PaCES trial: Dr. Zell (2022)

This is an automatically generated transcript.

Manju George 0:00
Hello everyone. I’m Dr Manju George. I’m the Scientific Director at PALTOWN Development Foundation, the nonprofit that supports COLONTOWN. And today we have Dr.Jason Zell with us, who’s going to talk to us about the PACES trial. But before we get started, I want to ask about how he got involved in doing in being a GI oncologist and doing this, this kind of work. Welcome, Dr. Zell.

Dr. Jason Zell 0:26
Thank you. Thank you. It’s an honor to be here. Yeah, I’d be happy to talk about that. So I remember in fellowship being pulled in many different directions, but by many different principal investigators, it was really the patients, one thing I love about gi oncology is the interdisciplinary nature of it. As a GI oncologist, I never feel like I’m the patient’s only resource, right? They have so many people around them, the colorectal surgeon, the surgical oncologist, radiation oncologist, interventional radiologist, and even in advanced stage or early stage, we’re all working together. We have 14 tumor boards at UC Irvine, where I work. Three of them are dedicated to gi oncology, upper GI, lower GI, hipato, every single week. So just a really exciting multi disciplinary disease. Now, specifically, I’m a cancer prevention researcher. And to that end, I had two legendary mentors. One was Frank Mason, who was 2008 ACR American Association of Cancer Research, Cancer Prevention researcher of the year, which is a global award. So he was a long time chemo prevention expert. And then my other mentor was Hoda Anton Culver, who trained under Henry Lynch at Creighton and became a very well known cancer genetic epidemiologist here in California. Because of her, cancer is a reportable disease in California, she was just named in the top 1000 women of science in the world. I think she’s 349 which is pretty good. And so I’m very proud to have two outstanding mentors, and they kind of with the cancer prevention and genetic epidemiology, both those lent very well to Colorectal Cancer Research and Prevention.

Manju George 2:13
Thank you very much for that. I think this topic is also of great you know, relevance to patients, because they’re they’re always concerned about what they can do. And then here in this trial, you’re saying that there is something that can be done

