Nephron-Sparing Management of Low-Grade UTUC with UGN-101 (Mitomycin Gel) for Instillation: The Olympus Trial Experience - Seth Lerner

Seth Lerner, the lead investigator for the Olympus Trial, joins Ashish Kamat to share the data that was presented at the 2019 AUA annual meeting regarding the Olympus Trial. The Olympus Trial was instrumental in the announcement by the FDA office granting priority review for the NDA for UGN-101, held by UroGen Pharma Ltd. This was a single-arm prospective phase 3 open-label study in patients with low grade upper tract urothelial carcinoma (UTUC). The primary objective was to evaluate the safety and tumor ablative effect of UGN-101.

Biographies:

Seth Paul Lerner, MD, FACS, is Professor of Urology and holds the Beth and Dave Swalm Chair in Urologic Oncology, in the Scott Department of Urology, Baylor College of Medicine. He is Director of Urologic Oncology and the Multidisciplinary Bladder Cancer Program and Faculty Group Practice Medical Director for the Urology Clinic. He earned his medical degree from Baylor College of Medicine, completed a surgical internship at Virginia Mason Hospital in Seattle, and returned to Baylor for his residency training. He completed a two-year fellowship at the University of Southern California in urologic oncology and reconstructive surgery under Peter Jones and Don Skinner before returning to join the full-time Baylor faculty in 1992. His clinical practice, education, and research activities are devoted to urologic oncology and particularly lower and upper tract urothelial cancer. Dr. Lerner is author of over190 peer-reviewed articles, and co-editor of a comprehensive Textbook of Bladder Cancer. He is the founding co-editor-in-chief of the Bladder Cancer journal. He established and directs the multi-disciplinary Bladder Cancer Research Program at Baylor and his research interests include use of selective estrogen receptor modulators for treatment of bladder cancer, gene therapy, integrated genomic analysis of bladder and upper urinary tract cancers, and outcomes of radical cystectomy and pelvic lymphadenectomy. He has 26 years experience as a clinical investigator for both NCI and industry funded clinical trials. He is the PI of the ongoing SWOG NCI Phase III trial comparing extended vs. standard pelvic lymphadenectomy at time of radical cystectomy. He is active in the leadership of several national bladder cancer research enterprises including chair of the Local Bladder Cancer committee of SWOG, founding and former co-chair of the NCI Bladder Cancer Task Force and current co-chair of the NCI CTEP Genitourinary Steering Committee, and he has co-chaired the Analysis Working Group of The Cancer Genome Atlas Project for muscle invasive bladder cancer for the past 7 years. He is very active in the Bladder Cancer Advocacy Network (BCAN) as a member of the Board of Directors, past chair of the Bladder Cancer Think Tank and co-chair of the management committee of the Bladder Cancer Research Network. Dr. Lerner is an active member of the prestigious American Association of Genitourinary Surgeons and is listed routinely among “America’s Top Doctors” and “Best Doctors in America.

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas.


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Ashish Kamat: So, it gives me great pleasure to have Dr. Lerner accompany us today. He's going to be talking to us about the Olympus Trial Experience. The Olympus Trial was instrumental in the announcement by the FDA office granting prior to review for the NDA for UGN-101, which is held by UroGen Pharma Ltd., and it's a really exciting time for upper tract urothelial carcinoma. Dr. Lerner is a Professor at the Scott Department of Urology in Baylor College of Medicine and has been a pioneer in bladder cancer upper tract and everything to do with ureteral cancers in general. Seth, please take it away.

Seth Lerner: Thanks, Ashish. So, what I'm going to share with you are the data that we presented at the AUA this past year regarding the results of this innovative treatment for upper urinary tract, low-grade urothelial carcinoma. These are my disclosures. I'm the Principal Investigator of the trial and Baylor does receive compensation on my behalf, and I've done consulting for UroGen for a number of years around this product and others that are in development.

So, the rationale for the study, I think we are in this audience, is very familiar with the burden of lower grade, upper tract cancer. Most of this or much of this can be managed endoscopically, with either resection or ablation. We're all aware that there are often limitations due to volume and certainly location and hard to get places, including the lower pole. It's obviously associated with a very high recurrence rate and repetitive endoscopies and even some people will do an intracavitary therapy with either chemotherapy or BCG, much like we're used to doing in the bladder. And so, unfortunately, because of that situation, patients are also faced with having to undergo a nephroureterectomy reduction in obviously total renal function and in many cases, puts patients either dangerously close or on dialysis.

