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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia, and I'm joined today by Dr. Rob Svatek, who is a urologic oncologist at UT Health Center, San Antonio. Thanks for joining us today, Rob.

Robert Svatek: Thanks for having me.

Zach Klaassen: We are going to discuss a newer medication in the non-muscle invasive bladder cancer space. This is cretostimogene, and so maybe just walk our listeners through what this is, what the mechanism of action is, and why this area is so exciting for these patients.

Robert Svatek: Thanks, Zach. This medication is not only a new formulation, but it's a new way of treating cancer, and it's using a virus, an oncolytic virus. The idea here is that the medication is instilled into the bladder and the cells of the bladder lining, the urothelium, are penetrated by the virus into all these cells indiscriminately. But only the cells that are harboring, let's say retinoblastoma or RB pathway defects, would actually transcribe the viral genetic material.

Normal urothelium would not transcribe it, whereas cells that are harboring cancer, if they have a defect in this particular pathway, this retinoblastoma pathway, which is very common in cancer cells, then those cells will actually take up the genetic material of the virus and transcribe it or make this protein. Now the proteins that are made then will result in the recruitment of immune cells to the tissue and that will help in the destruction of those cells. It's a unique type of way of killing the cancer cells.


Zach Klaassen: That's great. I think we're certainly going to get into the nuts and bolts of the PIVOT-006 trial, but it's been a big year for creto. Going back to the AUA where Dr. Roger Lee presented the CORE-001 data, and then more recently at the SUO where Dr. Mark Tyson discussed the BOND-003. Maybe just take our listeners through some of the key highlights of both of those trials to set the stage for PIVOT-006.

Robert Svatek: The CORE-001 trial, or CORE-1 trial, was a phase 2 single-arm study of creto CG0070, combined with pembrolizumab in patients with non-muscle invasive bladder cancer who were unresponsive to BCG. This data was presented at the AUA and showed some promise as a modality for those patients. The complete response rate at any time for patients was around 85%, and the complete response at six months was around 82%.

Now, BOND-003 is different in that it is again a phase 2 single-arm clinical trial without pembrolizumab. This is creto by itself. The preliminary data was presented at the SUO this last week, which showed a pretty remarkable response rate over 60% for patients at six months. These again are patients with BCG unresponsive non-muscle invasive bladder cancer.


Now I want to point out that this is preliminary data based on around, I want to say 66 patients of a planned 100, 114, but it was pretty remarkable, and I would say promising data. The company now is seeking fast track approval through the FDA to look at and investigate creto for that space.


Zach Klaassen: It's very exciting, and I think one of the things that we've seen in the last two trials is that the tolerability is actually awesome, and I think that is a nice spinoff into the rest of our discussion talking about PIVOT-006.

First, talk to our listeners about why the intermediate risk disease space is so important. It's maybe an orphan indication in the non-muscle invasive bladder cancer space. Just tell us what the thought process was between putting creto in that space and maybe some of the nuances behind the trial.

Robert Svatek: The intermediate risk population is defined as those patients with largely low-grade multifocal disease or low-grade high volume. It does include the solitary high-grade TA tumor, small solitary high-grade TA. But it's not the high-risk patients. It's not patients with CIS. It's not patients with high-grade T1, and it's not the solitary low-grade TA. These are the intermediate risk population.

Now, the current NCCN guidelines recommend intravesical chemotherapy as the preferred treatment or surveillance observation for these patients. The standard of care for these patients is not well-defined, and I think if you look across practices, it's a heterogeneous strategy. Some of these patients get BCG, some of these patients get intravesical chemotherapy. Many of these patients are put on surveillance with observation.


We really don't have a well-established defined treatment paradigm for these patients, and it's an opportunity for us to try to understand what is the best regimen for these patients and to offer a potential treatment for these patients. As I'm thinking it through in developing this, it's not necessarily for people that are naive to any treatment option. Maybe these are people that have potentially tried intravesical therapy in the past, but continue to have recurrent disease. That's how I'm thinking about this in terms of having a new agent in this setting.


If you look through the literature, there's really not trials that have just focused on intermediate risk for phase 3 trials. I think it's a unique opportunity for a disease state, which for many patients it's a burden. You have these patients with multifocal low-grade recurrent disease, and that's what we're looking at. Now this is a... So that's a little bit about the disease population.


Zach Klaassen: That's perfect. I think I'm going to pull up the trial design here because I want you to walk our listeners through that. I think that was a great explanation of especially the fact that we don't have a clear defined guideline-recommended treatment, and even follow-up for these patients, and it's a bit of a heterogeneous population. Walk our listeners through the inclusion criteria again and randomization and just where this trial's going to fit in this disease space.

