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Webinar: Bench to Bedside: Clinical trials to treat bladder cancer?

Clinical trials are like stepping stones to new treatments, but not enough people consider them as an option. The phrase “bench to bedside” describes how research goes from the scientist’s lab bench to your doctor’s bedside, helping you directly. We have two amazing experts, Dr. Charles Peyton, MD, and Dr. James (Jed) Ferguson, III, MD, PhD, from the University of Alabama at Birmingham, who are dedicated to making bladder cancer care better through research. In this webinar, they explain why getting involved in clinical trials is not just about helping yourself but also advancing medical knowledge.

Year: 2024

Bench to Bedside: Clinical trials to treat bladder cancer? | Part 1

Transcript (PDF)

Bench to Bedside: Clinical trials to treat bladder cancer? | Part 2

Transcript (PDF)

Bench to Bedside: Clinical trials to treat bladder cancer? | Part 3

Transcript (PDF)

Full Transcript on Bench to Bedside: Clinical trials to treat bladder cancer?

Patricia Rios:

Welcome to the Bladder Cancer Advocacy Network Patient Insight Webinar series. I am Patricia Rios, Senior Education and Advocacy Manager and your host for today’s webinar. I’d like to begin by thanking the sponsors of our Patient Insight Webinar series, Merck and UroGen.

Now, today’s topic is Bench to Bedside: Clinical Trials to Treat Bladder Cancer. The phrase bench to bedside describes the process of taking research results from the laboratory into the clinic so that it can directly benefit patients. It’s a short phrase for what is often a very lengthy and complex process. To help us understand this process and the role of patients as it relates to bladder cancer, we have two very special guest presenters, Dr. James Ferguson and Dr. Charles Peyton. Dr. Ferguson is a urologic oncologist and assistant professor at the University of Alabama at Birmingham, also known as UAB. He’s also a staff physician and scientist at the Birmingham Veteran Affairs Medical Center. Dr. Ferguson’s clinical area of focus includes cancers of the bladder, prostate, kidney, testes, and penis with a strong emphasis on urothelial carcinoma. He’s currently investigating the biological ramifications of ARID1A mutations on the biology and therapeutic vulnerabilities in bladder cancer, and has received a Veteran Affairs Merit Award for this project. You will hear more about this mutation during his talk.

Dr. Peyton is an assistant professor also in the Department of Urology at the University of Alabama at Birmingham. Dr. Peyton serves as co-chair of the Genitourinary Oncology Clinical Trial working group and is the principal investigator on several clinical trials at the University of Alabama at Birmingham. He serves as a member of the NCCN Guidelines for Bladder and Penile Cancer and is an AUA core curriculum author. His research interests include quality of life, therapeutic, and outcomes research related to urologic cancer.

I will now direct your attention to Dr. Ferguson and Dr. Peyton so they can begin their presentation.

Dr. James Ferguson:

Thanks so much, Patricia. I really appreciate it and thanks everybody for joining us. We’re splitting up the talk kind of in two parts. I’m a physician scientist, as Patricia talked about, and I’m going to share a little bit about how we get from the bench to almost the bedside. And then Chas is going to take over and talk about clinical trials and bladder cancer and what they give us and how we get there. So if you could advance the slide for me.

Bladder cancer, just like a lot of things, we spend a lot of time thinking about what’s the perfect drug for bladder cancer and how do we design the perfect drug? We want a drug to be absolutely lethal for the cancer cells, but totally benign to all of their normal cells. So that increases your therapeutic ratio so you have cure without side effects. That’s the perfect drug.

In order to get there, number one, we need to understand how bladder cancer cells are different than normal cells and different than normal bladder cells. And we need to design drugs that use these differences as an Achilles heel. These drugs need to have limited effects on normal cells in order to limit the side effects. This is especially important in systemically delivered cells, but even if we deliver it in the bladder, they need to be able to penetrate quickly and effectively through some of the natural defense mechanisms that the bladder has in order to get down to the root of the cancer and kill it. A huge caveat to this is that as we’re learning more about bladder cancer and other cancers, we’re realizing that maybe not every cancer is the same. Maybe there are subtypes of cancer that can be treated similarly. Maybe every single cancer is unique and every single patient is unique and we need to focus on what makes them unique rather than what brings them together in order to truly design effective treatments in a personalized medicine and a strategy. Next slide please.