And so, if we had a therapy that could help them keep their kidney longer or perhaps permanently, that would obviously fill an unmet need. We have reported on a compassionate use program with UGN-101, these were essentially N of 1 clinical trials that were split by the FDA and company. We treated 20 patients and the preliminary data from that, the group of patients showed that not only was this feasible and safe but really was able to ablate and maintain many durable, longterm responses in the target patient population for this trial. Just a little bit about the chemistry, it takes advantage of a thermoreversible gel that is semi-solid at body temperature, liquid at low temperatures. So, you can inject this gel that is impregnated, for lack of a better term, with mitomycin, and you can inject it through a ureteral catheter and that, at body temperature, it acts as a semi-solid and takes about four to six hours, because it's water-soluble, it'll pass eventually, but it allows a much longer contact time and retention of mitomycin C, which we know is effective in treatment of low-grade disease in the bladder. So that's the chemistry behind the product.

This should look familiar to all of us. So, it reminds me of the old injectors that we used to use for dilation for kidney stones. But because the gel is semi-solid, you need a pressure injector. But even under this circumstance, you can inject it through something as small as a 5-French open-ended catheter, and for the trial we used anywhere from between a five, a six, or a seven, and virtually all of the patients, these were retrograde installations.

So this is the design of this study. Again, I think it's really important to emphasize that these were patients that had biopsy evidence of low-grade disease and negative cytology. And so, once that was established, they were treated weekly for six weeks. And then within about four to six weeks after the last treatment, they underwent the primary disease evaluation, which of course was a ureteroscopy, and a complete response was defined as a negative ureteroscopy and cytology and/or biopsy that showed, again, absence of residual disease. And then, those patients that had a complete response had the option of continuing on to get additional maintenance therapy, maintenance treatments, and the schedule that you see out to about 12 months. So, these were administered monthly.

And then, here's another summary and because it had already been established quite a long time ago in a Phase III trial that the uptake of mitomycin C was improved in an alkaline environment, these patients took bicarbonate the night before, the morning of, and again 30 minutes prior to therapy, in order to optimize the penetration of mitomycin C, and then we had to assess the volume of the renal pelvis. And so, three measurements were taken, again, using a retrograde catheter with radiographic contrast, and the maximum volume that you were allowed was 15 CCs, and the concentration of the UGN is fixed at four milligrams per CC, so you can do the math on the maximum amount of mitomycin that any one particular patient may have received. The target population, again, we enrolled 74 patients and that gave us adequate power to demonstrate that the observed, complete response rate was superior to the rate of 15%. Now you might argue that that's pretty low, but this was actually the bar that was set by the FDA because this represents such an unmet need.

And so, just a little bit more about the inclusion criteria. We did allow patients that had a volume of disease more than 15 millimeters as long as the ... And the target lesion, the original diameter of the target lesion could have been larger as long as the urologist was able to ablate or resect down to no more than 15 millimeters. And then there was a minimum size of five millimeters. They could have multiple tumors, but the target lesion was prescribed and had to be somewhere between five and 15 millimeters and we did not treat ureteral disease. And so, by definition, this is all proximal to the ureteral pelvic junction. We were very meticulous in doing everything that we possibly could to verify that a patient did not have a high-grade disease. They should not have had BCG within the last six months, obviously no history of invasive urothelial carcinoma and no current treatment with systemic chemotherapy.

This is the final cohort. So 71 of the 74 plated the treatment and had their primary disease evaluation. Not surprisingly, the majority were men. This obviously is a disease of older patients and you can see that it was split, about half of the patients had multiple tumors at baseline, and then about half also had unreachable tumors at baseline. And I think we all know that that's a very common scenario and just a limitation, primarily of instrumentation and particularly trying to get laser fibers, for example, through a ureteroscope, that while you might be able to see it in the lower pole, you just simply can't do anything about it.

So we have data on the PDE, so the primary disease evaluation on every single patient, and we're reporting that 59% of those, or 42 out of 71, had an initial complete response, excuse me. And the majority of these patients have been followed. Two-thirds are out to their six-month surveillance, and among those patients, 89% have remained disease-free. So independent of whether they got additional maintenance therapy, everybody was followed with ureteroscopy at three, six, nine, and 12 months.

