Name: Designing Pivotal ADC Trials That Actually Enroll: Live Webinar with MD Anderson Investigator
Uploaded: 2026-05-06T16:16:12.273Z
Duration: 54 min
Description: Designing Pivotal ADC Trials That Actually Enroll: Live Webinar with MD Anderson Investigator

Transcript for "Designing Pivotal ADC Trials That Actually Enroll: Live Webinar with MD Anderson Investigator": Great. Thank you. Welcome, everyone, and thank you for joining us today. My name is Vince Calderon, and I'm delighted to be presenting alongside doctor Christian Spillante and Nick Quinn for the next part of our webinar series on single and multispecific antibody drug conjugates. Today's session is titled designing pivotal trial for ADCs and multispecific antibodies, translating breakthrough science into executable oncology programs. This is a rapidly evolving space, and the goal today is to give you both the scientific and operational perspective from regulatory expectations due to what actually happens at the site level. Before we get started, I'd like for each of us to briefly inter introduce ourselves. Doctor Squante, would you like to get us started? Hi. I'm doctor Christian Scholante. I'm one of the attending physicians at the MD Anderson Cancer Center at Cooper University Hospital. I'm our lead for our genitourinary oncology program and the director of our solid oncology clinical trials. Great. Thank you, Nick. My name is Nick Quinn. I'm a therapeutic area lead with PSI psych support, and specialized study support services team. My background is as a clinical research nurse. I was at Dana Farber Cancer Institute in Boston for about seven years. And there, I worked in our phase one research group as well as the head and neck oncology group. And, with PSI, I used that site experience to, bring a unique perspective to study design and overall supporting studies, for enrollment and operational success. Great. Thank you. And I'm Vince Calderon. As I mentioned, I'm a therapeutic area director with PSI within our specialized site support services group, and I oversee our therapeutic area leads. So let's go ahead and get started. Before we dive in too far, just to talk to you about the agenda, so that you know what to expect, we'll start by framing the industry shift and the new reality of antibody based therapies and why this moment matters. From there, we'll get into a regulatory reset, that's going on underway and and describing that, particularly around dose optimization, and the FDA's Project Optimus. We'll then move into some practical, matters and discuss designing trials, specifically the challenges related to ADCs and multispecific antibodies. And doctor Scolante will give us some feedback regarding, what he looks for in a trial design and how he navigates these firsthand with his patients. From there, we'll talk about some enrollment considerations and some other protocol considerations, and we'll walk through again, of course, enrollment strategy and how to reduce some of the operational friction. And then we'll we'll end by leaving you with a practical operational checklist that you can take back to your teams. As a reminder, please feel feel free to ask any questions that you may have, within the chat box on the screen, and we'll be sure to answer these before we wrap up today. So diving ahead, why are we here? So looking at the landscape, the numbers sort of speak for themselves. There are over 200 ADCs currently in active clinical development. More than 40% of oncology pipelines are now antibody based. And as of 2025, there are at least 12 FDA approved ADCs on the market. This is not a niche corner of oncology anymore. We hit a critical mass and development momentum is rapidly accelerating. ADCs have evolved dramatically. First generation cytotoxic conjugates have given way to to precision engineered payloads with bystander effects, novel linker chemistries, and increasingly sophisticated drug to antibody ratios. These are complex molecules with complex behaviors. And it's not just ADCs anymore. We have bispecific and multispecific antibodies, and these are redrawing the immunotherapy landscape. They enable t cell redirection, dual checkpoint blockade, and receptor co engagement in ways that we never really imagined even a decade ago. What this means operationally is significant. Sponsors are no longer looking for a CRO with Bandwidth. They need to partner with deep therapeutic area expertise and people who understand the science, the safety profile, and the site level realities of running these studies. Finally, the regulatory agencies have also taken note. They now expect dose optimization, evidence, and robust robust safety data before programs advance to phase two, let alone, of course, phase three. That expectation is reshaping how sponsors plan from the very beginning. So looking again, deeper into the regulatory reset, Project Optimus was launched by the FDA in 2021, and it fundamentally changed the conversation around oncology dose selection. The core shift is that the FDA is no longer satisfied with identifying a maximum tolerated dose and calling it a day. They want to see randomized dose optimization cohorts. They want PKPD modeling at early phases. They want the safety efficacy relationship demonstrated can't be assumed. And critically, this framework, which was built initially around small molecules, is now influencing ADC programs directly. Dose act expansion cohorts are expected to be scientifically justified and not just exploratory. What does this mean for sponsors and sites? Well, as Christian will tell us here in just a little bit, it's quite a bit. Phase one design must now include dose comparison arms. Sponsor agency and the meaning is critical before IND submission. You don't wanna get mid program and find yourself just then in a dialogue with the FDA, perhaps about dosing that really should have started from the very beginning. For ADC specifically, the PK complexity is significant. You're not just modeling one species. You're tracking free payload, total antibody, and ADC species simultaneously. The therapeutic area, excuse me, the therapeutic index is narrow, and that makes clinical pharmacology strategy a day one conversation, not a phase two one. And, of course, the FDA is not alone here. EMA harmonization is also ongoing, so sponsors should expect similar requirements across Europe in the near term. One practical note, site staffs need to understand the rationale for dose de escalation provisions. These aren't just protocol quirks. They reflect a regulatory expectation that sponsors can defend as they discuss with them. With that regulatory context in mind, let's talk about how this shapes trial design itself. So this slide gets at the core tension in this space where the science re meets reality. And I wanna work through this one with doctor Escalante here in just a bit, because these aren't just academic design considerations. They're decisions that directly affect which patients he can enroll