always be there, and that's why we're here. It’s nice to think that maybe 10 years ago it was 80% art and 20% science when we're dealing with second-, third-, and fourth-line cGVHD, but now it could be more 50/50. We’re on our way to being able to say, "I can look and know that if there's this particular presentation, this is the right agent to choose."

Adrianne Maurer

You bring up a really good point about how we approach the treatment of chronic GVHD. I feel like sometimes the word “chronic” makes you think, "Well, we're just going to tamp it down and make sure that it doesn't progress. We're not aiming for resolution." Resolution is what we're looking for in acute GVHD. But with the studies we're doing these days, resolving it is really more of the goal. What we're able to offer patients is perhaps not complete resolution depending on the clinical situation, but at the very least an improvement from where they are. The nature of chronic GVHD is just that, it is chronic, a lifelong problem. So being able to offer some improvement in quality of life with some of these clinical trials is really exciting for patients who are going to deal with this for the rest of their lives.

Erin Kopp

Having patients in clinical trials sounds like a panacea, right? Everyone should be on a clinical trial. It's contributing to you, it's contributing to the now, it's contributing to tomorrow. So then, why isn't everyone on a trial? The first things that come to mind are institutional barriers.

That can start with the providers themselves not knowing what trials are available. Also, research nurses are part of the nursing shortage. How do we foster an interest in our registered nurses and practice providers to be dedicated to clinical trials? It's a niche, there’s a level of expertise that's required. And if you don't have those resources in your own institution, are you going to be able to approve trials that need that dedicated practice? I have seen both of those issues. What about you? You're in a space that has clinical trials. What does it look like?

Adrianne Maurer

Yes, again, at the Hutch, we are very blessed to have excellent research staff. Something that I see quite frequently and struggle with a lot is how much time it takes to get a patient enrolled and start treatment. Sometimes, especially if a patient is presenting with multiple organ involvement or severe disease, you're struggling with, "Well, do I have the time to wait the week or two that it's going to take to get them enrolled in the clinical trial?" Sometimes it's even longer than 2 weeks. You wonder, "Should I just treat them with what I know will work? I know the steroids will help. Should I just start them on steroids and hope we can get them enrolled in a trial down the road or do I have the flexibility to wait?"

And again, this is coming from somebody who has easy access to all of these clinical trials. What is it like for other institutions who may know what trials are available. What’s it like when we know it’s going to take twice as long to get a patient enrolled because it's not right at their fingertips?

Erin Kopp

And then we need to know what treatment we can potentially do if they need a bridge to the trial without excluding them.

Adrianne Maurer

Exactly. We need to know the ins and outs of all of these trials, not just what's available and when, but what the nitty-gritty details are on all of them so that we don't accidentally exclude a patient from a trial while just trying to keep them stable.

Erin Kopp

Right. And APPs can play a huge role in that, right? We're the ones spending a lot of the time advocating for our patients and collaborating with the physicians, using ClinicalTrials.gov and other resources to find the most current clinical trial offerings. If you work in a community practice that does not have clinical trials, but you receive patients back to your practice who may have GVHD, it helps to have a connection at a tertiary center.

For instance, even though I work at City of Hope and I have access to trials, knowing that you’re at Fred Hutch, I can reach out to you and say, "Hey, I have this patient. I don't see any trials that are open here that are applicable." I can then get your clinical expertise and then find out what clinical trials are there. If we can get information about the parameters of the trials, we can avoid making a misstep in terms of prescribing something that could make the patient ineligible.

Adrianne Maurer

I've been thinking about doing a quarterly symposium at Fred Hutch, in conjunction with our long-term follow-up group, to help with outreach to local community providers, focusing on that clinical trial access point. Perhaps this is something we could broadcast on a quarterly basis, or more or less frequently depending on need, to say, "Hey, here's what we are currently offering. Here are the fast facts for each of these studies, the quick inclusion and exclusion criteria. If you think you might have somebody who could qualify for this, give me a call so we can talk about it."