So just a really quick theoretical view on how bladder cancers are unique. Well, they have unique mutations. We know this from the Cancer Genome Atlas trial in smaller tumor sequencing efforts that bladder cancer cells accumulate specific mutations that are in a fairly reproducible pattern, but different tumors can have different mutations that are driving their growth. They can have different gene expression than normal cells either through epigenetics or transcriptomics, which I’ll talk about a little bit later. They develop ways to evade immune surveillance, which makes immunotherapy that y’all may have heard about very effective. All of this to say that we need bladder cancer samples in order to do good basic science. So on the fourth bullet point, if you are approached by researchers to bank your tumors or blood or urine for genomic research and other research, please consider it highly because it really helps us to have those banked specimens to do really meaningful research on human bladder cancer samples. Next slide please.

This is a screenshot of the cancer Genome Atlas, also called TCGA. And basically what they did was took muscle-invasive bladder cancer samples from about 400 patients and sequenced them to find out what mutations were accumulating in each patient’s tumor. So on the Y-axis… Can you all see my pointer? Probably not, huh? Okay. You can see Patricia’s pointer. So as you go across each column, there is one patient, and every single color in one of those columns is denoting a mutation in whatever gene is listed on the left. Then those genes are ranked in terms of the percentage of cancers that have mutations in them. So TP53 is the most commonly mutated tumor suppressor in bladder cancer at 48%. And then as you go down the row, you see some other genes that are important, including ARID1A, which is number four and is present in mutated form in 25% of patients. So this starts to give us an idea about what genes are really in bladder cancer, try to understand patterns, and see if we can develop drugs that can target specific mutations in genes. Next slide, please.

So just really briefly about the broad strategies of how we study bladder cancer in the lab. The tried and true model is cell culture models. We can take cells from bladder cancer and grow them in the lab on plastic until they become basically immortalized and we can passage them kind of indefinitely. They’re easy to work with. They’re somewhat hard to kill. The caveats are that you lose a little bit of the biological context when you grow cancer cells on plastic. There’s organoids, which if you look to the right on subgroup A or figure A, kind of denoting how we grow organoids in the labs. You take a tumor, you seed it on a matrigel, which is kind of a jelly-like substance, and these tumors will grow in kind of three dimensions.

They lack blood flow, but they have some of the stroma and some of the connective tissue and even some of the inflammatory cells that bladder cancer has. They are short-lived so they’re difficult to passage and they lose some of their biological likeness to bladder cancer in vivo with each passage. But that’s one way to get a little bit closer to the biology of bladder cancer in the lab. These two models allow high-throughput drug screens to sprinkle different medications on these cultures to see what tumors are killed by certain medications.

Then the exciting thing about organoids is that you can imagine a situation where you harvest an organoid from a patient, grow it in the lab, test different medications, and then find the medications that work and put it back in the patient. The trick is doing that quickly enough so that you’re not allowing tumor progression in the meantime. And then finally, the kind of tried and true approach is over and under expression studies to determine which genes and pathways are important for bladder cancer growth. I’ll talk a little bit about that later. Next slide please.

The next step up from cell culture models are animal models. Probably the biggest workhorse in cancer research is the mouse xenograft. And the way that works is you take a mouse and generate a mouse that doesn’t have an immune system so that you can instill human cancer cells in a way that won’t be cleared by the immune system of the mouse. That allows the tumor to grow, and then it allows us to treat the mice with different medications or different genetic changes to see how they affect both bladder cancer tumor growth and also metastasis and spread. So on the right you can see a mouse there with a needle going into its subcutaneous space and planting some cells and resulting in a subcutaneous tumor on the flank. That’s one approach. Another approach is we can inject it directly into the bladder to form orthotopic tumors in the bladder.

And then finally, we can inject cells in the vein of the tail and look for how well and efficiently they form tumors in the lungs as kind of a metastatic model. So that’s probably the most commonly used tool in the lab for studying bladder cancer. Secondly, on the left, there’s mouse genetic models which are not quite as prevalent in bladder cancer as other cancers just because of the genetic drivers of bladder cancer are not quite as robust as other cancers. Third, there’s rats and mice carcinogen models. So this is where we take carcinogens that we have purified initially from cigarette smoke, put it in the drinking water of mice or rats, and they form bladder cancers within months. On the very far right, you can see a schematic there where it’s the cross-section of a normal mouse bladder.

Then we give them in the red 0.05% BBN. Please don’t ask me to pronounce the name of that chemical. It’s very long and complicated, but we call it BBN for short. So we treat them for 12 weeks and then switch them to tap water and then at 20 weeks, we cut out their bladder and you can see that a muscle invasive tumor on the bottom right in the mouse’s bladder. I think that’s important for patients to hear that we can take carcinogens and cigarette smoke and give them in relatively higher doses to mice and give them bladder cancer within a matter of months.

Then fourth and finally, larger mammals for toxicology studies. Once we have a medication that we think is effective for bladder cancer, we can give it to animals. If it’s never been used in man, we want to make sure that there’s no major toxicology issues before we give it in clinical trials. That’s mostly in the sphere of industry where that’s done currently. To wrap up, if we find a good drug or gene that is effective in animals, we can move on to human studies. Next slide please.