Dr. Jason Zell 2:30
Right, exactly correct, that actually comes from the patients. It’s usually considered the teachable moment when a patient has completed therapy, and then they ask, What can I do? Now, there wasn’t a lot to offer, but in the prevention world, we do have this the PACES trial. Today we’re going to discuss PACES preventing adenomas of the colon with eflornithine (?) and solondak (?). This is a double blind, placebo controlled phase three trial of these two drugs, which we’ll talk about more if we’re not to prevent recurrence of high risk adenomas and second primary colorectal cancers among patients with stage zero to three colon or rectal cancer. And there’s a lot of people involved with any cooperative group study. I have my co PI listed there, Paul Brown, Joe Unger, statistician, Robert Kraus on the surgical side, and then the NCT and CO PIs, which are very instrumental in keeping this trial going over the years. So this is the outline of the talk today. I rather than just give you a few slides on the trial, I want to give some background into Colon Cancer Epidemiology and Prevention, and then I’ll just briefly introduce the concept of chemo prevention, that is using drugs to prevent cancer, and really limited to aspirin and then the polyamine inhibitors. And that’s exactly what eflornithine and solondak do. They inhibit something called polyamine synthesis. So we’ll talk about that now. This slide is it’s really misleading, because colon cancer stage is not determined by the size of the tumor, like it is in lung cancer and some other tumors. It’s determined by the depth of invasion. So early stage adenomas, pre cancer, or in situ cancer, actually at stage zero, right there, those patients are eligible to be enrolled in paces, because we realize it’s just a spectrum of disease. But if the disease breaks through the wall, it’s a certain category of stage two, and then it goes into the lymph node. Stage three. If it spreads beyond that, it’ll be stage four. Patients present in quite a variety of ways, constipation, alternating Diarrhea-Constipation is common. Weight Loss blood in the stool, sometimes just iron deficiency anemia, where, because of microscopic bleeding in the stool, patients lose iron slowly over time, and that might be picked up in primary care doctor’s office, or just from fatigue. Maybe a patient has fatigue, and somebody orders a labs, abdominal pain, and then also, it really depends on the Site, Colorectal cancer is really different. It presents in the, you know, low rectum versus the right side of the colon. Presentation can be quite different, so more more bleeding and maybe possibly more symptoms on the on the left side or in the rectum. Next slide is here, showing this is not something unique to United States. In fact, it’s number three in terms of the most common global forms of cancer, at 1.8 million, and in terms of death, it’s number two. And if you look number two, three and four, top cancer puzzle does they’re all GI malignancies. So among GI malignancies, you know, these represent a major burden to the world, not just here in the United States. I have a lot of slides on statistics because, you know, I enjoy epidemiology, and I think for cancer, there’s a couple interesting points. It’s the number three cancer among men and women in the US, and the number three in terms of causes of death. Now, breast cancer is rare in men, and prostate cancer doesn’t occur in women. So if I’m writing a grant, I’m going to say that Colorectal cancer is the second most common cancer among cancers of men and women combined. So you might hear those numbers differently. Now here we’re looking at the green lines. The incidence of colorectal cancer has gone down since the 70s, and that’s largely because we have a unique screening program where at the time of screening, unlike prostate screening or breast screening or lung screening, at the time of screening, you can actually remove the precancerous lesion. That’s very unique to colon cancer screening. And of course, I’m talking about colonoscopy. Here’s some circumstantial evidence to show that as colonoscopy rates have risen, incidence rates of colorectal cancer have declined, but you do see that colonoscopy incidence is kind of plateaued. This is it’s not a test for everyone. I mean, I wish I’ve had mine. That’s all I can say. You know, I wish it was a test for everybody, but I realize it’s not, because almost 40% of patients are not getting it. So we do need better tests. We need tests that are or maybe just refined guidelines for at risk and low risk populations, because there’s just a proportion of patients that are unable or unwilling to do colonoscopy, but it’s the best we have now. In terms of race, ethnic disparities, there are some differences in this disease, uniquely, where African Americans have higher incidence and worse mortality. You can see over time, incidences declining in African Americans and whites, and mortality is declining, but there is still a disparity there, and it does show up as you look at some of the slides that following and also in other studies of colorectal cancer. There’s a number of reasons for this. When I’ve done a number of studies on mortality in colon and rectal cancer survivors, typically in our studies, anytime we’ve looked at this, it’s attributed to other things. You know, the more you can account for treatment differences, differences insurance or socio economic status. This disparity tends to disappear, but more needs to be done to eliminate it, and this is what I was referencing. There’s a lot on this slide relative survival by age and also by race, ethnicity. So there are some differences by race, ethnicity, but the probably the real take home point from this slide is to just show you. Let’s look at the difference here on the left, all stages, 64% survival. That’s just the bottom line, 64% so why isn’t that 100% now look in local stage, cancer is 90% survival. I mean, it’s, it’s extraordinarily high, and yet distance disease is only 14% and that’s something like we see in cervical cancer, which is why these are two cancers that are really uniquely suited for prevention, prevention strategies and screening. Right? If we could, if we could just catch every single colon cancer when it was early stage, our off stage survival over here, instead of 64% would be 90% but unfortunately, we don’t. Many patients are somewhere with more advanced disease. So that’s really the challenge. One of the things I find fascinating about studying this disease is that we can divide it into categories of risk, more so than many other tumor types, but colorectal cancer, we have a setup what we call intrinsic risk factors and extrinsic risk factors. Intrinsic are those you can’t do anything about right? You’re born with them, your age, your personal history of polyps or cancer, inflammatory bowel disease, race, ethnicity, family history. Then an inherited syndrome. On the other hand, though, there are certainly modifiable risk factors, and we call these extrinsic risk factors, diets such as processed meat, different cooking methods like smoking meats, for example, being physically inactive or obese. Those are separate risk factors, and the other ones are lower risk factors, but these are things that are modifiable. Now, in terms of genetic risk, there is, I mean, there’s multiple genetic familial