and how he manages manages these patients, clinically as well. So for ADCs, linker payload stability is fundamental design variable. Cleavable versus non cleavable linkers carry different PK profiles and different toxicity signatures. Drug antibody ratio selection and homogeneity directly impact PK, and variability in ratio distribution can translate to variability in both efficacy and safety. On target off tumor toxicity is a major concern. Interstitial lung disease with HER2 directed AUCs being the most prominent example. We have ocular toxicities and peripheral neuropathy, which are dose limiting, issues in in in many studies. And biomarker expression thresholds add complexity to enrollment, eligibility that sites need to operationalize. For bispecific and T cell engagers, the challenges are different, but no less real. We have CRS and neurotoxicity risks that we need to consider, and require step up dosing regimens. This often means inpatient requirements that the sites must be prepared for. And man manufacturing variability for complex, products is is the supply chain reality that affects study timelines. There's also themes that cut across both, single target ADCs as well as, bispecific and multispecific. The use of surrogate endpoints versus overall survival and what the FDA will accept continues to evolve over time. Adaptive trial designs are gaining regulatory acceptance, and patient reported outcomes are increasingly required, not just optional. Combination arms also add both operational and safety complexity that needs to be planned for at the protocol level and can't be retrofitted later. So, Christian, I'd like to bring you in here and I'd love to get your reaction. From your perspective at the clinical level, which of these design challenges creates the most friction for you and your patients when you're evaluating whether to participate in the study? Yeah. Thanks, Vince. I appreciate that. And I kinda want to start off by just kinda talking about where I come where a medical oncologist or myself comes from this in an ABC clinical study design. And so, you know, I think a key point to remember from the clinicians side as we're going through this is that ADCs are not really an emerging modality anymore. They're really kind of, I think, the next generation and a foundational therapeutic platform in oncology. And I think the next wave at we as we look in the next ten years of innovation in oncology is really not gonna depend just on better molecules, but on smarter development strategies that really prioritize the efficacy of the drugs and the and the patient experience with the drugs. Because at the end of the day, the most important person in this entire conversation actually ends up being the patient. And so kind of to launch into that, I always think it's fun to give a little bit of a history lesson from a oncology perspective, and I thought I would use kind of my background in bladder cancer as a really good example of why what we're doing on the SOC and what we're doing with ABCs in clinical trial development is so important. So just a clinical perspective on bladder cancer. Cancer. You know, I started my fellowship in 2012, and it's 2026. So I've been doing this for about fourteen years. But before that, we had a history. So, you know, when the world of cancer therapeutics started, we really didn't have much. We were learning to develop cytotoxic chemotherapies, the old school chemotherapy. And in the late nineteen nineties, we really developed our first active regimen for metastatic bladder cancer, a regimen called MVAC. It was a four drug IV chemotherapy regimen given every two weeks. And this was, like, the first active regimen in metastatic bladder cancer, but it was extremely toxic, extremely time consuming for patients, and was a miserable experience. But it changed patients' survival from about four months with metastatic bladder cancer to about eight to nine months with metastatic bladder cancer. So at that time, it was a huge development. And then we developed a new regimen, a drug called cisplatin and gemcitabine, which was much better tolerated and got people to about twelve months and really became the standard of care for the next fifteen years, including through my early years of fellowship. So all we had for several decades was cytotoxic chemo until the late twenty tens when the immunotherapy wave started, which prior to until recently was really all we were talking about oncology is was the immunotherapy wave. But immunotherapy and bladder cancer really just worked in a few patients. So we had some benefit, and some patients do really well. Responses were durable, but really just in a minority of patients. And then in around 2020, the COVID era, targeted therapy started to creep in. But, again, while this was biomarker driven, it was really very niche and only helped, you know, a few patients with certain biomarker mutations that we use in bladder cancer. So we were still struggling. You know, the average survival as of just five years ago for metastatic bladder cancer was anywhere from twelve to sixteen months. It was really you know, patients were dealing with significant toxicities from their treatment and short lifetimes to expect with metastatic bladder cancer. But really, for us, it was the ADCs, the antibody drug conjugates that really changed the game, particularly one called PADCEV or enfortumab vedotin. Initially, when we use this around twenty nineteen, twenty twenty, it was just used post chemotherapy and post immunotherapy for refractory patients. But for the first time, we had new real drugs with real activity in refractory disease. But then fast forward just a couple years ago to 2023, and these these antibody drug conjugates move to the frontline with immunotherapy. And this is really the huge inflection point. The trials that brought this out were really practice changing and game changing for patients. We went from about fifteen to sixteen months of survival with chemo to thirty two months with antibody drug conjugates and IOs. So higher response rates or durable responses, a clear survival benefit, and at the end of the day, much less toxicity. I mean, the transformation of this landscape in the in the fourteen years I've been practicing has been profound. I mean and what's this mean at the end of the day? Well, for the patients, you know, it's that, you know, getting to the wedding of their grandkid. It's, you know, getting to that graduation ceremony. It's meeting those life landmarks that really, really matter to them and have a significant impact. And not only being able to go to those ceremonies, but to be able to do it well and without a significant amount of toxicity. And I think that's really one of the most important things we can offer patients. And so where does that take us into what I'm looking for in an ADC clinical study design? Because that's really where I want to contribute to this talk. You know, I think there's some core