Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt University. And I am incredibly fortunate, as you are today, to have with us Dr. Jeannie Hoffman-Censits. Jeannie is an associate professor and she's the co-director of the Upper Tract Urothelial Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University Medical School. And we've asked Dr. Hoffman-Censits to talk about today an exciting trial that she's basically helping to formulate and to lead, that is a trial for actually patients with upper tract disease. So I'll let you take it away, Jeannie, and thank you very much for spending some time with us.

Jean Hoffman-Censits: Sure. Thank you so much for highlighting this trial, and for highlighting this population of patients. Really important, so thank you. So, here today to talk about ECOG-ACRIN 8192. So this is a preoperative clinical trial for patients that have high-grade upper tract urothelial cancer that had to be diagnosed by biopsy. No evidence of any clinically significant lymph nodes. So, in the current version of the trial, lymph nodes have to be less than a centimeter local regional. And patients who are really ultimately planned for a nephroureterectomy.

So, Sam, these are going to be patients that are going to be identified in clinics like yours. Patients that are coming into to the office that are being evaluated for gross hematuria or flank pain or other clinical indicators that get people into your office. And then when there's a plan for ultimately a nephroureterectomy, what we would love to have is a discussion about sending a patient for a discussion for neoadjuvant chemotherapy, and maybe even to one of the centers where this trial is open. So that's really the background in the patient population that we're looking at for this clinical trial.

Sam Chang: And so as a urologist, when I counsel these patients, we talk a little bit about the POUT trial and we talk a little bit about the possibility of neoadjuvant chemotherapy because we're trying to save. We may have more nephrons and better renal function to be able to give the treatments that we ultimately want to give. Tell us about this trial and what were these patients receiving during the neoadjuvant setting.

Jean Hoffman-Censits: Sure. Well, I love that you mentioned the POUT trial both in this context as well as your patients in clinic. The POUT trial, Jonathan Coleman's Neoadjuvant trial, our prior ECOG trial, looking at NVAC, all studies focusing on patients with upper tract urothelial cancer and really building the framework as well as the prospective data that really shows that perioperative chemotherapy, I think, is very important in this population.

And so the POUT trials, as you and I have talked about before, large randomized phase three clinical trials showing that postoperative chemotherapy improves disease-free survival, and so that's a really important study. I think that a lot of us in the United States really do, I think, extrapolate the data that we know about from muscle-invasive bladder cancer and the overall survival benefit that cisplatin-based chemotherapy provides in that neoadjuvant space, and I think are really used to working in that neoadjuvant space.

And so our prior clinical trial, ECOG 8141, which showed that preoperative NVAC, four cycles of methotrexate vinblastine and cisplatin, that dose-dense regimen was safe and led to a pathologic complete response rate of 14% was what we build on to design this larger trial, 8192. So in this study, the patients who are cisplatin eligible, so those with the creatine clearance of 50 or above again, no evidence of clinically significant local regional lymph nodes who have good functional status, normal cardiac function, and no significant hearing loss or peripheral neuropathy. Those patients will be randomized to either for cycles of NVAC, just like we did in 8141, or four cycles of vac plus Durvalumab, which is a PD-L1 inhibitor. All patients will then after their four cycles of pre-op chemotherapy will have a post-chemotherapy scan just to be sure that this is a patient still appropriate for surgery.

And then everyone will have a nephroureterectomy with a lymph node dissection. We'll look at pathologic responses as a secondary endpoint, but really in this large randomized trial, we're looking to enroll a little over 200 patients with a primary endpoint of looking for an improvement in event-free survival actually for this study. We know a lot of patients are not those, the cisplatin eligible. That's a big problem in our field of all this discussion about who is or is not cisplatin eligible. And we know that at least 50% of the patients that we see often aren't candidates for cisplatin. So in this trial, there's actually a second arm. So it's a second non-comparative arm. Just a phase, a smaller phase, two looking again at Durvalumab at this time in combination with gemcitabine, similar four cycles of neoadjuvant chemotherapy followed by NFU.