colorectal cancer syndromes, but these are the two most common familial abnormal posts and Lynch syndrome, hmpcc, hereditary non-polyposis of the colon. So you can see lifetime incident. So Colorectal cancer is 100% for patients with FAP, they look like the patients in that dissected colon here, where they have hundreds or 1000s of polyps in the colon, and eventually one of those will turn into cancer. So the treatment for these patients involves prophylactic colectomy, total proctocolectomy We remove the colon Lynch syndrome. You see, however, maybe 60% are proxy, so it’s not 100% lifetime risk. And then the general population is much here, and you’re starting to see that the over age 60, the rate does go up. Now this is I’m going to take a little left turn here just to focus on something that I was involved with back in the day. So this was published in 2014 this was my star student, genetic counseling student, Katie Catherine Singh, who did her genetic counseling thesis with me, and we were interested in some of the rates in Los Angeles County, we saw some differences by race, ethnicity in young people, which, which was really striking to me. It was, it was at one hospital in LA, and I thought, Gosh, could that possibly be happening in the rest of the state? So we had access to the statewide data set, and we looked at it. So on the left, I’m just showing you by gender, males a little higher instance than females, but showing that risk of this disease goes up over the age of 50, and really over age 60, that’s where the highest incidence rates are. So we looked in California at a large number of individuals with at risk for colon cancer in our state, and you could see this, bapc is the number only focus on. It means by annual percent change. So every two years, how much does the risk change? And it was only in people under age 50, where we saw that the rates were increasing that was really alarming. Because, as I showed you earlier, colon cancer rates have been declining since 1975 and another thing we found, which is not shown in this slide, is some of the the subsets that were affected, greatest were groups you would never think of as being at high risk, like 30 year old females that are Hispanic. That’s just not a typically, commonly discussed risk factor. And so overall, I think it’s important to look at the number of cases like you see 514 in the young group for men, or 438 These are small numbers compared to, you know, 20,000 in the eight year olds in each category, 32,000 so it’s there’s not an epidemic of colon cancer occurring in the young. That’s not the message here. But the message is the only group where colon cancer rates are rising is in young people, where we’re not screening in everyone else has negative rates, meaning the rates are going down over 50. So we weren’t the only ones to show this. There was three studies in total before this one came out, and this was one that really grabbed everybody’s attention. It was the national study in J N C I, three years later. And I think my quote with that in the New York Times was it was a little bit aggravated that, you know, the message still hadn’t gotten out three years later, but the question still is the same. What is the reason for this, and what do we do about it? So ACS updated their data in 2018 and just shows for men and women. This is the top graph shows rates are rising in men and women that are under age 50, and everyone else is in the bottom graph showing that the rates are going down. So it’s this unique construct, and this is by age group. If you look this is this for, you know, men on the left, women on the right. It’s really great graph. It’s a little complicated, but it shows you, on a logarithmic scale the magnitude of the effect. In other words, 20 year olds. There’s not a huge burden of cancer in that population, but the rates are going up. So it’s trying to give a balanced picture of what’s actually happening. So what was the upshot? Well, this in 2018 the American Cancer Society updated their guidelines to allow screening to start age 45 It wasn’t until 2020 that USB STF gave that a Grade B recommendation. So it really takes time to make change, and that change was considered to be not quite enough by most societies, but that’s where we’re at. A change was made. Maybe in a few years, it’ll be even lower, but we’re not. Area right now, we screen everybody, unless you’re an Irish group, would be screened earlier, but every average person will be screened at age 45 so with that, I want to shift to just a very brief introduction of carcinogenesis, which comes from Greek meaning cancer formation or the beginning of cancer, and really to understand cancer prevention. That’s what my mentor taught me, Frank Mason, you must understand how cancer is formed in order to prevent it. So here you may have seen this before. It’s the famous paper by Burt Vogelstein. Some people call this the Vogel ground, named after him, just showing that one of the hallmarks of cancer is that you get this progression from normal mucosa to a dysplastic change, which is like a pre cancer, to an early adenoma, polyp, to an intermediate adenoma, late adenoma, and then finally cancer and subsequent test as well. That’s already an important observation, but remarkably, each of these steps are characterized by genetic and epigenetic events, things that can occur to, let’s say, silence DNA so that certain proteins aren’t expressed. So this is the so called Vogel gram. It’s our model of carcinogenesis, and there’s no better model than there is for colon cancer. Now, as a cancer prevention researcher, this is how I look at it. If we’re looking at preventing cancer in healthy people that have no evidence of disease, well, that’s somebody with a normal colorectal mucosa. This would be primary prevention, right? So what’s the advantage primary prevention? Well, number one, these recommendations can be cheap and and highly efficacious, like, you know, exercise more or eat healthy variety of food, maybe mid Eastern diet, or something like that. These would all be primary prevention recommendations. The difficulty here is to run a clinical trial and primary prevention takes 30 years and hundreds of 1000s of patients, and they’re just not feasible. So where we would like the most information is in primary profession, often we have the worst quality of evidence to give recommendations because we cannot design studies, but can afford to just given out how large they would be. Now, secondary prevention now we’re taking patients with a pre cancerous condition, an adenoma or aberrant crypto or something along the spectrum, and then we’re going to say, Okay, if we did a clinical trial to prevent cancer, colon cancer in colon adenoma patients, that would be a secondary prevention trial. Tertiary prevention refers to patients who have had cancer. So if a patient has had cancer and they’re cured, well, it doesn’t necessarily go down to metastasis. That would be black, but it could these patients still at risk for an adenoma, high risk adenoma, and second primary cancer, and these are all things that could be prevention prevented in the tertiary prevention setting. So some people call both of these secondary prevention, and if you do that, that’s okay with me too. But when I say tertiary prevention, I’m really referring to cancer patients that are otherwise disease free.