This is just one example of some work that I’ve been doing with my group in the lab, just to give you an example of how we determine and find new targets for therapies and then hopefully get them into humans as quickly as possible. We had noticed that from some previous studies, both in fruit flies and ovarian carcinoma, that fruit flies with mutations in ARID1A and EZH2 didn’t survive. They died. And a group of ovarian cancer researchers had found that ovarian cancer cells with ARID1A mutation can be killed with pharmacologic inhibitors to EZH2. And we hypothesized that bladder cancers would behave the same way. And bottom line is we found this to be true and we studied the molecular mechanisms and determined that bladder cancers with an ARID1A mutation underwent a switch in their signaling pathways that led to cell growth and proliferation.

So initially, ARID1A wild type cells proliferate through the MAP kinase signaling cascade. But then on the far right as you see with ARID1A mutation, they switch up MAP kinase signaling and then activate PI3 kinase signaling through the MTOR cascade. And then when you hit them with EZH2 inhibitors, it upregulates an endogenous inhibitor protein of PI3 kinase that turns this pathway off and results in cell death. And on top of that, you can hit it with PI3 kinase inhibitors that are a bit more specific. So EZH2 inhibitors and PI3 kinase inhibitors are already developed and tested and FDA approved in humans for other indications. So we know that they’re safe and we think that they’re effective, so we’re currently working on opening a clinical trial for patients with stage IV bladder cancer with ARID1A mutations to be randomized to EZH2 inhibition. So next slide.

So that’s all that I was going to talk about and that gets us to clinical trials and Chas can take over.

Dr. Charles Peyton

Yeah, thanks so much, everyone. Thanks for inviting us to talk. My name is Chas Peyton. I’m a urologic oncologist just like Jed and do a lot of bladder cancer as well. I’m going to give you kind of the more clinical spiel of this. He’s very much a surgeon scientist and does both sides of the equation. I do more of the clinical side than anything else.

I’m going to talk to you more about the kind of nuts and bolts of what clinical trials are. So Jed gives you the kind of ideas of what happens in the lab and how we develop some of these things. And then what happens once they get to clinic? How does that work? First question that many of you as patients may have been asked by some of your providers is, why should I enroll in a clinical trial? Well, really, clinical trials are the pathway that we actually move this medicine that we develop in labs to clinical practice, which clearly has a lot of red tape around it and regulations that we have to abide by to make sure things are safe and effective.

Clinical trials can address unmet needs in patients. They’re usually specified in the areas where we don’t have good success rates. We have multiple areas in bladder cancer where our success rates need improvement. And they’re used to test new therapies for safety and efficacy, which is the most important thing. Additionally, we can use clinical trials to compare new therapies against what’s considered gold standard or other treatment options as well.

Another reason that clinical trials exist is not necessarily just therapeutics, but also trials to address quality of life in practices that we do so need to know that for muscle invasive bladder cancer, one thing that’s standard practice is removing your bladder, which has a lot of quality of life implications and clinical trials allows us in a way an avenue to study those implications and what that means to patients in terms of survivorship and how they do long-term. Patient-reported outcomes is a critical component of clinical trials. It’s always incorporated. Then, of course, obviously it’s devastating to be diagnosed with something like bladder cancer, but if you can find a silver lining in anything, participating in clinical trials can give you the opportunity to pay it forward to those folks that are not yet diagnosed and may be in the future. So you can go to the next slide please.

This is important in understanding how clinical trials work. So there’s different phases of clinical trials. So the preclinical investigational studies and work that’s done for years and years and years is exactly what Jed was just telling you about. That takes decades, on the order of decades for some medications and some therapies. Then the drug is approved for testing in humans through a variety of regulatory pathways. And phase 1 studies are really where things start. Phase 1 studies are very low numbers, very few institutions and sometimes they are single investigator studies that are very limited and very tightly regulated because these are new drugs, new therapies, new things that we believe we know how they’re going to interact in humans, but we really don’t know. We don’t know until they’re tested.

The risks are can be a little bit more dramatic in some of these patients, but the opportunities are there, too. So those are very limited studies that are done very closely and it’s just the drug that you’re talking. There’s no comparison on them. You’re just looking at safety. It’s essentially safety and effectiveness. So looking at the safety of the medicine and what the effective dose or regimen is to get the patients to the appropriate biologic availability of that medication or that drug to make sure it’s effective to see it works.