Sam Chang: What I love about this evaluation, you love when trials are set up to try to help justify your own suppositions or biases. But I love that now we're trying to explore at least on an evidentiary basis that some type of treatment upfront leads to some benefit down the line and to be able to accommodate a wide variety of patients in terms of platin eligibility, I think is fantastic. When you look at the combination of your PD-L1 plus chemotherapy, do you think there'll be any concerns regarding tolerability? There doesn't seem to be an kind of metastatic or adjuvant, but what about in this setting? Do you think there'll be any problems?

Jean Hoffman-Censits: Yeah, I think that's a great question. And one that we always think about, especially when you're investigating a novel therapeutic combination in a patient population with curative intent. So we have built this study with safety parameters. We've discussed this at various different meetings and in collaborations and different frameworks. So we're going to be looking to be sure that the first 10 patients that go through that experimental paradigm are able to get surgery in the timeframe that we expect. So if we see that as a safety endpoint, we will certainly sit down and kind of review the study with our safety committees.

But as you mentioned, the combination of chemotherapy with immunotherapy is not novel. So there are multiple different clinical trials in different diseases, disease states in urothelial cancer, as well as others where this combination of chemotherapy plus immunotherapy seems to be effective in, although that there are toxicities, none of them are unexpected when you put the two drugs together.

Sam Chang: So tell us how either individual sites can become uninvolved, or if surgeons have individual patients that may qualify, how can we get patients accrued for this trial?

Jean Hoffman-Censits: Sure. So the trial is currently open at about 90 sites and another a hundred sites are evaluating this study to decide whether or not really it should be on their protocol docket. So it certainly is open in a variety of different places across the country. Of course, sites can look at clinicaltrials.gov to see if there's a site that's open near them. And if not, patients could potentially travel to look for a site. It is a short period of time. So it's in the preoperative setting, four neoadjuvant cycles of chemotherapy, and it does look pretty similar to standard of care. And so that's the kind of thing that sometimes I think our patient population may travel for. It's not a study where there is no kind of end date and it goes on into perpetuity. 

Sam Chang: Yeah, you've got the light at the end of the tunnel in terms of, Hey, we're going to have this procedure, this is where we're going to go. This is what we're going to look for. So I think that's great. When would you hope to enroll the last patient? Guesstimate? Hopes planned.

Jean Hoffman-Censits: Yeah.

Sam Chang: Yeah. We want to support this. We got to get patients enrolled for sure.

Jean Hoffman-Censits: Yeah. I mean, the estimate for enrollment is going to take a couple of years, honestly, Sam and I think that this trial opened in that kind of tail end of COVID and I think we've all seen a lot of shifts in terms of our patient populations and clinical trial enrollments. But since the start of 2022, I think there's definitely been more momentum behind this study. And so we're happy to see that both nationally and in our own center as well. Even the patients coming in for evaluation had slowed down during the pandemic. So they were really starting to see things pick up now and people be able to think about getting back to normal in multiple different ways and including thinking about things like trials.

Sam Chang: Yeah, no, I think that those are great points. Jeannie, it's always a great pleasure to get to talk to you, pick your brain about urothelial carcinoma about upper tract disease. And I look forward to the urologic community, the surgeons, hopefully being supportive and enrolling. And because you're right, a lot of this in terms of the initial discussion possible enrollment is really dependent upon the surgeon. So hopefully we'll be able to be supportive and be able to enroll patients. And to be honest, I think the paradigm with just as you stated regarding bladder cancer, it took us years, but we're getting the point where most surgeons now will at least have the discussion and we're finding appropriate patients for neoadjuvant chemotherapy. I really think that we have a great opportunity here to be helpful for our patients. And so I personally want to thank you Jeannie for all your efforts and whatever we can do, whatever can do here today to help enrollment, I think is only beneficial for all the patients. So again, thanks for spending some time with us and we look forward to supporting this trial.

Jean Hoffman-Censits: Well, thank you. Thanks so much for highlighting it. Highlighting both the trial, highlighting upper tract urothelial cancer, the multidisciplinary paradigm for how we think this disease should be treated and managed. Absolutely. We rely on our urologic partners to think about this disease, to talk to their medical oncology partners about patients with the disease and how to manage. So thank you so much for all of your work and highlighting patients with upper tract urothelial cancer.

Sam Chang: Great. Thanks. Take care, Jeannie.

Jean Hoffman-Censits: You too.