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Sam Chang: Hello, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center and we're quite fortunate to have Dr. Rob Svatek. Rob is actually a professor of urology at the University of Texas in San Antonio, and I've followed Rob's career for some time, a true surgeon scientist, and he'll be presenting at the AUA 2024 in the session called Trials in Progress. And actually, you'll be presenting the PIVOT-006 trial, is that correct? So Rob, can you give us a rundown of what you'll be presenting?

Robert Svatek: Thanks, Sam. It's good to be here with you this morning. So PIVOT-006 is a phase three randomized controlled trial for patients with intermediate-risk, non-muscle invasive bladder cancer. And it compares a new novel therapy called Creto versus observation for people with intermediate-risk non-muscle invasive bladder cancer. The trial hopes to enroll about 364 patients over 30 months, and we'd like to show an absolute improvement in recurrence-free survival of about 10% for patients with intermediate-risk disease. As you know, this population is a unique population in that they have a really high recurrence rate, fairly low progression rate. So that provides us with this opportunity to really look at absolute efficacy of a drug rather than relative efficacy against some other entity. And so there's a number of reasons that those are great trials. They're efficient, they—

Sam Chang: Help answer a question.

Robert Svatek: Help answer questions. Yeah.

Sam Chang: Exactly right. And so these patients then undergo a TURBT, can they have a perioperative dose of chemotherapy at the time they can? And then once they have the diagnosis of intermediate-risk disease, and that's diagnosed based on AUA criteria, EAU combination—

Robert Svatek: AUA risk criteria which, just as a reminder, these are patients, they don't have t1/2z, high-grade T1.

Sam Chang: Don't have CIS.

Robert Svatek: They don't have CIS. And also, they're not the low-risk unifocal, no recurrence, small. It's not those patients either.

Sam Chang: So it's actually a very broad, and in some ways, it is a heterogeneous group, but in all honesty, it's probably the broadest group that we actually treat.

Robert Svatek: And there are a lot of patients with this disease.

Sam Chang: And we struggle with what to do, what actually is great things. So then they're randomized to surveillance versus a six-week course of crevice imaging. And then tell me about the dosing.

Robert Svatek: So it's a six-week induction course. Once a week for six weeks. They'll get a maintenance regimen at three months, if they have a clear bladder, they'll get maintenance, which is once a week for three weeks. They'll get that again at six months. Then it deescalates to one instillation at nine months, one instillation at 12 months. There is the option of re-induction at six months or three months if needed. But it's a total of 14 installations over the first year if they're responding well.

Sam Chang: Got it. Got it. And so, as a trial in progress, there'll be an update. So, how is enrollment going?

Robert Svatek: Yeah. So, we've got a lot of sites interested in participating. We already have some sites activated. There are about five patients that are currently enrolled in the trial. We're welcoming new sites on board. So if you're interested in participating, we want to let everyone know that we would be happy to entertain and welcome new sites.

Sam Chang: That's important. And is this through the SUO-CTC? Is this through just the CG Oncology group? Tell us about that.

Robert Svatek: Both. Yeah. So CG Oncology is the industry sponsoring the trial, but we are working with the SUO-CTC.

Sam Chang: And then, so the goal then, you said, was about 30 months?

Robert Svatek: Yeah. So, we're thinking, Sam, that if you look at the control population, they have about 30% of those patients will recur in one year, roughly. And so, we think taking that down by 10%, an absolute difference of 10% at one year would be meaningful. So that's what we're looking to do. And we can do that with 90% power, 365 patients, and that accounts for a 10% dropout rate.

Sam Chang: Oh, fantastic. So you're talking about a huge relative decrease in reduction with that 10% decrease. That's fantastic. As you all are looking at that in terms of primary endpoints, are there other secondary, I'm sure you're looking at the safety profile. Are you also, in addition, tell me about any biomarkers or what type of both urine and tissue, what are you banking? What will you be looking at?

Robert Svatek: Well, I think one of the exciting things about this trial is the novelty of the agent. I know that you met with Mark a little earlier about the BOND-003 trial, but this drug is really new to our field. It's an oncolytic virus that is replicated in the cell, specifically in cancer cells that have RB pathway alterations. And so, the side effect profile is actually very limited to grade 1, grade 2, relatively small numbers, no grade 3 events that we've seen. And so, there's an opportunity for markers as well. The virus replicates in cells that have high levels of the ETF1 promoter. And so, you might think that the presence or absence of ETF1 may predict response to this medication. So that's one biomarker, for example, we should be looking at.

Sam Chang: Sure. That you'll be looking at.

Robert Svatek: So safety is really one of the added benefits of this compared to an observation or surveillance group is we can really get an idea of what the actual safety is because we'll have a really good control arm and get a good sense of what the actual adverse events and safety are.

Sam Chang: Yeah, that's fantastic. I was just thinking about, 'cause you'll be comparing it to patients who are on a surveillance cysto only versus here's the medication.

Robert Svatek: And you know some of those patients have. They'll have local side effects.

Sam Chang: They'll have symptoms. There's no question they'll have symptoms, but it really will be quite telling that if the side effect profile is quite similar, which I... Historically, we've been involved in our institution with early, early versions of this trial going through it, and the ability, at least in our center, patients tolerated it seemingly quite well. And so, that ability to basically decrease recurrence rates with minimal side effect profile, obviously, is going to be quite, quite positive for all our patients.

Robert Svatek: I agree. And I think that this will give us a real clear understanding of the activity and the side effect profile. So I'm very excited about the methodology of the trial.

Sam Chang: As you describe the mechanism, honestly, I'm like, "Wow." This is to be able to have actually a replicating virus specifically in those cells that have the RB pathway. I'm just thinking about the complexity of this and then encoding GM-CSF as well. This, the combination of cytotoxic and immunologic actually impacts these patients. Makes me think that's—

Robert Svatek: Yeah, I think that's a great point. The way I think of it is the direct killing of the cell through cytolytic activity, and then the aftermath, the anti-tumor immunity that develops the indirect effects and the GM-CSF, which all work toward anti-tumor immunity, which is a large part of how oncolytic viruses work. We know and understand anti-tumor immunity in bladder cancer is real, and I think this drug capitalizes on two different mechanisms.

Sam Chang: Well, Rob, first of all, thank you so much for really continuing the whole surgeon-scientist abilities. Your ability as a surgeon, as a clinician, and combining that with all you've done in terms of your translational research has really been incredibly important and impactful for our field. So thank you for that and I appreciate so much your leadership in these trials as well.

Robert Svatek: Sam, thank you so much for the opportunity to talk with you today. Appreciate it.