Phase 2 studies includes a lot more patients and it’s more focused on safety as well but more efficacy. How well does this work in the general population amongst a lot of patients? Then the next step is phase 3 is large rollout studies. We’ve proven that this is safe. Now we really want to know more about the efficacy and more of this secondary end points on how it impacts other measures, not just cancer cure or cancer treatment, more quality life, symptomatology, various other things.

So once a new treatment has gone through a phase three study, they can be submitted to the FDA to get reviewed and confirmed for safety and effectiveness and the FDA may or may not approve it for whatever it is applied for. The study may prove that it’s effective for one component of cancer treatment but not another, and it’s up to the FDA to review an enormous amount of data that’s collected in phase 3 studies to decide whether or not it’s appropriate to approve it. And then phase 4 studies are really beyond drug approval, and that’s more like comparing one drug to the other, seeing what’s even better once we get beyond the approval of these drugs. Next slide please.

So participating in clinical trials. This is a slide from UAB where we have this posted on the website. The first thing you have to know is what trials are available, and this can be found from your local provider and websites. I have a link right there in the middle of that wheel. It says Find the Right Trial, and you can click on the link and be linked right to a bunch of studies at UAB to investigate what’s available. Then if you know a trial is available, and it may not be available where you are getting treated, but there may be one in the area. And if you ask your provider who is taking care of you to investigate it, if they don’t have that opportunity, others may if you have the means to travel there. And then there’s a pre-screen eligibility where we see if you’re eligible by the general criteria, which is age, stage, history, and various labs.

And if that pre-screening checks out, meaning that you meet all the criteria to enroll in the study. Then you do an legal informed consent. Informed consent process is something we do every day in the hospital for various things. But in clinical trials, it is a true mountain of paperwork sometimes. A lot of times patients are a little burdened by the amount of stuff they’re handed to sign. A lot of that is necessary for protection of both the patient and the institution and the various folks and stakeholders involved. But it is a lot. It’s a lot to throw a 90 page document in a patient and expect them to read it, understand it, and sign it. This requires kind of a little bit of handholding and understanding and explaining what’s what. So a lot of times, it’s a lot of trust that the folks that are telling you to enroll in this really know what they’re talking about. And for the most part, people do. They wouldn’t be offering you the study if they didn’t believe in it, aren’t thinking it was important.

And then it goes to the real screening criteria. So once you sign an informed consent, then we have to get even deeper into the criteria for screening, meaning all those labs we got were just age-appropriate labs and stage. But now we have to get… In certain studies, you’ll have to get pathologic confirmation of the diagnosis from a centralized pathology that’s sponsoring the study. You may have to get labs drawn at a certain place where they can regulate the lab draws and various other detailed screening things that allows us to check all the boxes to make sure that the clinical trial you’re enrolling to, that everything is standardized. When you have medicines in the pre-clinical setting in an controlled lab, you’re able to control all the variables that you’re testing.

In trials, it’s much more challenging because you’re enrolling multiple people throughout the entire nation and maybe lab practices aren’t necessarily standard across the board, so there has to be some way to standardize those things to control for all the differences amongst institutions. That can be quite a challenge and one of the headaches of doing trials like this. Then enrollment. You get enrolled into the study and some studies are randomized, some are not. Randomization means you’re assigned to one treatment group or the other. And sometimes the patient will know what treatment they’re getting. Sometimes they won’t. Sometimes the provider will know what treatment they’re getting and sometimes they won’t. So double-blinded means that the patient doesn’t know what they’re getting. Neither does the provider. Or single-blinded, the patient doesn’t know, but the provider does.

Blinding a study is really important in reducing our biases of what’s going to happen when we report the results. If I don’t know if you’re getting drug X or a placebo, I’m less likely to monitor you or think about you or presume that something is going on that may not actually be going on if I really don’t know what medicine you got, right? Some trials that’s available and you can do that, but it can’t be done in all trials. And bladder cancer has a particular area where it’s hard to do that, particularly when you’re doing surgery. You can’t randomize somebody to get surgery and not know that they didn’t get surgery or certain medicines that go in the bladder that have clear side effects and whatnot.

So non-randomized studies, you’re just testing a medicine or testing something else that just you observe over time. And a lot of this you have baseline study characteristics and patient-reported outcomes that you have to address. So then as you participate in the study, you have regular monitoring and you assess the effectiveness and the side effects of these medications or whatever intervention is ongoing. Participation is a lot more paperwork, a lot more appointments than probably you would get otherwise. But that’s part of the benefit of enrolling into study is that you get a lot of attention, sometimes more attention than you want.

In terms of follow-up, there’s a standardized surveillance. Surveillance has a lot of variability amongst providers sometimes even though there’s guideline-dependent surveillance. For something to be standardized, we have to make it the same for everyone. And the follow-up times can be variable. So next slide please.