questions that we as clinician ask when I'm looking at an ADC clinical trial. You know, is the target biologically relevant, and is the target expression meaningfully associated with, you know, tumor behavior or treatment sensitivity? That's probably question number one. Question number two is what's the patient population we're evaluating? Is the comparator arm appropriate and reflective of our real world standard of care? We're living in an era where standards of care are changing at a very rapid pace, and you wanna make sure that the comparator arm is really reflecting that and not reflecting something outdated. And then finally, does the study clearly define that therapeutic index? You know, treatments are great if they help you live longer, but you also wanna live with more quality. So balancing that efficacy against toxicity and treatment and tolerability, I think, really matters. And so what do those endpoints look like in real world time? You know, trial endpoints can have a number of different, you know, defined criteria. And, typically, I would say the overall survival still remains the gold standard, but also looking at things like response rates and progression free survival have really moved to the front line. And I think it's important to remember when we're looking at these things is is the are those numbers clinically meaningful and not just statistically significant? We always talk about statistical significance, and I think that's a great thing. But but what does that look like in terms of the real world, you know, meaningfulness to patients? That's something I look for. Because at the end of the day, I have to pitch these trials to my patients, and they have to agree to enroll on them. So we need to have meaningful things to talk about them. And then, you know, Vince brought up a really good point about safety considerations. I think one of the best and strongest points of an ADC clinical study is the safety considerations. Because in most cases, while we do have some unique off target toxicities that Vince mentioned, like interstitial lung disease, in the case of enfortumab vedotin neuropathy and ocular toxicity. Generally speaking, because ABCs act like kind of a Trojan horse for cancer treatments, you know, inserting themselves into the cancer cell and then releasing that cytotoxic payload in the cancer cell rather than just kind of throughout the whole human body, we do tend to see less overall side effects. But, you know, we still do have to monitor them because off target toxicities can be significant with these. So, you know, that's something we pay attention to, but I would say that's actually one of the biggest strong points of ABCs. And then again, you know, the dose optimization. We're not just looking for the highest tolerated dose anymore. That used to be what we did with clinical trials for the past fifty years. Now we're really looking for what dose, not necessarily the highest tolerated dose, what dose gets you the optimal benefit. So that can be part of the big challenge of these studies and something that's usually done in the early phase one trials. So at the end of the day, when I'm reviewing ADC data and reviewing a clinical trial for ADCs, I'm really looking at which benefit which try which patients are gonna benefit from this trial, how durable is that benefit, what toxicities are likely, How does this trial compete with the existing standards of care? And, really, will patients be able to remain on treatment long enough to really realize the full benefit? I mean, the at the end of the day, this is what we're looking at. Great. Thank you. Thank you, doctor Squalante. You know, that's that's a really important perspective. Not only your your feedback, of course, as as an investigator, but hearing the patient's perspective and and how these, treatments can really impact their lives, I think, really refocuses and and or maybe focuses our attention even more on, on the patients and and the outcomes that they'll experience and how these these products and the work we do, you know, really impacts their lives and can improve their lives moving forward. So thank you for that. It highlights, you know, how receiving your input and your feedback is, again, as an investigator is really important when we design, protocols from the very beginning. So thank you again. I'll hand it over to Nick. Nick, if you would like to start, by discussing some enrollment strategies for these types of studies. Yeah. Absolutely. So when we are shifting into the enrollment strategy portion of these studies, I think the biggest point here is that, specifically in first line ADC development, it changes enrollment, in a a pretty fundamental way. So when you look at later stage settings, or later line settings, I should say, there's often more time to identify patients, evaluate treatment options, and bring a clinical trial into the consideration. But in the first line setting, patients are moving faster, standard of care, options are more established, and that enrollment window can be, quite a bit smaller. So, operationally, when we look at how we're, recruiting patients, that model needs to shift upstream. It's less about identifying patients once they've already reached the study team, and it's more about understanding where those patients first become visible in their care pathway, whether that's the initial diagnosis, pathology or biomarker review, tumor board discussions, external referrals, because we've seen that when the study only enters the conversation after that treatment direction has already been established, then the opportunity for trial enrollment is is more than likely already lost. And that's why with these first line ADC studies, prescreening becomes so much more important. You know, eligibility has to reflect real world treatment timelines, not just the ideal version of what it might look like for the protocol. And from a site support perspective, that's really about building those early handoffs, within that care pathway so the trial can be part of that treatment decision, sooner rather than later and before it might not no longer be an option. And, doctor Squanty, that's you know, from an investigator lens, I'm curious what you think about, you know, ADCs in that first line. treatment decision. So when is when there's lot of act, such an established, you know, standard of care. yeah. This is where a lot of activity is happening right now. This is where most things so just to kinda get background of how typically drug development works in oncology is usually when a new drug is developed, it starts in, like, the refractory metastatic setting. But patients have already been on treatment at this point. Biomarkers have been identified. Next generation sequencing has been performed. So those trials are typically not as difficult to enroll to for a number of reasons. One, patients with refractory disease have limited treatment options and are usually looking or motivated to look