Manju George 18:18
Dr Zelle, I have a question. So the the terms primary, secondary and tertiary is basically looking at the progression of normal mucosa to cancer?

Dr. Jason Zell 18:33
it would be. These are really terms to show if, if you are a cancer prevention clinical trials, or you’re enrolling in a cancer prevention clinical trial. Which type of category does it fall into? A primary prevention trial would be a trial that’s focused on this first group, the normal mucus, the average population. Secondary prevention would mean you’re you’re now in a limited group. These people have polyps or some kind of adenoma, and you’re trying to prevent you have a trial to prevent cancer in that population. That would be a secondary prevention trial. The way the term is used most commonly is in heart disease, they have primary prevention, secondary and that’s it. And secondary means you already had a heart attack, but they’re still recommending aspirin, right? Whereas some people recommend aspirin to prevent heart disease in the first place, that’d be primary prevention. But if you prevention, but if you had a heart attack already called secondary cancer is a little more complex in that we have these intermediate endpoints, like adenomas, and then we have cancer, and so we think about the secondary and tertiary prevention.

Manju George 19:35
Okay, okay, so it’s basically the population that is that you’re looking at.

Dr. Jason Zell 19:41
that’s exactly right. This defines the population and okay, in terms of clinical trials, why is that important? Because each of these are, are, are risk groups, like the primary prevention group is the lowest risk group, so they don’t have very many endpoints. Now, “polyp farmers” form polyps, right? So you can design a study with a smaller sample size, if you know you’ve got an at risk population that’s going to form polyps correctly. Some of these people in the primary prevention setting, they may never develop a polyp in their life. And then in the cancer setting, their risk of adenomas is somewhat akin to a polyp patient, if anything more, but they’re also risk for other events, progression and whatnot.

