So Pat, this was a Herculean task, and you rose to the task and love to hear you share your thoughts with our broader audience.
Patrick Hensley: Yeah, thanks, Ashish. It's a pleasure being here with you. Really excited to talk about this initiative. So without further ado, I'll kind of give you a broad overview.
Our task was to generate a bladder toxicity index that could measure specific toxicities from various intravascular therapies. We developed an international group of urologic oncology experts, myself and co-lead Seth Lerner. And again, our goal was to kind of define and measure local bladder toxicity as it relates to specifically intravascular therapy. There were other domains that looked at, for instance, surgical toxicity and toxicities of the bladder from radiation therapy and systemic therapy.
So our goal was to look specifically at intravascular therapies. And our goal was kind of twofold. The first was to objectively characterize toxicity in the bladder from intravascular therapy specifically for clinical trials and make correct attributions of toxicities to specific drugs or interventions, and then also kind of long-term to obviously mitigate side effects to these drugs.
We looked at a number of domains that we thought were very pertinent and salient to intravascular therapy toxicity. So we'll kind of walk through at a high level each one of these.
We thought it was very important to, number one, define a patient's baseline bladder function from storage and emptying and symptomatology. To know where a bladder is currently, we need to know where it started pre-treatment.
Next, we wanted to identify appropriate measurement intervals. I think it's important to characterize each individual toxicity, measure its crescendo and its resolution without being too overly burdensome on trial investigators and patients in terms of survey burden.
Next, we wanted to guide toxicity measurements and attributions. So which toxicity should we measure and how important is it that we attribute those toxicities specifically to the investigational agents?
We wanted to define adequate dwell time for intravascular agents. And this was one of the more challenging topics that we had to tackle because as you know, the mechanism of action and the preclinical pharmacokinetics can vary considerably in between different drug delivery systems, different drugs themselves. So that was kind of a moving needle and one that our group spent quite a bit of time on.
We wanted to identify dose-limiting toxicity, incorporate patient-reported outcome measurements in this initiative, as well as define some constitutional symptoms. As we know, a lot of intravascular drugs are absorbed negligibly at a systemic therapy level, but we do see some systemic and constitutional side effects that need to be appropriately measured.
To define baseline bladder function, we really broke it down into storage and emptying domains and wanted to incorporate some commonly used patient-reported outcome measurements like IPSS, which is validated in both men and women, as well as commonly used patient-reported outcome measurements in intravascular therapy trials, including the EORTC QLQ-NMIBC24 index.
In terms of identifying appropriate measurement intervals, the FDA did provide some guidance in 2024 and how frequently and commonly we should be querying patients on trial for things like health-related quality of life. However, this guidance was not specific to intravascular therapy. So we had to think critically about the timing of these assessments with respect to their surveillance of stochasticity schedules and their intravascular instillations.
In terms of identifying which toxicities to measure and making appropriate attributions, from a clinical trial standpoint, this kind of dichotomized into two concepts. The first is when you're looking at NCI CTEP trials that are IND-exempt and are not looking for a label change, can you kind of streamline the toxicity measurements that we collect versus a drug that's coming to market in a registrational trial format? Collecting appropriate ubiquitous toxicities throughout the trial I think is very important.
So this was the first point for NCI trials that are IND-exempt, and again, not looking for a label change, there's kind of a push towards characterizing only higher grade toxicities, grade three or higher, and not a lot of emphasis on appropriate attribution of that toxicity specifically to the intravascular therapy agent.
Versus recent FDA guidance in August 2024 from the FDA in terms of optimized dosing schedules for investigational therapy agents, which suggests that even low grade smoldering grade one and two toxicities could be very burdensome as we see with a lot of intravascular therapy agents. And these need to be captured and they need to be appropriately attributed.
We wanted to identify, again, adequate dwell time. Listed here are a number of kind of pharmacokinetic properties and dosing administration properties of individual intravascular therapy agents that could impact what would be considered an adequate dwell time. And kind of the conclusion from the group is that it depends on the drug, and it depends on the mechanism of action of that individual therapy. So this is still kind of a work in progress.
And in terms of defining a dose-limited toxicity, I think this is a critically important facet of this toxicity index. We want to define DLTs to ensure patient safety and appropriate dose determination and dose finding trials. And we want to maintain some consistent nomenclature across trials. Considerations when we were trying to define dose-limited toxicity, including dwell time and appropriate intravascular therapy, contact time of the drug with a bladder, any undue treatment delays and any significant adverse reactions.
So those were the main overview of the big topics that this group tackled, and we were very excited to put that group together and really pick the brain of the IBCG faculty because this is a critically important topic and frankly, an unmet need to date.
Ashish Kamat: Yeah, thanks Pat. Again, as being part of the Advisory Board in our core committee, you know that when we think about topics for the retreat, we really try to figure out where the unmet need is and try to help address that. And this was one of the more challenging one because clearly you have to assimilate all the information that we already have and then try to bridge the gap between what's needed, what's practical, what's desirable, and so on and so forth. So your team did an immense amount of work, and of course the retreat was, I think, hugely successful, but there's a lot of work left to be done and really looking forward to having you back once the manuscript is ready, and once we have all the actual statements and all of that in there.
But in closing, I want you to leave the audience with maybe your thoughts on do you think that this is something that is just US-centric or, and again, I'm biased, but I want to hear your thoughts, do you think this is something that is needed worldwide?
Patrick Hensley: I absolutely think that these scales and toxicity measurements are pertinent worldwide. As drugs get approved and marketed, there's different access to these novel treatments. But ultimately, we need a scale to harmonize toxicity measurements across trials, not for cross-trial comparison, but so that when we're looking at comparing efficacy and toxicity and describing available treatments to patients, we need to be comparing apples to apples in terms of these scales. And I think it's really important to define bladder specific and bladder centric toxicities.
There was a lot of discussion about the updated CTCAE scale, the version 6.0, and it's very helpful, I think, for systemic toxicities. But if you look specifically within the bladder realm, I think it leaves something to be desired in terms of the granularity at which we attribute toxicity as to intravascular therapy specifically for bladder toxicity.
So a lot of work to be done. I look for this to be broadly applicable on an international scale and across trials and in clinical practice.
Ashish Kamat: Yeah, I couldn't agree more. Pat, thanks as always. Great to see you.
Patrick Hensley: Thank you very much.