Now, at the AUA, we reported on specifically the patients who were endoscopically unresectable, and that was 48% of the cohort and as I point out here, the CR rate was identical in those patients, 59%, and again, the vast majority of those patients have remained in a disease-free state, at least out to six months. So I'm just throwing up here a couple of representative cases. And so, you can see a low-grade tumor on the top left, some evidence of necrosis post-treatment and on the bottom right, the obviously accessible with a laser. This actually was a patient of mine. When I biopsied that area post-treatment, he still had a residual low-grade disease, so he was not one of the complete responders.

By and large, the treatment is really well-tolerated. But, the big issue that we're reporting is that there was a significant minority of patients had some evidence of either hydronephrosis, ureteral edema, ureteral stenosis, and the vast majority of those patients were able to be managed with stenting, in some cases balloon dilation. I had to do that on one of my patients. Life-threatening and fatal events were quite uncommon, but this is an elderly patient population so you see three fatalities due to, one due to stroke, failure to thrive and sudden death, and none of these were related to the treatment, however.

So in conclusion, we have observed in this really innovative, first of its kind clinical trial with UGN-101, which is a thermoreversible gel impregnated with mitomycin, was able to ablate low-grade tumors and associated with a high initial complete response rate that appears to be durable and follow up continues to accrue. And then this high initial response rate was also seen in roughly half of the patients that had resectable disease and the NDA has been filed. We obviously haven't heard anything back from the FDA. And if approved, obviously will provide a nice alternative for patients who otherwise may be facing a nephroureterectomy. And obviously, I just want to say all thanks to the patients, families, and their caregivers, and very importantly, I've listed all of the urologists and the study team at UroGen and happy to take any questions.

Ashish Kamat: Thank you so much. I mean, that's really encouraging data. A couple of questions. So, one of the things that people have often wondered with this type of drug and you alluded to measuring the renal pelvis volume, et cetera. How simple is it for someone that is trying to administer this and actually calculate the volume? If you could just take us through some of the steps that you do in order to do that?

Seth Lerner: Yeah, I think it's pretty simple. So obviously, there's tremendous variability in the capacity of the renal pelvis and the [inaudible 00:13:21] system, but we just do it with a retrograde injection of contrast. So, you fill it to a point where obviously you don't want to over-distended it, and just fill it and measure the volume that you put in, drain it, obviously document that radiographically. We repeat that twice and just take the average of all three. And I think the smallest volume was somewhere in the seven CC range.

I would say though, that there is a bit of a learning curve to doing this because the product, obviously, is something we're not familiar with. And I have to tell you that I had, like a lot of people, some of you know, experience in putting in BCG or chemotherapy through antegrade, through a nephrostomy, but I hadn't really taken this approach of bringing them into clinic, which is what we were able to do, and put a catheter up, confirm the position of the catheter in the renal pelvis radiographically, and then inject this. And I've found this to be, the patients actually don't mind coming back and forth. They seem to be okay with the procedure. They prefer that to a nephrostomy tube. And I'm doing this now for patients that I'm treating with BCG or off trial, other chemotherapy drugs, and found it relatively seamless. Obviously, you got to be set up in your office to do this and have fluoro. Some of the patients were treated in outpatient surgery centers or a hospital-based outpatient facility. But yep.

Ashish Kamat: Great, great. And that, I was just going to say, so the patients tolerate this well in clinic and if and when this drug is actually available for use, you foresee that most of the patients would be treated either in the office setting or same-day surgery setting. Any need for anesthesia in any of these patients?

Seth Lerner: I don't think so. I mean, I think that there were probably a handful of centers, where for a variety of reasons, they didn't have a setup in their outpatient clinic that made this sort of seamless. So, I'll just walk you through what we did. We, like probably most other people, do all of our cystoides in a clinic-based system cystoscopy suite, and we just have our fluoroscopy down the hall. So I would put the cysto with a flexible instrument wire, put the catheter up over the wire, tape it to the leg, and then take the patient over to fluoro, position them supine, and then, usually the first time I'd shoot some contrast just to make sure I'm in the right place and then take an image of that and remember it for the next time, and then put the drug up, take the catheter out, we're done. And so, it's a different workflow. And then I think for patients that, I'm sorry, for centers that just are, their setup is in an outpatient surgery center, then the workflow basically is the same. It makes it a little easier because you're probably doing that on a fluoro table to begin with. So, but we're, I mean, either of those would work, I think.