Dr. Jason Zell 20:21
So I think with those definitions, I just want to talk about the history of prevention in this disease and well, it’s not been great. You know, fiber, fat and folate, we’ve had clinical trials to prevent adenomas in adenoma patients, and guess what? None of those worked. So that’s very disheartening. And it doesn’t mean that a low fat, I’m sorry that a low fat, high fiber diet is bad for you. It just means that if you have patients eat their regular diet, and you throw in a packet of wheat, brand fiber, it doesn’t statistically decrease the risk of adenoma. So probably in the diet, all these things are surrogate markers for a healthy diet, probably, and that’s why the observational evidence that these things might be helpful didn’t pan out in clinical trials. Low physical activity and high BMI increase risk of colorectal cancer in the Nurses Health Study. And high BMI by itself, is associated with increased risk of adenomas as well as risk of colorectal cancer. So these are things that are modifiable, that we know impact colorectal cancer risk for any of your members in COLONTOWN, I think this is a wonderful resource. The American Institute for Cancer Research. They have a book online that you can download for free. You sign up as a member, which doesn’t cost. And in addition having a lot of good statistics on every cancer type, they also have recipes like heart healthy, cancer healthy recipes. So I find it to be a really cool organization. They estimate by staying healthy, weight, exercising, fill up on fiber, rich foods, about half of colorectal cancer could be prevented, and it’s also by limiting red meat, processed meat, and avoiding alcohol. So now moving to chemo prevention really the talk of paces the clinical trial. So non steroidal, anti inflammatory drugs are drugs that are used to decrease inflammation, like Well, someone back in this study, or Motrin, ibuprofen, CEA, coccyb, Celebrex, there’s many of them in Patients with the familial adenoma these drugs definitely cause regression of adenomas. You can it can cause them to disappear. Aspirin itself causes a 25 to 35% reduction in recurrent adenomas, if you you know, in a clinical trial setting. And then the Cox two inhibitors which have more cardiovascular risk, they were associated with a greater reduction in adenomas. So in a prevention setting, especially primary prevention, we can’t recommend everybody takes Cox two inhibitors, even if there’s a low 2% risk of heart attack and stroke, that’s a huge number for a healthy population. Now if we’re talking about cancer patients, maybe the risk is different, but it’s just a unique thing to the field of prevention. You have to have a very safe regimen, because even the smallest side effects, if we’re going to apply them in a primary prevention setting or a secondary prevention study, that that low risk of cardiovascular events might be too much. And that’s what’s happened here with the Cox two inhibitors. So how does aspirin and the NSAIDs work. They inhibit these enzymes called cycloxygen, Cox one and Cox two, and also prostaglandins. So you get these are things that are in the inflammatory cascade and that can be very cancer provoking and aspirin and insights decrease that currently people ask me this is probably the most common question I get from oncologist when I speak about prevention. Is there any recommendation for for aspirin for cancer prevention? Actually, there is, but it’s a very, very limited group, usbf, which is very conservative, says you can recommend aspirin for use of primary prevention of cardiovascular disease and colorectal cancer in adults age 50 to 59 that have a greater than 10%-10 year CBD risk and are not at risk for bleeding, etc. So I mean, that’s a varying and they give that a B rating. So in other words, not really. USB doesn’t really recommend aspirin unless you happen to be that category, you’re 50 to 59 and you have more than minimal risk of cardiovascular disease and no contraindications, no reasons not to take aspirin, then you can take it for both CBD prevention and colorectal cancer prevention. Okay? This was the landmark study in New England Journal almost 20 years ago, looking at aspirin versus placebo in 635, colon cancer patients. And here you can see the curves on the right show that aspirin, the incidence in aspirin group was much lower in recurrent adenomas in three years. So this led to and this work on NSAIDs and Astron led to the large nctn study of 2500 stage three colorectal cancer patients, which we call CA, LGB, 80702 this was a complicated design. It was a study of stage three patients, given first they were randomized to either six or 12 months standard chemotherapy, Fox, and then they were randomized to receive placebo or cilicoccib (?). When those Cox two neighbors and the cilicoccib,bwas used because it was thought to be to justify the risk in this population, the low risk of cardiovascular events was justified, and this trial was, but that’s inaccurate. The trial is completed. Results are negative, so it did not there’s a slight difference. It was non statistically significant. So this trial is not going to show any benefit of NSAIDs in the setting. And they were really looking at disease free survival. Does cillicoccib prevent the time until colon cancer comes back, which is much different than the way PACES is designed. So let’s talk about that. The fundamental premise here is that polymeans are these chemicals, substances in the body that are essential for life. We need them for wound healing and for growth, for gating through channels, the way your cells signal with each other. It’s an important part of that now, in excess, however, cancer formation is enhanced, and this is in epithelial cancer such as prostate breast and colon. So how do these how does this polymean pathways work? Well, polymeans are derived from something called ornithine, which is a product of our urea cycle. So when we get rid of nitrogen compounds in in urine, it’s through this cycle in the body that we call the urea cycle, and ornithine is a product of that. So polymeans originated from ornithine. And basically we have two drugs that I’m showing here that can inhibit their formation or their net polymine pool in the body. So if ornithine is a suicide inhibitor of this first enzyme, or anything to carboxides so if you block this synthesis step, you’ll have lower amount of polymeans in the tissue, and then solondak which is a non steroidal, anti inflammatory like ibuprofen, it works through a different mechanism to promote quick exit of polymeans from the cells. So the two of them uniquely will lower net polyamine pools. Now my mentor, Dr maiskins, had conducted this study of the fornithine solondak versus placebos in patients with colorectal adenomas. So these are polyp patients. They go for colonoscopy, if they had any polyps, they were removed and then they were enrolled to receive either combination of one to reduce polyamines in the colorectal mucosa or placebos. Now, how did, how did they come up with this idea for study? Well, they ran a series of phase one and phase two studies showing what they term “a dose de escalation”, the lowest possible dose of these drugs that could be used while still having an effect on the colorectal mucosa. That’s really the target tissue that we’re working to prevent cancers in here. And then the primary endpoint was total adenoma recurrence at the end of three years. So this is a true Cancer Prevention Study. It’s got a real carcinogenesis endpoint is not looking at overall survival, disease free survival, it’s looking at new cancer formation, in this case, colon adenomas. Interestingly, the study was powered to enroll 375 patients where they had an interim analysis after the 267th patient had their colonoscopy, and the DSMB halted the study for efficacy, which is a safety measure, so that no one else gets in the placebo arm, and we just take if the