Again, what are the benefits of participating in a clinical trial? Well, the benefits of participating are access to treatments that aren’t necessarily available elsewhere, meeting an unmet need that we don’t have, and therapeutics for hard-to-treat conditions that have failed multiple other treatments. And therapeutics where no other options are available like that unmet need I was talking about. Again, lots of attention, lots of support. When you’re on a clinical trial, typically you’ll get contact information from a coordinator and you’ll have their work phone. Ours, at least, there’s a direct line to that person. If you’re not on a trial and you try to call your physician, everyone knows the headache that you get when you answer a nurse. Then they give you this person, then they give you this person. Eventually, you just leave a message and 72 hours later, then finally somebody gets back to you on what your question is.

Well, when you’re on a trial, you get a direct line, usually. Not all of them, but usually you’ll get a direct line to somebody who has a direct answer waiting for you. And that’s because you’re important and you’ll get a lot of support and there’s a lot of money invested in these trials that provides that. You can contribute to advancing medicine. And there’s survivorship benefits obviously.

So what are the risks and side effects? Well, sometimes they’re new medicines. We don’t know exactly how risky again they’re going to be. Although we think they’re safe or else they wouldn’t be in trial. Side effect profiles are less well understood, and there’s a possibility that if the medicine that we put you on is ineffective. There’s certain space in kidney cancer that we deal with right now that we’ve had countless trials in the adjuvant space for high-risk kidney cancer that have been negative. And it’s been incredibly frustrating to put these patients on medicines that have side effects and they really haven’t helped. But that can happen. That’s part of trials.

And then we also wrestle with overtreatment in some of these studies and undertreatment. And then they can be time-consuming both for the patient and their support family around them because there’s a lot of appointments, a lot of phone calls, a lot of visits. So next slide.

What are the real-world expectations, why you would put on a trial? Again, I just mentioned the dedicated coordinator and support staff, lots of phone calls and appointments and discussions. We have to be strict about the adherence to the protocol. That’s hard because in real-world medicine outside of a trial, there’s flexibility. We say you need the surveillance study in three months. We give you a pretty flexible window with that. On trial, we’ve got to get that surveillance study done in three months within a seven-day window or else the data may not be allowed to be captured going forward for that date because it will get flagged or dinged or whatnot. Then many of your trials require more appointments, labs, imaging, and studies that would’ve been used otherwise. They’re all basically standard of care, but sometimes we would go up and above the labs that you would need, particularly when you’re having an investigational medicine or trying to understand what it does.

Paperwork. Tons of paperwork. Legal consent can be a burden like I talked… The other thing is I haven’t talked too much about is that a lot of these studies also include patient-reported outcomes, which are surveillance questionnaires. They can be kind of a burden to complete sometimes. But the benefit is we’re learning more about what these medicines and what these treatments do and the side effects and quality of life implications of these medicines when you complete those. But they also kind of make the patient have a little bit more introspection and understanding of what’s actually going on with them and be able to better describe their symptomatologies.

Travel. If you’re at an institution that has a study and it’s far away, that can be a problem for some patients. And telehealth is still reasonably new since Covid, but it may or may not be allowable for various studies. Next slide please.

What does it look like on my end when I’m enrolling patients? This is a study that I have open at UAB, and I can go on this website right here and I can see exactly what studies are available. These are all nationally listed. This is a co-op study through Alliance, which is a big group that UAB and various big institutions are a part of that we can get these studies through our regulatory system pretty quickly because they’re run through these mega co-op groups. When I look in here, I can see exactly who the study champions are, who I need to call if there’s a problem, and then I can see the accruals down on the right hand corner. This study, for instance, we’re looking at patient accruals. UAB is the green one that has the nine next to it. So we put nine patients on this study, which is good. That means we’re getting people enrolled. We’re the second highest enroller for this study in the nation. That 21 is not one institution. That’s a bunch of institutions.

Anyway. So this is kind of what we see on our end and monitoring these because these are big studies usually that are done through multiple institutions with a big enrollment criteria. You can’t get it all done in one place. You never can. So you have to have a diverse population throughout the nation. Next slide.

So this is finding clinical trial opportunities. You got to talk to your treating provider, ask for a specialist if you don’t have one, if you’re just seeing a general urologist in the community. Sometimes they’re not going to know necessarily about trials if they’re not as interested in bladder cancer as Jed and I are. So you may want to say, “Hey, I’m interested in learning more about trials. Is there any places around here where I can have an opportunity for that?” You can go on this website. You can go on NCI and find out trials. But even better than that is clinicaltrial.gov. That’s the easiest place to find trial opportunities. The website is a little hard to navigate when you’re a patient, but with a little bit of clicking around, you can probably figure it out. BCAN is another obviously great support network for trials, and then there’s local support groups you can go by as well. Next slide.