for options. The first line setting is where things usually move next. Once you've proven that something has activity in refractory disease, say refractory or othelial cancer, then you wanna look at it in frontline disease and see if that has a benefit in that setting. But this is more challenging because patients at this point usually aren't on treatment. And patients nowadays don't want to hear they have metastatic cancer in the frontline and have to wait eight to twelve weeks to start treatment. So really the coordination of the trial and the clinician is super important here, and I I agree with pretty much everything on this slide. Patients are being identified quickly, but we also have different restraints in the frontline that are unique and set. This is when you're doing most of your testing on the tumor to identify biomarkers. And that process is becoming actually more complex and not less complex as we identify more and more biomarkers. I'm testing for more biomarkers and tumors now than I ever have, and we only expect that number to increase. You also have to remember something that we didn't really cover in this slide, which is a trick to how we do that is we need tissue samples. And in the era where biopsies tend to be all about the same size, we're running out of tissue in some patients to test for all biomarkers. And putting patients through additional surgical procedures or biopsies is not something that many patients wish to do and can actually be a major operational challenge for frontline clinical trials. I'm experiencing that in the real world right now with clinical trials I have open. So, you know, that coordination of understanding what trials exist compared to standards of care and knowing what you need to test for remains really important to minimize that downtime and delay to starting patients. So that's where the middle side, the prescreening matters more than ever. You know, knowing what you're doing, knowing where it's going for the patient. And then doing all the eligibility screening remains really important. So, you know, the front line's where it's at right now. And I think from here, you know, we'll move things into curative intent settings. That's kind of like the final frontier, the earlier stage disease, the the curative setting in combination with existing standards of care. But I think from the clinician standpoint, it's important to remember that you have a patient sitting in front of you who needs or wants to start treatment. Clinical trials can take time to screen, test, and prepare for, and being ready to do that remains, as an operational standpoint, one of our biggest challenges right now. Yep. That yeah. Absolutely. That's a great point. You know? When you know, with my experience working at the site level, when these first line treatments come up, specifically for a clinical trial, there's always that hesitancy. Right? As you mentioned, these patients probably aren't being treated currently. So, you know, this is a whole new world for them. They're being introduced to all this, you know, in a pretty stressful time in their lives, Yep. and being able to understand what the clinical trial is and what the benefit is compared to the standard of care, I think is huge in helping patients make informed decisions. And, you. know, from our site support view on it is making sure our our investigators and our site staff are, you know, educated as as to how to present the trial as a as a viable option to these patients. And like I said, what's a a pretty stressful time for them, definitely? Yeah. And if you think about the amount of information they're getting in this narrow window, right, I mean, you're telling someone they have cancer. That's already a bomb you're dropping in their lap. Then you're telling them the stage of their cancer, which in a lot of these trials is metastatic or stage four cancer. And then you're explaining to them what that means. And then you're explaining to them the standards of care. And then you're trying to also explain to them what a clinical trial is and how that might impact their care. It's a ton of information in a very short period of time. Yeah. Yep. Absolutely. And so kind of going along with that, I'll move along to the next slide here. When we're looking at a a clinical trial, especially a global ADC trial, loading for you guys, or is it just on my screen that it's ticking? Yep. I can see this. Okay. Perfect. So one of the most important points when we look at the complexity of a global ADC trial, it's not just the the scientific piece of it, but, it's execution at the site level. And starting with that is site readiness. So not every site is gonna be equally prepared to run a complex ADC study. You know, it's infusion capability comes into play, pharmacy support, side effect and safety managing expertise, the standard of care locally in that region. All that can vary significantly by geography, and within institutions as well. The site realistically on or, ideally on paper, looks like they will be able to enroll a bunch of patients no problem. But if they're not operationally ready, then that's gonna create issues down the line, and it's going to ultimately affect not only study performance, but enrollment as well. Country feasibility, so biomarker access, the local standard of care as I mentioned, vendor footprint in that region, import export logistics, customs. It's a lot of background details, but in reality, it often determines whether execution at the site is gonna be smooth or it's gonna be rather difficult. And then standardization in global programs, that can vary across the board. That's one of the biggest risks. So with ADC specific training, pharmacy workflows, dose modification guidelines, all of this needs to be built in and standardized within that site early, and pretty clearly as well, so there's no there's no mistakes. And under all of that, there needs to be some sort of central support model. So we can vary things country by country, region by region, but, ultimately, there needs to be a central model in there. So one that, coordinate safety communication, biomarker logistics, vendor oversight, troubleshooting in real time. All of that needs to be, centrally supported. And, you know, if sites aren't trying to solve everything by themselves, that makes things a lot easier for them. And I think the question with this becomes not just whether a site can open the study, but whether the the program and the study is set up to run consistently and, consistently across sites of varying regions and countries. Vince, I kinda wanna bring you in here with this. In your experience, you know, looking across a global ADC study, where do you often see, you know, operational friction at the site level or at the country level that if, you know, if there's early planning, we might be able to mitigate those types of issues. Yeah. That's that's a great question. Thank you, Nick. You know, there of course, there's no two sites