results are positive, there’s no way that completing the next 108 patients will make it not positive, then they’re going to halt the study. It’s exactly what happened. So. Here is what they found. If you look at the first the purple is in the placebo group, there’s a 40% rate of adenomas after three years. Now that is exactly what the placebo rate is for any aspirin or vitamin D study, vitamin D, other studies, calcium studies, that’s what we expect an adenoma population 40% of the time, three years later, they’re going to have new polyps. But in the combination polyamine inhibitors, which is a funny thing, that was reduced to 12% that difference is a 70% reduction, which is much greater than we had seen. Remember, with Astron around 30% or silicoccib 40% now, what really grabbed my attention was over here on the right when we looked at high risk adenomas, those advanced adenomas or multiple adenomas, these are the ones that go into form cancer more quickly. Those are reduced by 92 to 95% now, essentially, especially in its current form, paces, is a study that replicates a prior adenoma study, but now in cancer patients, I’m a medical oncologist, all my patients have cancer already, right? So this is not a pilot prevention trial, but once patients complete their therapy with maybe surgery or chemo, radiation, surgery, in the case of ecrt cancer patients, followed by chemo or not chemo, you get to a point where we go into surveillance. And this trial was designed to be implemented between your standard year one post op colonoscopy and the year four post op colonoscopy. So there were no need for extra colonoscopies. And our objective is to see whether this combination of fornithene, which is two pills of 250 each, so 500 milligrams every day, and one pill of the selendek 150 milligram a day, or their matching placebos are effective in reducing the three year rate of high risk adenomas or second primary colorectal cancer. So again, as I said, this trial is different than CT, LGB, 702, we are not looking at overall survival, disease free survival, as a primary endpoint. Those are all secondary points in paces. Our primary endpoint is really related to carcinogenesis, something brand new, brand new polyp, or high risk polyp, I should say, or a brand new cancer. A small percentage of recurrences will be a new cancer formation in that time. So with that, I want to show you what the windows registration look like it is a little bit confusing for I mean, most trials you you enroll on a clinical trial at a cancer center when you need treatment. This, this trial is not like that. It’s the opposite day zero means patient had surgery, then maybe they get chemo, maybe, maybe they don’t. And so we have this very large registration window from, let’s say, four months out to 15 months out. Because what we learned is that many people are getting their colonoscopy earlier, especially in rectal cancer. If you imagine, some of them have had nine months, you know, six to nine months of treatment before day zero. It can go on for quite a long time, and so they’re getting early colonoscopy. So bottom line is, we want to use that first colonoscopy when it’s done, as long as in the window period, and soon as a patient has that colonoscopy done, they’re eligible to enroll in the study. Again, this is for stage 012, or three. We do stratified on stage in the design, so we’re going to account for it. But it’s very it’s very much open to all stages that are non metastatic. And what does it look like on study? Well, one thing I should mention before we get further is in Dr Mason said the abnormal study the there’s no differences in any of the side effects noted in the primary paper. So it seemed to be tolerated extraordinarily well compared to placebo. Now, in subset analyzes, it was found that there is a 7% difference in audiogram thresholds, which is hearing the thresholds in that study, which were required before and after. Now, just to put that in perspective, these drugs, well, a foreign thing in high doses, 50 times higher than the dose used in paces or in the prior adenoma study, can cause hearing loss. So it’s a known side effect of a large dose of a foreign to the other studies, like Carol Fabian’s study in breast cancer at University of Kansas showed no difference in audiograms. This study, it was not statistically significant, but it was 7% different. And so it’s thought to be real. Also, after discontinuing the drugs, the patient run drugs for three years. Three months later, they discontinued the drugs, the audiograms were within 1.5% of placebo. So it seems to be a very subtle and transient effect. There was actually no difference in hearing in other words, not that the patient or the doctor reported or could tell, but in audiogram testing, there’s some subtle finding that could be related to the drugs, and that’s the only known side effect, difference between placebo. Now someone back, of course, in. Other hand, has a there’s a lot of potential side effects. You can read those if you look up giving ibuprofen. But the difference is, we’re using just one, one pill of solid X, a very low dose of solid x. So it wasn’t no difference for sort of seeing in the prior trials. So patients are enrolled to get their baseline audiogram colonoscopy. CTs are not required. If they have stage three, they’re going to get CT is otherwise not required. And then they’re going to take three pills a day to afford anything, one cell index pill for three years before their next colonoscopy, they have four visits. That’s what the stethoscope indicates in their first year, which would be their second year post op. And then at your three post op, which is your two the study you go to six month following. So in other words, this follows NCCN guidelines, exactly what you would be doing anyway. And then there’s this annual exam at the end, where we’re just following to see if there’s any side effects or any benefit in the later colonoscopies that might occur. And this is what the study looks like. So patients are registered and then stratified on stage, as I mentioned, they’re randomized in one of two arms, and for nothing, sond act or anything, placebo, solid act, placebo. This trial years ago was a four arm study, but it was accruing slowly and it was needlessly complex, so we closed those arms, and now this trial reflects exactly the adenoma study that I mentioned before, the post op year four, which would be intervention year three. Colonoscopy is done at the end, and then we’re going to count up high risk adenomas or second primary colorectal cancers, and compare in the combination polymed inhibitor group versus the placebo. Also, we have an end of study colonoscopy now. I will say the accrual now is 343 of 389 patients. So we’re getting there. This trial should close. It’s going to close next year, one way or another. It looks like this trial will complete accrual which is fantastic. So you know, if it’s something that interests you, or your sites, or someone you know, please refer them. We still need help along the way, but thankfully, we’re approaching 90% accrual completion at this point that this is the study is really not relevant. That’s the latest I had through 2022, I need updated figures, which are released, usually every six months, but the next report was late anyway. It does show you that out of all this, will be 237, patients enrolled at that point. There was mostly just grade two side effects in any group. We don’t know which group is in placebo or or not, but it appears to be tolerated well, I can see the the blinded reports, where I can’t tell which ones and placebo arm versus, you know, the treatment arm, those are public, and the rates of side effects appears to be about the same. So just as we expected from the prior studies, the pills are tolerated? Well, how well they work that way to be seen in our analysis. So with that, I’ll stop sharing my slides. Any questions?