Ashish Kamat: Thanks. From an efficacy standpoint, you mentioned that the CR for these patients was 59%, and about two-thirds have had a six-month followup and remain, the majority, about 90% remain disease-free. Based on your involvement with these patients, do you have any sense as to which type of baseline characteristics in the patients are the ones that you can say will do better or, or is there any such hint?

Seth Lerner: I don't think we really have much to say about that. So yeah, because we don't really have data to identify any particular features of the patient's tumors that predicted complete response. But I tell you what I'm really excited about, and I think a lot of the investigators sort of share that enthusiasm, and I know you have these patients where, to me, the sweet spot is these patients with lower pole tumors that you've proven that they're low-grade, you just can't get it to them and you're facing an alternative of maybe a percutaneous resection or a nephrectomy. And the beauty about it is the gel, you have to inject kind of top to bottom, but it'll fill the entire collecting system. And since the drug is evenly distributed and mixed with the gel, you're going to be able to get chemotherapy into areas that you can't get a laser fiber into or a Bugbee fiber into, and with contact time, it appears to be effective, at least in the majority of patients.

Ashish Kamat: Right.

Seth Lerner: So, the other part of it is the higher volume tumors. I think with our current instrumentation, getting up into the upper pole and the mid pole was really not a problem. But oftentimes, just from a volume standpoint, you can't deal with it. And so, that may be another opportunity and the patients with large-volume tumors that otherwise would need a nephrectomy.

Ashish Kamat: Yeah. And, that's the one point I wanted to emphasize, and I don't want to put words in your mouth, but you would recommend that the patients are optimally [inaudible 00:19:33]-

Seth Lerner: Yeah.

Ashish Kamat: However you can before you use this, and not use the mito gel as a replacement for good endoscopic management. Is that correct?

Seth Lerner: That is, that's Seth Lerner's view. Yes, I would agree with that. I think from a patient standpoint, I think they would expect us if we're there and we have the ability to ablate stuff that is accessible and that we can see, that we should do that. And then, maybe use the UGN-101 to clean up, so to speak. And then obviously there are lots of situations with, or either we can't get to it or it's too much volume or you get into bleeding and you can't see and you have to stop the procedure. So yeah, I would agree with that.

Ashish Kamat: Okay. And then one question about the, you were able to stenosis and nephrosis. Those numbers seem really a worthwhile trade-off for the patients because they're facing a nephrectomy anyways. But in order to manage these, did the study group use steroids for example, which the bladder tends to help with...

Seth Lerner: Yup.

Ashish Kamat: ...mitomycin-induced strictures. So, any tips on how you could decrease the incidence of these urial stenoses or the severity?

Seth Lerner: Yeah, good question. I don't have the medication usage in front of me, but it would make sense, steroids might make sense in particularly challenging situations. I think that this is a reflection of a couple of things, obviously, repeated instrumentation. Mitomycin is a desiccant and if it gets into the soft tissue, it can cause necrosis. I mean, we've all seen these lingering kind of necrotic lesions in the bladder and there, I don't think you really see with other chemotherapy agents or BCG. So, that's the part that I've kind of wondered about. But, it could also just very well be due to repeated instrumentation. So, if you're having a particularly difficult time, getting a stricture to resolve, steroids might help. But...

Ashish Kamat: Okay.

Seth Lerner: Yeah.

Ashish Kamat: As we close, any last-minute thoughts or concluding thoughts for our audience that you want to convey?

Seth Lerner: Yeah, we just, I mean the ... I've been involved in this now for a few years and what's remarkable to me is how enthusiastic the investigators were to get the trial started, to treat patients on it. It was an incredibly engaged group of surgeons in troubleshooting, coming up with ideas of how to administer the drug, different catheter sizes. And so, I mean, hats off to the patients obviously, but a really strong, committed group of urologists who got this done.

Ashish Kamat: Absolutely. And, I do want to, once again, give a shout out to you, specifically, for always leading the way and especially here leading the way in this very important study. I know we ran a few minutes overtime, but I think it was very important and thank you again for sharing your pearls of wisdom.

Seth Lerner: Yeah, thank you. Appreciate it.