that are built the same. There's no two study teams that are built the same. So understanding what each site needs, what each study team needs, and what the protocol, is directing us to is a very important step. We take that time, of course, in advance of of beginning the study to think through of, you know, all the challenges and the risks that we might be able to anticipate, understanding, of course, that we can't anticipate all of them, but trying to anticipate and proactively addressing those in advance. So, you know, oftentimes, we'll see logistical challenges as we look to import drug perhaps in different countries, or export samples. There could be regulatory challenges that we work through with, of course, the the the local teams to to overcome. There's training, challenges that we need to address because, again, each team in site and and country culturally may absorb the information differently. So those are all just different challenges that we take into consideration in advance and then operationalize that as we implement the study, globally. Great. Yep. Thank you. And that kinda moves us into our next slide here when we talk about, protocol design, and executing that at the site level. So, you know, we've talked a lot about how the how complex these studies can be. Sometimes on paper, they seem pretty clear, biomarker confirmation required for eligibility, other screening requirements, treatment timelines. All of that makes sense on paper, but operationally at the site, teams are managing multiple handoffs between departments, short treatment windows, delays in coordinating for tissue sampling or biopsy coordination. You know, what we've seen a lot since COVID is a lot of sites are working, with smaller staff, smaller resources. They have a lot of other studies they're running, and they have their standard of care patients as well. So they're dealing with all of this on top of, you know, trying to enroll patients to a clinical, you know, a complex clinical trial. So making sure that we can convert protocol requirements into practical workflows at the site. It's not it's not just helpful, but it's essential for the study to succeed. Sites need clarity on what happens when, who owns each step, where handoffs occur, and where there's going to be breakdown, that we might be able to step in and mitigate. And that's where operational tools become very critical for these studies. So workflow guides, training materials, visit planning support, All of this can help bridge protocol intent into day to day execution, and not just for the site, but for the patients as well. So patients who are participating, if things are running smoothly, and they have a clear understanding of what's required of them at each visit, that's gonna ultimately help retention in the long run. So I think the key here with this slide is that a study can be scientifically strong, but if that scientific complexity is not translated into something that the site can operationalize, it's gonna be a lot harder to do that consistently across the board. And then I had mentioned a little bit about cross department coordination. With these ADC trials, this is huge. You know, our sites rely very heavily on having clean and clear cross department coordination. These studies can touch a lot of groups. There's external referral teams. There's the main study team, different investigators, pharmacy, pathology, infusion, radiology, and all of them are where patients are gonna be move moving through the excuse me, moving smoothly through that care pathway. But the challenge is sometimes these groups don't interact on a consistent basis. They might not be one cohesive unit. They sometimes will work in parallel, sometimes in individual silos. But with a study like this, every missed handoff has the potential to create delay, or in inconsistency down the road. So in principle, the coordination really needs to move through that patient journey rather than sitting in parallel and running alongside it between, disconnected groups. What we've seen is when these groups are aligned, patients move faster, patients move smoother, execution is easier, and it's more consistent. So, and, again, Christian, to bring you into this from the site perspective and as an investigator, where do you typically see friction with with cross department or cross functional handoffs, specific. patients are coming in for ADC studies, whether that's, radiology, pathology, Right. safety, profile monitoring, things like that? I would say it's the second step on this, eligibility and biomarker review. So this is probably the biggest source of difficulty right now for reasons I've started to describe, which is there's a lot of eligibility requirements and often biomarker review requirements for clinical trials nowadays. And many giant health care systems, including ours, are kind of a matrix organization. Meaning, you know, I have purview over my department, but I'm also interacting with radiologists, pathologists, interventional radiologists. So you're you're you're navigating a whole health care system and, you know, educating people on how much biopsy do you need. Do I need you to take another pass? Did you preserve it in the right kind of liquid to make sure it's going to be eligible, for central testing? Has our pathology department gotten up to date on all the reflex biomarkers we want tested, so there's not a delay. These are very difficult challenges to navigate, and these are changing on an almost annual basis. So, you know, in the old days, you might have developed something once every few years, and everyone would get up to date on it in a reasonable period of time. But our our landscape is changing so rapidly and so quickly, it's hard to keep everyone up to date. So you are really navigating a massive beast and trying to rein it in. So I think that's where our biggest source of friction comes in in ABC clinical trials is really making sure the eligibility and biomarker review is taking place, again, in a reasonable time frame. Because while you're doing all of this testing and making sure it takes place, you have a patient sitting in front of you with cancer who wants to start treatment. So that's where our biggest challenge, I think, exists nowadays. Great. Thank you. And that leads us perfectly into our next slide, which is patient identification, pathways for these ADC studies. So you mentioned, you know, biomarker, and pathology review is huge with identifying these patients. You know, in these ADC studies, that patient pathway is usually established well before the study coordinator is brought into play for, trial consideration. So as you mentioned, it's with diagnosis, pathology review, biomarker, ordering and sampling, making sure that that's, you know, going to be okay, with what is required for the study. So if if the study team doesn't have visibility into these patients until we're far along in that process, there's a real risk that these potentially