Manju George 38:12
Yeah, thank you for all the information. I have a question. So there is, no age restriction, right, like from 18 on to whatever age?

Dr. Jason Zell 38:25
18 upwards, yes, we yeah, we just made the decision not to limit an upper limit of age. Of course, one thing I didn’t talk about is the audiogram screening thresholds. The older you get, the the more problems you have with your audiogram. So a 90 year old would be welcome to participate, but they would have to, you know, pretty much normal hearing. So that is just a factor,

Manju George 38:52
The reason I asked about the age is that, you know, the people will be on drugs for three months, three three years, right? SoAre you expecting the effect to be there during the time that they’re on on those drugs? Or what is the expectation that it will be there for the next, you know, 20 years?

Dr. Jason Zell 39:12
Yeah, so that’s a great question. You know, the FDA asked us that question, and that’s the whole reason we follow for five years, once a year after the study is done, because we don’t have any data in these other trials, if there’s durability of effect. In other words, let’s say we see a big benefit of three years does that benefit disappear? You know, five years later, we really don’t know, and it would be nice to know if there was a durable effect. And that’s one thing this trial will be able to answer.

Manju George 39:40
Okay. And then related to that in the studies with, say, aspirin, is there reason to believe that, like, you know, if you’ve been on it for a period of time, does that benefit translate, like long term? Is there data?

Dr. Jason Zell 39:56
No, I don’t believe we have data on that. No. Now the the when it comes to aspirin, then again, it goes back to dose, because the aspirin recommended by usbf is at 81 milligrams, whereas the dose shown to be beneficial in colon cancer patients was 325 milligrams, which is not a recommended dose. So, so that’s one important consideration that there’s some other unique things about aspirin. We certainly have more, much more data on AST, because people have been taking that for a long term, for many years. But in terms of durability, where you start and then stop, I’m not familiar with those data.

Manju George 40:35
Okay, okay, that makes sense. And then my other question is that, like, height is also supposed to be a risk factor for colon cancer, right? It seems that tall people have longer or longer in distance, and that makes… Have you heard that?

Dr. Jason Zell 40:49
I have not. I mean, tell me. I’m gonna look it up right now, so I don’t know that. I mean, intuitively, yeah, I don’t know that’s an interesting thought. But, I mean, I’ve seen things about BMI, so if height is tracking with BMI, yes, that would be related, but height by itself, I’m unfamiliar with that.

Manju George 41:11
I was curious that if you had heard then you know whether, after the trial results out, you know whether you could recommend it for, like, people with a certain height, you know, I was just thinking,

Dr. Jason Zell 41:25
I don’t think we’ll be powered for that. I think you need a lot of patients, a lot more than we enroll.

Manju George 41:33
That makes sense. And then so with the FAP and patients with, you know, increased susceptibility for farming these polyps and adenomas. Do you believe that, like, you know, in many years, this would be a strategy, instead of getting, like, total proctocolectomy, is that what the goal is?

Dr. Jason Zell 41:56
Yeah, actually, that’s a great question. So just a few years ago, the study of these same two drugs in fap patients was published in the New England Journal, and in that study, there was no difference between these drugs. It was used in combination with aspirin. It was a different design, but still, you know, there was no benefit of one or the other versus combination so and no true placebo arms, a little bit confusing, but in the proctolectomy patients, there was a small subset of those FAP patients had not had their colectomy yet. There is a big difference. The study was empowered to look at that, but it was something like a 70% difference for one is solondak vs placebo. So the thought is, if you’ve already removed the colon, it might not do much to prevent the duodenal polyps and the other polyps that occur, but if they still have their colon intact, there seems to be an interesting signal there that would require further research.

Manju George 43:00
Okay, we have, like, a couple of patients who are really young, you know, with FAP. And you know, they’re, they are wondering, if you know, whether it will be worth having colonoscopies every few years compared to having a top total proctocolectomy. And I mean, I think we have some people overseas where, you know they don’t have this trial, and you know they were kind of wondering when the data would be available and when it be useful for them.