Then just briefly, I’m going to go over just as an example… We’re a typical big academic institution. What are the trials that we have open at UAB? I’ll just tell you for bladder cancer. This is the Alliance trial. This is for non-muscle invasive bladder cancer. It is a phase 2 trial of intravascular gemcitabine plus Keytruda, which is a medicine made by Merck. It’s a systemic infusion, so it’s both local treatment with chemotherapy and then systemic treatment with immunotherapy. That’s for BCG unresponsive non-muscle invasive bladder cancer. So that’s one.

And then we have another non-muscle invasive bladder cancer trial. So let me just talk. So the unmet need in that first trial is that these are a specific group of patients that don’t respond to BCG and they’re the highest risk of disease progression to muscle invasive disease. So that’s the niche of where this trial is fitting in. There’s a lot of trials in this space. This is one that’s been enrolling reasonably well, will hopefully conclude within the next year in terms of enrollment.

Then we have the BRIDGE study, which is also meeting another unmet need. Many of you as bladder cancer patients, you’ve heard about the BCG shortage that we are always suffering from in the community. This is asking the question of, well, can’t we use something other than BCG? Let’s see, we’ve been using BCG for 40, 50 years. This is a great trial. This is going to be really helpful for patients. One of the most helpful trials I can think of. Basically we’re just randomizing… We have the data now to support the upfront intravesical use, in the bladder use of two different chemotherapies in the bladder may be as effective as upfront BCG. This is basically comparing the two upfront. You see this is a phase 3, whereas the phase 2 is above just one medicine, no comparator arm. This is a phase 3 where we’re comparing two drugs to each other. Next slide please.

And then finally, this is a more advanced… This is an industry sponsored trial we have at UAB, which is looking at a really revolutionary, very interesting way of delivering medicine. And it’s from Janssen. And basically this is for muscle invasive bladder cancer. We’re giving you neoadjuvant therapy or therapy before bladder removal surgery. And it’s using cetrelimab, which is an immunotherapy medicine that’s basically… To describe it easily, it’s Janssen’s version of pembrolizumab, which is the other medicine I was just mentioning. It is a PD-1, PD-L1 inhibitor that causes your own body to kind of fight the tumor. Then we know that that would work in neoadjuvant therapy.

So the trial is randomizing patients to getting or not getting this device called the TAR-200, which is this little device down here. It looks like a pretzel. It’s inserted into the bladder, and as opposed to just giving an intravascular dose of medicine that’s liquid that you pee out, which is how we usually do it, this medicine elutes the drug through this little device in the bladder as you make urine and it stays in there for two to three weeks. Then we take it out and put a new one in. This is a very revolutionary type of delivery of medicine that we know is effective, but we’re trying to evaluate whether or not this is effective in patients with muscle-invasive disease. The trial has been out and it’s been proven to work in non-muscle-invasive disease. Now we’re seeing how effective it is in the muscle-invasive setting of this trial. So you can go to the next slide, please.

This is what the trial is just showing you and how it’s randomized. There’s two arms. Some of the patients are going to get the cetrelimab plus the device in the lower arms. Some people will just get the immunotherapy alone. That’s classic of how you’re organizing a clinical trial comparing one treatment to another. Then there’s primary and secondary endpoints. The primary endpoint being assessment of pathologic complete response and secondary endpoints being tolerability and recurrence-free survival. You can go to the next slide, please.

And then lastly, not all clinical trials investigate medicine. So this is a trial that we opened at UAB that’s now closed. It’s nationally been enrolled and BCAN has been completely involved with this from day one and it’s called the CISTO trial. It is comparing intramuscular therapies to surgery treatment options and basically is a quality of life study. So people in this finite group of patients that I mentioned earlier where they’re BCG unresponsive disease, they have the option of trying… The best option for cure is removing your bladder. Most patients don’t want that done, so there’s other bladder-sparing methods with various different intravascular medicines to try. This study was basically looking at the quality of life assessments of what went into that choice first of why that patient chose to not have a cystectomy or to have a cystectomy upfront, and then how they did over a long period of time in terms of health-related quality of life, urinary, sexual function, treatment preferences, decision regret, financial toxicity, you name it. This was a quality of life trial that was looking at how patients responded to their treatments.

This is just as important as all these medicines that I’ve been talking about the whole time because if we don’t know how patients respond to standard of care or treatments or what’s the importance of their quality of life long term, then we really don’t really know how well we’re treating them. So a very important other concept in trial literature. The next slide.