Robert Svatek: The inclusion criteria include patients that have any of those tumors that are defined by intermediate risk. As you can see, there on the left side of the screen, solitary large volume, low-grade TA or multifocal TA, or they had low-grade recurrence in the last year. It also includes solitary small high-grade TA, and they're randomized in a one-to-one fashion to either the treatment or to observation. Of course, all the patients have had a TURBT and they can have received perioperative chemotherapy as is standard practice. That doesn't exclude them.

They could have had BCG or intravesical chemotherapy in the past, but they cannot be BCG unresponsive and they cannot have CIS. They're randomized one-to-one arm A or arm B, and the treatment, which maybe we'll get into in a moment, the treatment will be given as an induction and a maintenance pattern. The disease assessment shown here is every three months cystoscopy with cytology for the first two years and then every six months starting in year three. Zach, would you like me to talk about the treatment regimen?


Zach Klaassen: Yeah, that would be great, and I think just tell us a little bit about what that induction and maintenance looks like for those patients that are randomized.

Robert Svatek: The treatment regimen was developed really based off of what was learned from the CORE-1 and BOND-3 trials, so it's a six-week induction period once a week for six weeks. The way that this is given, and there's a 15-minute instillation of the sensitizing agent, which helps to prepare the urothelial layer, followed by injection of the drug into the bladder through a catheter once a week for six weeks.

They get a maintenance treatment at three months, and that's once a week for three weeks. They get a maintenance treatment at six months, again once a week for three weeks, and then at nine months they would get one instillation, and at 12 months they get one instillation. That would be the treatment arm.


The control arm, arm B, they get surveillance without any medication. If they recur, if they develop disease recurrence, they would be offered the option of receiving creto. They would have reached the endpoint obviously, but we want to offer the drug to those patients in the event that they do recur during the course of the study.


Zach Klaassen: I like that trial design because it is a disease space where we don't have a gold standard, but offering those patients at the time of recurrence in arm B, the treatment medication is excellent, and recurrence-free survival is the primary endpoint, correct?

Robert Svatek: That's right.

Zach Klaassen: Excellent. I think having the investigators meeting just recently, it's very interesting. We're going to get a lot of translational information out of this trial as well, which for a population that has been well studied in terms of intermediate risk, I think it's going to be really important as well. What are your thoughts on that?

Robert Svatek: I think it's really a unique type of treatment. I mean, using this oncolytic virus to stimulate cancer cells, to make cytokines, which then recruit immune cells to the bladder, and also to increase production of GM-CSF. It'll be interesting to look at what happens in the urine, which is a reflection of the bladder. The best that we can do for now as a surrogate of what's going on in the bladder, what happens in the urine over time. Also, does that correlate with responders and non-responders?

I think it is a unique drug, and so I think it'll be interesting to see what happens to the immune profile in the bladder during the treatment. We don't know a whole lot about low-grade disease, and so looking at the profiles of those tumors at baseline, I think we're going to learn a lot just from that because we just haven't studied that to the extent that we've studied it in muscle-invasive and high-grade T1, for example. That'll be another kind of ancillary, translational research that we will do in the context of this trial.


Zach Klaassen: That's great. Bring our listeners up to speed on where we stand with PIVOT-006. It's early days, but how many sites are involved? Do we expect this to grow relatively quickly? What's our end time that we hope to have everybody enrolled for this trial?

Robert Svatek: Good question. I mean, we have, I want to say close to 60 sites that have voiced interest. We have one site that is actually being activated as we speak. I think activation is going to occur over the next, over basically Q1 of 2024, and I think that enrollment will be reaching a good point in the summer of next year.

Now, these patients, as you know, there are a lot of these patients that are suffering from intermediate risk disease. There's quite a bit of this, so I'm hoping that accrual will be relatively quick. We're shooting for 400 patients, and so I'm hoping that we could have 20 to 30 enrolled per month, and the readout would be fairly quick because these patients do recur quite often. I think in the control group, we'll see recurrences pretty much in the first two years, we see quite a bit of recurrences. I think the readout will be relatively quick.

I mean, there's always unanticipated obstacles, but for the most part, I think we're targeting a population that there's not a lot of competing trials in, and there are a lot of patients suffering from that disease. I'm optimistic that the accrual will be relatively quick.

Zach Klaassen: That's great. It's been a great conversation. I think this is a very exciting trial, and any concluding statements, any take-home messages for our listeners as we wrap things up?

Robert Svatek: No, I would say what I like about this trial is unlike a lot of the other activity which is going on in non-muscle invasive bladder cancer, which is exciting and which is not to be, this is not derogatory in any way, but this is a randomized controlled trial. We've seen a lot of phase 2 data. We've seen a lot of things going on without control groups, but I really like this because we have a control group and I really feel excited about seeing activity against a control group, and that's what we really need with these new immune agents. That's what's really got me excited about it.

Zach Klaassen: That's great. We appreciate your time. It's going to be fun to see the PIVOT-006 trial enroll and certainly seeing data hopefully in the next couple of years. Thanks so much for your time, Rob.

Robert Svatek: Thank you, Zach.