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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we've gone transcontinental. We're trying to avoid any trade war disputes at this point, and we're quite fortunate to have actually a rising superstar.

I'm in Nashville, Tennessee, at Vanderbilt, and Dr. Marie-Pier St-Laurent is actually in Vancouver at the University of British Columbia and is finishing her third year of fellowship there and will be staying on with the superstars there.

And she gave a presentation looking at actually a new version, new formulation—new mucoadhesive formulation of gemcitabine and its possible impact as a trial in progress for those patients with bladder cancer. So, Dr. St-Laurent, thank you again for helping us forge ties across the border. And we look forward to your presentation. And then hopefully some time for some questions and answers afterward. So, welcome.

Marie-Pier St-Laurent: Perfect. Well, thank you so much for the invitation. Really great honor to be presenting this, so thanks a lot. So just briefly, just presenting this clinical trial, which is in progress. So I don't have results yet to present to you. And I just want to highlight that this is an investigator-initiated clinical trial, but it's being done in real partnership with the Vancouver Prostate Centre in Vancouver with our research center, where the novel drug has been developed.

So it is a phase II/III multicenter clinical trial. And just to be more clear, it is for upper tract urothelial carcinoma (UTUC). So it's not bladder cancer. It is upper tract urothelial carcinoma that we are investigating the use of this agent. Just a bit of background for those less familiar.
When we talk about upper tract tumors, the alternative of kidney-sparing treatment is quite limited. We know that high-volume—let's say 2 centimeters or more—low-grade tumors are difficult sometimes to really properly stage. But even if it's still low-grade, we don't have great alternatives to do—otherwise, I'm doing a nephroureterectomy.

There is some approved treatment, such as the hydrogel form of mitomycin C (Jelmyto). Currently, it is not available in Canada, so for us, it is a limitation. But even if available in the States, the efficacy is somewhat limited. But also, the high rate of stricture can be concerning in some patients. So there are not that many options.

And knowing that gemcitabine has shown quite high efficacy and safety in the treatment of lower tract bladder tumors, it has quite limited side effects. The idea is to see if we can combine that active agent of gemcitabine with some kind of diluent that will make it a more acting paste and stay longer in the upper tract. Maybe we can have a great treatment here.

So here's the—if you want to scan the QR code to go on ClinicalTrials.gov (NCT) to see more of the details about the trial. But as I mentioned, this is an investigator-initiated trial, which will be prospective, multicenter, and single-arm phase II. And then, if positive, will progress to phase III. The aim is to assess the efficacy and the safety of this novel drug, which we call ST-02 from Sustained Therapeutics, which is the spin-off company that worked on this drug.

So it is a mucoadhesive gemcitabine paste. And the idea or the aim is to assess the efficacy for chemoablation. So we're talking about having a residual 5 to 15-millimeter low-grade upper tract tumor and seeing if it responds to the agent in terms of being chemoablated. The primary objective is complete response (CR), which we assess at three months with conventional ureteroscopy.

So the CR at three months is our primary objective. But we have other secondary objectives, namely seeing the durability of response 12 months post-CR. And there are other things we'll be looking at, but obviously, we'll be assessing safety and how well tolerated it is in the patient, the rate of stricture, and things like that.

Just giving you a bit more detail, it is a mucoadhesive gemcitabine polymer suspension. So one of the components is the active drug, gemcitabine, that we are familiar with. The particularity is the diluent, which is a water-free polymer suspension that becomes like a gel when it is in contact with liquid—so water or urine. So in contact with urine in our system, it will become a gel and has the property to adhere to mucus.

The dose that we administer during the trial is 200 milligrams of gemcitabine. It is in the form, as you can see on the syringe, of a 10 cc liquid. The study goal is to enroll 30 patients for phase II. So we're looking at CR rates. So we did make a futility cutoff to decide whether or not we are going to be moving to phase III. But for phase II, we plan to enroll 30 patients. And if we have more than eight CRs, we'll expand to phase III with a total enrollment of 70 patients.

The treatment schedule is something that urologists are quite familiar with, and also from other trials like the OLYMPUS trial. So we are doing an induction schedule, meaning once a week for six weeks, with the gel being administered in the upper tract.

And in the trial, how we designed it—we wanted it to be convenient for both the urologist and the patient. So the option is to be done either retrograde or antegrade, meaning that patients can either have a retrograde catheter inserted for their weekly treatment in the cystoscopy suite or antegrade via a nephrostomy tube that has been inserted. So the patient just comes into the office, we administer the drug, and then they can go home without anesthesia.