So in conclusion, we’ll wrap up here, your clinical trials, they’re great opportunities to meet unmet needs and move medicine forward while receiving some cutting edge therapies and support. Bench to beside, 10 years minimum. Wouldn’t you say, Jed? At least. And then consider enrollment and ask for opportunities locally. And with that, thank you and we’re happy to answer some questions and open this up for discussion.

Patricia Rios

Great. Thank you both for an excellent presentation and for covering what happens in the lab and then what happens at the clinic or bedside. So Dr. Peyton, you mentioned the timeline from bench to bedside is around 10 years at least. You also went through the different phases, phase 1, phase 2, phase 3, phase 4. I’m curious to know how many of the trials actually make it? What percentage make it to that phase 3, phase 4? There’s a lot of investments in these trials. Do all of them make it to the end?

Dr. Charles Peyton:    

Good question. I don’t know the exact answer to that question, but it’s very limited. And Jed, you can comment on this more than I can. Most investigational drugs in the labs don’t even make it to the phase 1 trial and then it is attrition thereafter. I don’t have an absolute number for you, but there’s a lot of great ideas in the lab that don’t pan out in humans, and that’s repeatedly..

Dr. James Ferguson:  

I think we should be a little bit specific about that timeline. I think what you’re talking about is discovery of a drug, testing the drug in vitro, in the cells, and in animals, moving to clinical trials, and then de novo, a brand new drug. That takes a long time.

Dr. Charles Peyton:    

Right.

Dr. James Ferguson:  

But for example, the study where I was talking EZH2 inhibitors and PI3 kinase inhibitors, those are medications that are already being used for different indications. So that’s a little bit different. They’re already FDA approved and being used in humans. So if you find a new indication for them in bladder cancer, the timeline is a lot quicker. I don’t want to paint a bleak picture like everything is going to take decades. In some cases, it’s a little bit quicker than that.

Patricia Rios

Thank you for explaining. I think that speaks about the complexity and that it’s not a linear process necessarily and just so much that there is to learn about this. You talked about different clinical trials at UAB and there’s a question from one of the participants who’s interested in knowing how the clinical trial findings at UAB are shared with other bladder cancer researchers.

Dr. Charles Peyton:    

That’s a good question. The three bladder cancer trials that I mentioned are national trials. They are not my trials, I’m just the leader at UAB, right? There’s a national PI as well, like the BRIDGE one where I was talking about the upfront BCG versus… It was a phase 3 randomizing. The lead PI on that is Max Kates. He’s at Hopkins, I know him and he asked me to open the trial, so I opened. Urology is not that big of a group. Urologic oncology is not that big of a group. And then the people that really like bladder cancer in the country, we all know each other. We go to meetings annually and then we get updates on these big trials on how they’re doing, how they’re accruing. I get periodic emails from the leads on these nationally as far as how well they’re enrolling and whatnot. It’s constant communication.

And when you’re talking about big clinical trials that have a lot of money invested in them, a lot of dollars, the sponsors who are paying for it are monitoring that data very closely. There’s constant communication on what the results are. Now, if you have a local trial, which can be done … an investigator initiated trial, which is a local trial in your own institution, that’s something that we always want to do and strive to do with something like what Jed is talking about. That data would be kept here. We would not necessarily make it public until we understand more of what our data means because no one else is looking at it. That’s a very different scenario than what I had described.

Dr. James Ferguson:  

Then ultimately, you share your findings at conferences, national conferences, and BCAN think tanks and publications and get the word out there to get on the stump and share to the world what you’ve learned.

Patricia Rios

Thanks for answering that.

Dr. Charles Peyton:    

Any more questions?

Patricia Rios

There was a question that we… You mentioned the cost on the researcher’s side. Are there any costs for the clinical trials for participating for patients? Do insurance cover them? What is the patient’s financial responsibility, if any, if participating in a clinical trial?

Dr. Charles Peyton:    

Usually they’re completely covered. With any clinical trial, there’s standard of care and your insurance in and of itself will cover standard of care. They’ll cover that. But drug expenses and all that stuff, the insurance companies are never going to pay for, are not paid for by the patient in general. For instance, that trial I discussed with the company that was sponsoring is Janssen. I mean, Janssen has invested millions and millions of dollars in this and it’s paid for. The cost of the patient shouldn’t be any more than standard of care. In fact, it’s less and a lot of times because for people that are traveling a lot of ways, there’s ways to petition the company to give you stipends for travel and various other ways to get reimbursed for some expenses that may be out of the ordinary for some folks if you’re coming a long way, for instance.

Patricia Rios

Thank you for answering that.