Dr. Jason Zell 43:28
So I can send you the the New England Journal paper, because you have to read it very carefully and look at those patients in the pre colectomy group. I think it’s really remarkable. My guess. I don’t have any inside scoop on this one, but my guess is that if I were the company, I would explore this combination pre colectomy patients alone, because I think you would see a big difference, just like they saw by accident in the prior study.

Manju George 43:54
And then in that study, you said that the comparison was not with placebo, but with plus or minus aspirin.

Dr. Jason Zell 44:00
Yes, yeah. So there’s also some combination of efrodonodine, solondak and aspirin and so all of them reduced polyps, but they couldn’t say that a combination was better than one or the other. A placebo arm would have helped, but it would have been unethical, you know, the way that was designed. So that’s just the way we are with clinical research.

Manju George 44:19
I think I had one more question, and I can’t remember it right now. This was about like the, you know, in patients with the PACES, is really enrolling patients stage one to three, and it’s not the general population, right, correct?How would what you find translate to people with average risk?

Dr. Jason Zell 44:43
So I don’t think it will. I mean, some of the work I’ve done has looked at genotype, prediction of toxicity for these drugs, you know, and if we could better, if we could better predict who would be likely to have an adverse event like hearing or cardiovascular disease based on a genotype. Some of the work suggests that the people at the have the lowest risk of adverse events, have the highest potential benefit from the drug. So if we could just find those people before, maybe you could extrapolate it to a general population based on genotype. But I think with these drugs, they’re safe, but again, for the primary prevention setting, probably not safe enough. The only thing you know we can recommend in that setting is like, where SPF 30 sunscreen for melanoma prevention. You know, these are really broad safe recommendations. Don’t smoke, right? We can do that, but it’s hard to recommend drugs in that setting.

Manju George 45:43
Okay, okay. And then the other thing would be like, I’m also kind of curious that, why did you decide that you would the time for the duration of treatment to be three years? Like, what was the reason behind that?

Dr. Jason Zell 45:57
So the prior adenoma studies were tissue studies. They took polyp patients and they looked at mucosal changes up to a year later. But you know, adenomas take time to re-form, so it’s three years, is pretty standard for any adenoma interval, if you want to show a difference, because you know, there will be a 40% occurrence in the placebo group, and so meaning that’s the risk of any adenoma patient. So I think, based on the prior data at three years. Also, that happens to be the exact interval for colon colonoscopy surveillance. It was just very convenient.

Manju George 46:27
Okay, okay, that makes sense. And I was thinking that if, for example, you know that you had to take it for, you know, not as long, like if you found that the effect was the durability of response was long. And then, you know, you only had to expose patients to a shorter duration, then I can imagine it being useful for, like, a population study,

Dr. Jason Zell 46:49
yeah, yeah, exactly, yeah, yeah, yeah.

Manju George 46:54
The other question I had was about, you know, in many patients, for example, in my case, you know, I I’ve had a colonoscopy every year. I’ve got five colonoscopies, and I just finished five years. So this was just one, you know, polyp that became an adenoma, an adenocarcinoma. So that’s the other question I had in the in the population that you’re looking at with stage one to three cancers, what is the rate of polyps that you normally see?

Dr. Jason Zell 47:30
The rate of polyps, any polyp, would be around that 40% maybe higher – closer to 50% actually, I should change that – post year four because that’s when you’re going to get your second colonoscopy. It’s even higher. So like 55% or so now, about half of those will be high risk adenomas. 27% will be a vis adenoma, or multiple adenoma, or a large adenoma greater than one centimeter. And that’s that’s the focus of PACES trying to eliminate those. It will also lower the risk of the other average polyps. But you if I was talking to a bunch of gastroenterologists, they would say, Why worry about those polyps? Those other ones we can just remove. They’re no problem. They’re slow growing, and that is kind of true. So the ones we want to prevent are the ones that can escape colonoscopy because they’re aggressive.

Manju George 47:31
Okay, so you’re saying that, like after your diagnosis, at the next year of colonoscopy, there is like a 55% — ?

Dr. Jason Zell 47:31
Oh, no, I’m sorry, no, that would be at the four year colonoscopy, no, at the first one, it’s like 15-20 Yeah, something like that.

Manju George 48:00
Okay, so over time, in patients who have already developed colon colorectal cancer, there is an increase in the incidence of polyps.

Dr. Jason Zell 48:44
Yes, which is why the guidelines you know, you say five years, no more CT scans, no more CEA, but you still need colonoscopy for life. That’s the recommendation for that reason.

Manju George 48:55
Okay, okay, I think that I’ve asked all the questions that I can think of, and this was very helpful. Thank you so much for all the information and good luck with the trial.

Dr. Jason Zell 49:06
Okay, thank you, Manju and to COLONTOWN.

Manju George 49:10
Very nice talking to you today.