Once a week for six weeks, it's given. Then we'll have a disease assessment six weeks later. So that means the three-month endpoint will be assessed. And then patients will undergo surveillance ureteroscopy every three months for a total of 12 months post-CR. So this means the patient is on trial for 15 months. And there's one maintenance dose that can be administered at all of those assessments. So every three months, if there's ongoing CR, an extra dose can be given at that time.

So that's the schedule that we are following. Currently, we are enrolling in Vancouver, at the University of British Columbia. We have this trial site in Halifax established. Toronto is our next one coming in the upcoming weeks, and then we're continuing with other sites in Canada. So London, Montreal, and others are coming. We expect to have approximately seven centers involved in Canada.

And like I mentioned, if phase II is positive, then we'll want to expand to sites in the USA as well for phase III. So if anyone is interested, here are some of our contacts for reaching out. I didn't go into detail, so those who are interested in looking at inclusion or exclusion criteria can pause and read them in detail.

But basically, we're enrolling patients with either primary or recurrent low-grade, non-invasive tumors. They need to have at least one measurable tumor above the ureteropelvic (UP) junction, between 5 and 15 millimeters. Patients must also have a life expectancy of at least 12 months.

And what we exclude are high-grade tumors, muscle-invasive disease, or patients receiving other chemotherapy or BCG, as we don't want interactions with our investigational agent. More detailed criteria can be found on ClinicalTrials.gov (NCT).

Sam Chang: Dr. St-Laurent, that's fantastic. Very exciting whenever we have the introduction of a novel delivery system in an under-- I don't want to say underappreciated, but we have limited options with upper tract disease. So you mentioned Jelmyto, and it looks like that dosing schedule with this is not too dissimilar, as well as the patient population, with those. Jelmyto being a certain type of polymer that thickens with mitomycin. This is different.

Can you spell out the differences? I just said, well, we've got gemcitabine versus mitomycin C in Jelmyto. The polymer with Jelmyto, when cold, is liquid. It is not so viscous. When it achieves room temperature or body temperature, it then thickens. And then in six to eight hours, it breaks down. Tell me about the mucoadhesive properties of your type of instillation in the upper tract.

Marie-Pier St-Laurent: Correct. So, yeah, you're right. So there are two differences. Mainly, it's the active agent, as you pointed out. We're not using the same chemo. And then it's that kind of diluent and how it actually converts into some more solid form. Well, not solid, but paste. So the process is different. So it's not a question of temperature. It's a question of being in contact with water or fluid.

The second is the property to be more adherent to mucosa, which we hope-- or the idea is that it's going to stay in contact and stay there for slightly longer. I'm not the one who developed the product, however. And I cannot share all of the details of its exact components, obviously, the same way I don't know the details of the components of Jelmyto.

But the difference, we hope, is that it's going to stay slightly longer by being adherent to the renal pelvis or in the upper tract before it goes down and washes out in the ureter. The impression we have is also that it's going to be staying between 6 to 24 hours. But beyond that, we don't expect it to remain—and so far in the preclinical data, it's not going to be in the urine past this time.

So those are mostly the differences. Will there be one superior to the other? I mean, the trial is not designed to see that, but hopefully, we'll see good CR rates. But yeah, stay tuned to see the results.

Sam Chang: Then the next question I have to ask, which I'm sure you're asked all the time—how does it work in the bladder?

Marie-Pier St-Laurent: So it has not been studied in the bladder.

Sam Chang: Another project for you. Another issue.

Marie-Pier St-Laurent: I know.

Sam Chang: Yeah, exactly. So—

Marie-Pier St-Laurent: That's why we recently had a conversation about that. So the bladder would be an interesting idea, in the same way we saw some ENVISION trial regarding the UTN product being in the bladder and seeing that. Regarding ST-02, so this is a smaller startup company. We have to tackle one thing at a time. And again, I'm the investigator leading this, but I'm not part of that company, so things need to align in different ways.

So at this point, we're looking at the upper tract. But clearly, the idea of doing some sort of chemoablation in the bladder is interesting. And perhaps we'll see some trials in the future.

And in our context, let's say in Canada, sometimes we do have some delays between diagnosing the patient and getting to do the TURBT. So there's quite an interest there, especially for patients. If they have a low-grade tumor and they can avoid surgery, if they're frail or older, that can be quite interesting to see if they could benefit from an alternative to that surgery.

Sam Chang: I mean, the idea of chemoablation has been around for decades and decades, but really never widely utilized, especially in the U.S. Much more so in Europe. But now, I think there's increasing interest in the whole idea of chemoablation and the ability of this to just, as you say, have different types of binding capabilities when exposed to water and urine. And then adhering to the actual lining of the mucosal layer makes it obviously quite fascinating.