eligible patients are not gonna be seen in time. Especially, you know, we've talked a lot about these first line ADC studies. Treatment decisions are being made very quickly. If the study team is not aware of these patients or the study is not introduced to these patients, early on, that patient is more than likely going to be lost to the study. Those loss points can be pretty predictable. So if there's, issues with biomarker testing, or slow biomarker turnaround, inadequate tissue, that's available, limited visibility from the overall study team or the referral team, and or standard of care just being introduced, before that study is even considered. Upstream visit visibility matters in all of this very much. We wanna make sure that we're consistently looking across the board to identify these patients early on in that process. And, operationally, that means, you know, thinking about earlier biomarker testing, tumor board engagement for study awareness, referral pathways, you know, where are these patients coming from? Is it more internal or external referrals? Is there, any specific networking, that the site can tap into to look at these patients before the referrals come through? And with these studies that, you know, are moving very quickly and these patients are moving very quickly in parallel, these patients often get lost before they ever come into screening, before they ever even sign consent. They disappear much earlier in the pathway. And I think when we look at this, Vince, you know, from a strategic planning standpoint, how early do sponsors really need to be thinking about patient identification when they're building out these studies, especially with biomarker driven ADC studies? You know, when a sponsor is designing the study and they want enrollment, to be realistic, where do we think is the best way that we can use our knowledge of these patients at these sites and how the sites operate, to, you know, plan that in their in their protocol development. Yeah. I I I don't think you can think about this too early. I don't think there's ever a too early here. If you think, oh, this is we're not at that stage yet. You're already too late. I think to to doctor Scolante's point earlier and really emphasizing keeping in mind what the patient is experiencing, not only, of course, being learning that they about their disease and the potentials options of, ahead of them, then thinking about, you know, the the clinical trial, the questions that has the whatever else they may have going on in their life. It's it's a lot to weigh. And so thinking about and considering those patients from day zero, as you're designing a study is I I don't think we can value that enough. I I wanna dig into this just a little bit because I know we also received a question via our chat, regarding this exact point about when do we lose, patients, before they have the option to even consider the trial or enter the trial. And and and to you, doctor Scolante, I would like to ask, Yep. you know, build on that. Of course, not only that question, but what support do you ask of of of your partner CROs, of your partner sponsors that could help you navigate these challenges as well? Right. So I think we do discuss that. You know, when we're looking at, in opening a clinical trial, we are gonna be looking at the support, you know, in terms of how the testing's gonna be done, biomarker turnaround. That's a big question I ask is, you know, what kind of central testing are you required? What kind of tissue are you requiring volume of tissue? And what's your turnaround? Because, you know, the biomarker testing is a fixed amount of time in many cases. We cannot make it go faster. So I need to be able to talk to patients about that time and why that time may be worth considering doing when you're considering it in the context of a clinical trial. And I I agree with you. I don't I don't think there's ever too early to be talking about it. My attitude is, you know, there's a question when are patients most often lost before trials are being considered? I think that depends on who you mean by considering it. If you're talking about me, when I'm walking into that patient's room for the initial consultation, I've probably already considered them for trial if I haven't done the legwork to see if I'm screening them and and getting the ball rolling in case they want to enroll. So I don't think I think if you decide it in the patient's visit, you are too late, and you you you need to be doing it well beforehand. And and I think these are the key five points where the patients are coming lost, no reflux testing, delayed biomarker turning around, inadequate tissue for testing. Those are the top three for sure in terms of the of the of the problems we run into. And I think you can't consider these things too early. This is where we're moving with clinical trials. So I I just wanna, you know, kinda give you guys also a real world example of this since this is a PSI talk of of something we I recently did. We know we were reviewing a trial. I'll talk in kinda general terms, but let me give you kind of, like, these examples. I mentioned the kind of the landmark for bladder cancer with, antibody drug conjugate called enfortumab vedotin. So when we're thinking about trial and drug development, I think enfortumab vedotin is kind of really a gold standard. The reason is, it targets a pathway called Nekton four on bladder cancer, which is expressed in probably about ninety five percent of bladder cancer tumors. We don't even test for that. So there actually is no biomarker. This is like an ideal ADC. I don't have to do the testing. I don't have to do any lag time or specialized pathology turnaround. We just kind of enroll. We know that a small percentage of patients won't respond, but because such a high percentage of patients do, there's no, regulatory requirement or really clinical requirement to do any reflux testing. But recently, we looked at another drug, you know, targeting a different pathway, HER2, atrastuzumab razatechin, which is an antibody drug conjugate in development, approved in China, but in development in The United States for a number of tumors, including lung and colon. And there was a trial for colon cancer looking at this in the frontline. Now this is a great example of why these things are so important. You know, HER2 pathway expression is probably only present in ten percent of colon cancer patients. So you need to know that you need a biomarker for this because you're not gonna treat everyone when only ten percent of patients are expressing that biomarker. So you need to do the testing. But you also need to know that this isn't something that's always routinely done in the front line. So you have to be prepared to do that and add that testing on when you're considering patients for clinical trials. So then you might say, well, why do we even wanna do this if it's in just ten percent of patients? Well, in most cancer centers, colon