Dr. Charles Peyton:    

A couple other questions we can address if you want us to. Rose was asking about radiation before surgery. Not usually would be the answer there. And then they asked about EV, which is a new nectin-4 inhibitor that is a new type of chemotherapy and it has been doing very well. Results have been good with a lot of that. Neither Jed and I are medical oncologists. Our colleagues in medical oncology are the ones who give those medicines. We get to see the results of them a lot of the times. The results from the EV medicine when it’s combined with immunotherapy has been very robust so far in my experience. There’s a big trial ongoing right now that will be the updated results from GU ASCO, which was done several months ago, was very encouraging but not conclusive.

Oh, good. So your husband was on trial at Penn, so he probably gets treated by Phil Pierorazio, and we all know each other there.

Patricia Rios

One of the questions that we got during the registration process was around bladder transplant research. Is there anything around that that you can share with us today?

Dr. James Ferguson:  

That worked very well, but I could tell you that just off the bat, the challenge with bladder transplant is going to be every transplant needs vascular supply. And in order to make vascular anastomosis with the small and multiple blood vessels that go to the bladder is going to be the major barrier there or one of the major barriers. So I think that’s something that people are trying to get around and address.

Dr. Charles Peyton:    

There’s work in the mid to early 2000s on, not necessarily bladder transplant, but scaffold matrix bladders that have been seeded with people’s own stem cells to grow urothelium. That was done in the early 2000s and it was well investigated and not particularly robustly successful.

Dr. James Ferguson:  

Again, because of blood supply.

Patricia Rios

Good to understand that. And then there was also a question about tumor genomics profiling. At what point should that be done for a patient, and should a patient request that?

Dr. James Ferguson:  

Yeah. That’s a great question. I love doing these because the patients on here are so smart and so well informed.

Dr. Charles Peyton:    

Yeah, that’s right.

Dr. James Ferguson:  

It’s great. But it’s a moving target. It’s not always covered by insurance currently. I don’t think we have enough data in each decision point to support it for the payers. So that’s fairly variable. You can pay for it out of pocket. Now, let’s just assume that money grows on trees and we could get it done for everybody. We don’t always understand how to interpret the data and act on the data. That’s the next big thing is trying to make sure that we understand how we can act on the data. I think we’re a little bit further along in that process in the stage IV setting. And as we get more knowledge from stage IV, we’ll be able to hopefully trickle that down to earlier stages as well.

Dr. Charles Peyton:    

Jed is right on the money. I mean, oncology just in general has grown tremendously. Then this is what precision oncology will be. We’re not there in every cancer, but that’s the idea is to tailor the treatment to the patient’s genomic profiling of those tumors. Because a lot of times, we over treat patients. A lot of times, we under treat patients. And understanding that is what he’s commenting on. It’s not there yet, but within our lifetime, it will be hopefully commonplace. But again, like anything else, getting it paid for is hard.

Dr. James Ferguson:  

So the short answer to your question, I think if you had the means to get it done and can afford it, I think you’re not going to lose much by it. But I think at some point in the near future, we’ll have a better idea how to use that data.

Patricia Rios

Related to clinical trials, do they often cover the cost for profiling?

Dr. Charles Peyton:    

It’s often incorporated in many clinical trials, yes, because that data is really important to see how medicines or therapies will react with some genetic mutations and not others. So it’s very common to have that.

Dr. James Ferguson:  

And it’s getting cheaper and cheaper and quicker and quicker. So it used to be when they sequenced the human genome initially, it took years and years and years and years and billions of dollars. And now it costs about a thousand bucks and takes a couple of weeks. So it’s just amazing the technological advances with next generation sequencing.

Patricia Rios

That is very true. I think about when the genome project got started, but it also reminds me of a conversation we were having before the webinar started about research in bladder cancer and how many advancements there have been in the past five, 10, even a year. So as we reach the end of the webinar, I wanted to ask from both of you, what is the single most important message you want our participants today to leave with?

Dr. James Ferguson:  

Chas, you want to start?

Dr. Charles Peyton:    

Sure. I mean, we were talking about clinical trials today. I guess my most important thing to say is that, as a patient, you should be open to those opportunities and talk with your treating provider about them, if any are available to you. Sometimes you’re not right for the trial or you won’t… And that’s okay, too. But first step is at least asking.

Dr. James Ferguson:  

And I would just say keep the hope and keep plugging, and there are amazing possibilities in the near future and in the pipeline. So stay involved with BCAN and ask your providers for information and be an advocate for yourself and just keep the hope up. I mean, we can all beat this.

Patricia Rios

Those are great words to bring us to close. I want to thank both of you, Dr. Peyton, Dr. Ferguson. Thank you so much for taking the time to share information about clinical trials and answering questions from our participants. I also want to thank our sponsors, Merck and UroGen, for making this webinar possible. And of course, to our participants. We hope to see you next time. Have a great evening, and thanks again for joining us.

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