And right away, you start comparing it with the TAR-200 agent. And, well, the downside to that is you have to have a device in place. And this is actually a catheter-based treatment. It could be applied to different scenarios. Let's go back to the upper tract placement. If a patient has multiple tumors, they're still eligible as long as they meet the size criteria, correct?

Marie-Pier St-Laurent: Yeah. So we've designed it to be pragmatic and convenient while ensuring safety. So it's a question of size and superficiality. So if, let's say, you have two tiny tumors, and then the total is not above 15 millimeters, that is still a possibility. But we want the patients to be, let's say, kind of debulked.

So what we do is, the patient comes in for ureteroscopy. If they are interested in the trial—let's say it's a big tumor, or they just keep recurring—you can laser ablate some of the tumors.

So you ablate some of the tumors, and then you have that residual, let's say, lesion that you're going to be treating. So either it was a big one and you managed to get it below 15 mm, or if you have two or three, you remove some and leave one residual tumor. The other thing is patients with urothelial carcinoma elsewhere in their GU tract. As long as those were treated, they are not excluded.

So the patient isn’t excluded if they have a contralateral tumor or a small bladder tumor that was completely resected. The key point is that the drug is not going to be treating the other sites.

Sam Chang: No, I appreciate it very much because it's very, very real-world. It's difficult to find a single tumor in these cases, especially in this uncommon disease. So it really makes sense if you look at the Jelmyto data post-FDA approval. At least in the U.S., there are different publications that describe this type of "sandwich" combination therapy that you just described—bulky tumors, laser, treat. Or treat first, then laser, leading to a decreased tumor volume, etc.

So I can see some combination of this treatment working, and perhaps even being better tolerated with gemcitabine, as opposed to a mitomycin-type treatment. Pure speculation—we don’t know yet. Logistically, as you place the medication through a urethral catheter, do you measure the volume? Is it under fluoroscopy so you can see the—

Marie-Pier St-Laurent: The drug?

Sam Chang: The renal pelvis.

Marie-Pier St-Laurent: Yeah, good question. Actually, initially, when we wrote the protocol, we had that in there. We wanted to measure the volume in the pelvis, and so on. And then we wondered, is that actually necessary? Not really. We're still going to be putting the same amount of drug. So, as long as the patient has normal anatomy, no obstruction, etc., we record the volume of the pelvis, but it’s not a factor that influences dosing.

So if the value is available, we will gather it. But regardless, we're administering the same dose. Because we can administer it antegrade, meaning via a nephrostomy tube, as long as we confirm proper placement, which is done at the time of insertion by the interventional radiologist. When it's time to administer the drug, we don’t routinely use fluoroscopy or other imaging.

We confirm that the nephrostomy is in place—I will say it’s common sense. You have your nephrostomy, you ensure urine return, confirming adequate placement. You flush the nephrostomy to confirm patency, and then we administer the drug. So that's how we do it antegrade.

For retrograde administration, you must confirm that your catheter is in the correct position. So once you do your retrograde pyelogram, confirm the position, and then drain. You just instill your drug. You do not need to repeat contrast imaging at that time.

Sam Chang: Got it. So this is a trial in progress. We're taping this post-ASCO GU, which was February of 2025. One year from now, will we have some preliminary data, at least the three-month CR rate possibly? What's our goal as we enroll patients in these initial centers in Canada?

Marie-Pier St-Laurent: Well, I hope I will have some preliminary results. It's hard to anticipate. As with most clinical trials, we had a slow start. We just opened in Vancouver recently. As of today, we have three patients enrolled because we're less than a year into enrollment, but we have multiple other sites coming. So it's always a matter of how long it will take for them to open.

It's a rare disease, so it's hard to predict enrollment numbers. And as I mentioned, we are looking for 30 patients. I'm not sure I'll have preliminary results by next year. That would be great, but maybe in two years.

Sam Chang: And at that point, it may be an updated trial-in-progress report. We could say, "We've enrolled 18 of the 30," etc. Because that three-month mark in a chemoablation study, I think, is really important. Obviously, longer-term follow-up is crucial—12 months, etc.—but that three-month mark, at least in the Jelmyto trial, was quite predictive of how patients did long-term as well.

So, hopefully, we'll have data soon. And we already have your commitment that as soon as we get that preliminary data, you'll return and give us an update on UroToday.

Marie-Pier St-Laurent: For sure.

Sam Chang: All right, fantastic.

Marie-Pier St-Laurent: For sure. I'll be excited.

Sam Chang: Dr. St-Laurent, thank you so much for spending some time with us. And congratulations on your upcoming completion of your fellowship and your faculty position in Vancouver. Thanks again, and we look forward to hearing from you again.

Marie-Pier St-Laurent: Well, thank you so much. Yeah, great. I'll be happy to return.