cancer is still probably our top three disease that we treat. So even though the percentage is small, the absolute number of patients that could benefit from this remains quite large and probably more than bladder cancer patients who are all expressors. So, you know, understanding those first three pathways, the reflex testing, the delayed biomarker turnaround, and the adequate tissue for testing really is where we need to be and where we need to coordinate with our CROs in terms of opening the studies. Because once we do that, we need to be prepared on the clinical side to be able to turn that around. Great. Yeah. Thank you both for that input. And then moving on to this next slide here. So this is bringing everything together. When we're looking at, you know, operationalizing and designing a new ADC study, we wanna look at this as a a putting in place a a functional operational checklist to, bring the study to life. So when we look at in the feasibility phase, the focus is on bringing the right infrastructure in place. And that includes understanding biomarker testing by country, assessing pharmacy and IP logistics, PK and PD sampling capability, reviewing the competitive landscape by region, and making sure that the right regulatory conversations are happening early off early enough. Then moving into, study start up and site initiation, that focus shifts to site readiness. So have sites completed, you know, ADC specific safety training? Are those modification pathways built into the study tools? Imaging schedules are aligned with radiology, or is biomarker retesting workflow, clearly established at the site and, understanding that the site has practiced, you know, the the overall flow of how the study will be done at the site, as we're moving patients through screening all the way through study follow-up. And then once the study is live, conducts or, conducting the study is, operationally can be challenging when that first patient is coming through. So have, have safety review signals been put into place? Are we monitoring, the the deviations on the protocol? Is enrollment being tracked against the projections? These are all things that we need to think about while we're designing these studies. And what I think is is reinforcing that is that successful ADC execution is not just one decision point. So it's a series of decisions that are being made throughout the process of of getting the study activated, of enrolling patients, and making sure that we're checking those boxes early enough and understanding what that flow is gonna be at the site. And, Vince, I think to to bring you into this a little bit to, kinda close this discussion here, when we're looking at a checklist, for operationalizing a study, are there one or two elements that you think are, most often underlooked, and what has the biggest impact downstream? Yeah. You know, I think I I might sound like I'm beating the same drum here, but I I I think really losing that patient's perspective and the patient's experience often trips us up and traps us as we're developing protocols. So I think, you know, again, keeping in mind the patient journey and as as they progress through, symptom display to to trial entry to on study, we really need to consider all aspects of that patient and that patient's experience, and make sure that we're addressing their needs, through our through our protocol design. I think that really does address a number of these boxes. I think also, of course, we need to, evaluate and consider our our site teams and our site partners, not only, of course, our investigators, but the investigator supporting team as well because, again, these the the sites have have many, many team members as doctor Scolante was alluding to earlier and understanding their needs and what will be important to them as they are operationalist the operationalizing the study on on our behalf, on behalf of our sponsors is a is is a key criteria as well that we need to make sure that we are viewing this from all lenses, if possible in designing. Thank you. And then, we did have a question. So what are the most challenging aspects of managing a dosing preparation and administration from an ops perspective at this night? And I'll I'll start with this and then doctor Suquante, if you wanted to chime in. Mhmm. But, you know, I think when we look at these challenges, it's usually centered around coordination and timing, and consistency as well. So first, when we look at ADC dosing, it's not simple. There can be weight based dosing, protocol specific adjustments, toxicity driven dose reductions, and so sensing to have clear guidance on who's confirming the dose, how the dose is being calculated, what does it need to be recalculated with weight loss or weight gain, and how are those changes being communicated between the investigator, the study coordinator, the pharmacy, the infusion team? And if there's not a tight handoff, errors or delays might happen, that are going to be affecting patient dosing. Yeah. And I think from the clinical side, I agree with everything you just said. You know, I will actually say my experience with ABCs has been this generally is improved compared to previous standards of care in terms of infusional time. Old school chemo is usually quite a lot more time. These tend to be shorter infusional time, but coordinating that is is usually easier. I will say this changes a little bit when you talk about bispecific antibodies because then we tend to talk about hospitalization. So considering that is important, especially if one of the off target effects is something called ICANS or immune cell, associated neurotoxicity syndrome or cytokine release syndrome. Those are things we have to monitor for much more closely and much more intensely than other traditional therapies. But yeah. And I just I wanted to click back on what you said a a little bit ago in terms of, you know, remembering in this trial design, and I will say I do do this when I review trials with you guys is thinking about how this is gonna look for the patient. One, because I have to sell it to the patient and make sure it's something they're gonna wanna do. But I I kinda say in every new patient visit, you know, it's easy for me to tell you what I think you should do, but at the end of the day, I don't have to go through it. So remembering, like, kinda like that walk in your shoes, you know, mantra that we're taught when a kid walking in someone else's shoes. Like, at the end of the day, this is all going to the patient. They're the endpoint for this. So I think that's one of the key things when when developing these and considering these across sites. Yeah. Absolutely. I think so often when these protocols are being developed, it can get lost, right, that at the end of this, there's a patient, and they have to go through the the treatment. They have to go through the visits. If it's overcomplicated or if there's a lot of requirements on their end, you know, it it might not