Erin Kopp

That's a major unmet need. I get excited thinking about that, especially if you're able to do it regionally. The barrier then is how do you get patients to consider clinical trials? One potential issue that comes to mind is cultural background. In the United States, we can't ignore the fact that there have been many groups who have been exposed to clinical trials in an unsafe fashion. And while we have many laws and rules in place to protect people, that level of distrust for the system has not been completely eradicated. So, when we're talking about diversity and inclusion, we need to have intentional conversations acknowledging that right off the bat, and then find effective ways to address it. We don’t want them to feel like guinea pigs. They might think, "I want something that I know is going to work. I'm afraid of being sick. So really, why are you asking me to do a clinical trial?"

When I look at a clinical trial and then explain it to a patient, I want to be able to give comparators. I want to be able to tell them, "Standard of care offers this. In the clinical trial we're looking at, these preliminary results equal this. These are the things that we're thinking about based on what we understand about your disease and the potential benefit."

I start there because these are human beings who have gone through quite a bit. And many people, regardless of the level of understanding they're coming in with, do their best to educate themselves. In my space, I'm only working with adults and adult learning is so different. I have to be vested in the decision-making so that it's patient-directed. Those are some of the tools that I use in those two spaces. Do you experience that? And what kind of expertise can you lend?

Adrianne Maurer

I can echo all of those sentiments. I also compare the side effect profiles. I get nervous using steroids in our older population, and even in our younger population, in patients who have had some bone density issues, patients with long-standing diabetes who haven't tolerated steroids in the past, and patients who've had fractures. And with patients who are already on other immunosuppressants that they're not tolerating very well, I'll sit and say, "Okay, these are the side effects that you're expected to receive from the standard of care. If we went with a clinical trial, these are the expected side effects with this medication." And most of the treatments that we're offering right now involve ruxolitinib, belumosudil, or acalabrutinib, whose side effect profiles are much more tolerable than things like the traditional tacrolimus, sirolimus, and cyclosporine.

That tends to get the attention of the patients. They start thinking, "Okay, well maybe we don't know exactly how well it's going to work, but at least I'm going to feel okay for the most part."

As you mentioned earlier, leaning on the preliminary data from other studies is also really helpful in letting patients know that if we don't have hard and fast data that a certain treatment is going to work for their case in particular, they can look at all of the progress we've made in other areas.

Erin Kopp

The thing that I'm hearing the most in talking with you is that at the core of the therapeutic relationship is trust and understanding. Looking at this whole discussion, it’s clear that the goal is to provide the best care and the most advanced available care with the outcome of trying to improve a patient’s quality of life.

Adrianne Maurer

Absolutely.

Erin Kopp

The pearls that I’m coming away with is that we need to engage patients and ask each of them, "What is your goal? What does quality of life look like for you? Are we meeting those goals with what we're offering right now?"

There’s the clinical objective side, where we’re looking at labs and the progression of symptoms, but we have to add in that quality-of-life piece. The next part is really bringing a level of understanding and education to the treatments and interactions with the patient. When I listen to you, Adrianne, I feel like I'm listening to an expert. So, if I'm the patient on the receiving end, knowing I have somebody who's invested in me, who also has a really strong working knowledge of what's available, is what's important to me. Because when we ask people to do clinical trials, it is a trial, right? It's a gamble. All of it's a gamble.

Adrianne Maurer

I think you're hitting the nail on the head. The relationship we have with these patients is really important, and they're going to trust us. They're going to listen to us. If we’re suggesting that a clinical trial is the best way for them to go, they're going to believe that, because they've spent enough time with us to know that, as you said, we are really invested in not only their health care, but their emotional and psychological status, too. We’re not here to put the patient in harm's way just for the sake of science. We truly think this could be beneficial.

Erin Kopp

Yes, I think that's an excellent way to sum it all up. This has been enlightening for me, Adrianne. We're on the same coast. We have similar approaches, but I still heard about things you're doing in your space that we don't have here. So, I'm very grateful. Is there anything else that you’d like to say?

Adrianne Maurer

We've already said it a couple of times, but the best advice we can offer is if you think a patient is eligible for a clinical trial, know your resources. Use ClinicalTrials.gov, find the contact information, and try to get a patient plugged in. The best way for us to really engage clinical trial accrual is to share knowledge with each other and to lean on our colleagues. Our colleagues are going to have different experiences at different centers. And just like this conversation with you, Erin, you can learn so much more about what other places are offering and what other treatments are available for patients just by connecting with your peers.