be the easiest sell from from your point of view as an investigator. Right? Like, if if there's a lot of safety oversight, they need to be coming in very you know, once a week, twice a week. If there's inpatient administration, all these things come into consideration when a patient is choosing, their next treatment. So I think that's, that's a really good point that you made that, you know, these these studies seem to be set up for success from the patient point of view. Great. Thanks, Nick, and thanks, doctor Squante. So just a few key wrap wrap up items and key takeaways before we get to, any questions that may be remaining within the chat box. But four key takeaways from today's session. So first, the science is moving faster, really faster than ever. ADCs and multispecific antibodies are reshaping our oncology development, and and they really bring new opportunities alongside, though, greater design, safety, and operational complexity. So we just have to remember this field is not slowing down. If anything, as I said, it's it's moving faster. So second, the regulatory expectations have shifted and probably will continue to shift. Dose optimization, safety characterization, and scientifically justified development plans are now expected even earlier in in design, considerations. That requires more deliberate, trial design from the very beginning and it rewards sponsors who engage regulatory agencies proactively. Third, enrollment, as we were just discussing, is is one upstream. Success in first line and biomarker driven, studies depends on identifying patients earlier and embedding the trial into real treatment pathways. If we're not supporting enrollment before the standard of care decision is made, we're ready behind. And fourth and finally, execution determines feasibility. Even strong protocols can fail operationally. Sites must be equipped to manage biomarker workflows, treatment timelines, safety monitoring, and cross functional coordination in practice, not just on paper. So the next generation of antibody based therapies will be won by the ability to translate scientific innovation into executable site ready clinical programs. Translate scientific innovation into executable site ready clinical programs. That's work we do here at PSI every day, and it's a perspective we hope we brought you today as well. So, again, I just wanna thank, doctor Scolante. I wanna thank Nick for for joining this, this discussion. I wanna thank everyone else that that attended as well, and and thank you for your attention, as well as participation via via chat. So let's go ahead and turn to any remaining questions. We have one. It it's actually a comment, but it it's a comment that communication is crucial between all the site teams, and it really seems that over communication from the very beginning is critical. So, again, maybe doctor doctor Scolante, if you'd like to to chime in here from your perspective as an investigator. But I I I think that this is a very, key comment, and and, thank you for that that comment as well. Yeah. I I couldn't agree more. I and, again, it's not a question, so there's there's nothing for me to answer, but I completely agree with that statement. I was reading it when it popped up, and I and I couldn't agree more. Over communication is fine. Over communication between the CRO and the site is essential. And then once it's at our site, over communication between me and the teams is essential. We wanna really take the burden off the shoulder of the patients and not have to, like, inundate them with more than they need. And then there's another question coming in. How do you, as a provider, site prioritize certain ADCs if they're competing in the same space? And then investigational versus SSC. Okay. So this is a good question. Let's let's take that in two parts. So you don't want competing trials. That's always never a good situation. Right now, the good news is, I don't have that challenge. The ADCs are rapidly developing, but because they're in different spaces and different diseases, we're not really currently running into too much competition in the same space. If we were, it really would come back into looking at a lot of the preclinical and early phase data to kind of make an assessment of what looks the best, although that's not perfect. We all know that early phase data doesn't always translate the same in phase three trials. So but, you know, really, sometimes we do when we get offers for competing trials, have to look at the preclinical data and safety data and kind of make an assessment of what we think will be the best option for our patients. The then to answer investigational versus standard of care, that's kind of what I have to do with every trial. Why do we want to consider a trial over the standard of care? Well, that's because every standard of care was once a clinical trial, and that's really what I have to kind of explain to patients. That the standard of care that I'm offering you used to not be the standard of care, and then a clinical trial made it the standard of care. So the concept really is, you know, investigational agents are always trying to improve upon the standard of care that we currently have to, you know, make those landmark jumps in overall survival from sixteen to thirty two months to benefit patients. And it is important as part of informed consent to tell patients you can't guarantee that. That's always a question I get. Well, can you guarantee this is gonna be better? No. Because if I could, it would be the standard of care, and it would be the approved, you know, regimen that we're using. But I think every patient that has the option should be offered an investigational agent when they have the option versus a standard of care, and then they have to make that informed decision for themselves. That is one of the most difficult parts of my job is trying to explain to patients why clinical trials are so important. We do live in a big age of medical misinformation and, you know, increasing distrust of the medical community. So, you know, I have to often explain to patients that, no. You're not a guinea pig. We don't view you that way. You know, is this something I would do for my family member? That is something I often do explain to patients. You know? I'm not selling you anything I wouldn't do for myself or for my own family. That can be a compelling argument, especially if it's true, which it usually is. But, yeah, you know, my goal and my my dream is to have a a clinical trial in every space for patients. That's a pipe dream. We don't have that right now. But, you know, unless we do, we're never gonna kind of move that needle forward. Great. Thank you. I know we're nearing the end of time, so I I think we'll, unfortunately, have to leave it here. I I greatly enjoyed the the discussion, and I hope everyone did as well. So I just wanna again thank, thank you, doctor Escalante. Thank you, Nick, and thanks everyone for for attending. Take care.