The Unique Challenges of Phase 1 Oncology Trials - Dan Otap and Jenn Weinberg

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HANNAH LIPPITT: Hello and welcome to the Totally Clinical podcast brought to you by Teckro. Totally Clinical is a deep dive into the freshest trends, big-time challenges, and most excellent triumphs of clinical trials. I'm Hannah, your host. Join me as I chat with industry experts, trailblazers, thought leaders and, most importantly, the people benefiting from clinical research. So, tune in, settle back and don't touch that dial. It's time to get Totally Clinical.

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This episode, I am joined by Dan Otap, principal alliance and partnerships lead, site alliances at Genentech, along with Jenn Weinberg. During the podcast, we discuss the challenges of phase 1 oncology trials for research sites, why they're so complex, and what solutions could be implemented to ease

the pressure on sites.

HANNAH LIPPITT: Welcome to the podcast Dan and Jenn, it's great to have you both here. Let's start with your background and how you came to be working in oncology. Starting with you, Dan.

DAN OTAP: Thank you both for having me on the podcast. And I do want to mention that and I'm a huge fan of your entire group. It’s been a pleasure working with you guys over the years and getting to know you. And you bring

a lot of joy and a lot of fun to what you do. And I think it's important, and I'm just very grateful for that. So, who am I and how did I get into research? For me, kind of like many other folks in this industry I would imagine, I started in clinical trials by happenstance. So, my first position was a research study assistant at Sloan-Kettering Cancer Center in New York. I basically was an entry level site coordinator position in neuro-oncology. I worked in that role and ultimately moved up in management to a regulatory lead position. And from there, I was recruited to Columbia University, which is also in New York by a dear mentor of mine, Andrew Lassman. So, Dr Lassman went over to Columbia to rebuild their neuro-oncology clinical trial and clinical practice division. So, I was the research manager in that group and established and worked across groups that included neuro-onc, neurosurgery, rad-onc and neuropathology and was involved in their brain tumor center. And, after a short period of time there at Columbia, I was also asked to take on a new role, a new division to develop a compliance division within their cancer center. So, Herbert Irving Comprehensive Cancer Center, based in Columbia University. So, I was there, had a dual role for a couple of years. And ultimately, the last role that I had at Columbia was the associate director of regulatory affairs, where I led teams involved in IND submissions, IITs, monitoring, auditing and multi-center clinical trial management. The last site role that I had was at City of Hope, which is a cancer center based in Southern California, where I served as the executive director of community practice research on operations. And fast forward to 2020, I took my current position at Genentech in their gRED clinical operations division, which is research and early development. And that's where I started working on the sponsor side of things, focusing

on site alliances and relationship management.

JENN WEINBERG: I actually just like Dan came into research by accident. I started at a Phase 1 healthy volunteers' clinic, and that couldn't be much different than going into ending up in early-phase oncology trials. But then I went from working in that clinic and to monitoring for a CRO. And then I went on to work for pharma. And when I started there, I was hired for neurology trials, which is what I knew and what my background was in. And then I had a colleague actually go out on maternity leave, and I was thrown into the deep end of oncology, early-phase trials. And that was back in 2007. So now, almost 16 years ago, here I am! And when I started obviously being thrown in, it was definitely not my choice. And I was always looking at my watch and asking when I was going to be able to get out of oncology. And especially after coming from that Phase 1 environment where everything is very organized, very, you know, it's just a very easy setting. It's a lot of work and a lot of volume. But, to go from that healthy volunteer setting into an early-phase oncology setting where the patients are just very sick and had multiple therapies beforehand, just really, again, couldn't be much different and it made the learning curve for me that much more painful. But I had some really great mentors along the way. And honestly, some of my best mentors were sites that we were working with and study coordinators and PIs who took the time to help me learn. Probably some of that was because I was admittedly not aware of everything I felt like I needed to be going on in the oncology space. But I really did learn a ton from them, which I'm so thankful for. But then, much later, after several re-orgs and restructuring within the pharma companies, I was actually given a choice. And I was faced with the fact that I actually liked oncology and I couldn't believe it, but I chose to stay in it. And it was really a good self-check, I guess. But I was definitely driven by the need to continue to work on these oncology trials. So, I guess that was a big factor in why I chose to stay in it. And since then, again, I haven't seen anything else. But also, I've worked as a program lead, a clinical operations manager, CRA manager, a local study manager, and most recently as a global study manager.

And I think the one thing that I've realized in moving through these roles is that no matter what our best intentions are, we just tend to make everything a little bit more complicated than we maybe need to. And I just will say that this is part of what I've learned in working with the sites every step of the way.

HANNAH LIPPITT: I really love Jenn that you were thrown into this kind of really challenging situation. And then you came to love it. You came to choose it. Now, if we think about oncology trials, they can be, as you pointed out, very complex and really challenging for site staff, especially during Phase 1. Could you elaborate more on why this is, Dan?

DAN OTAP: I mean, when you think about clinical trials in general, when you think about oncology particularly, you think about complexity automatically, right, the patient cases are more complex. Jenn, I think you mentioned earlier about heavily pre-treated populations, co-morbidities, etc. so there's that level of complexity. But then when you think of Phase 1 oncology in particular, you think of even more complexity, because there's first and foremost, safety oversight concerns, right? So, medications that are truly early-in-human or first-in-human and truly have unknown pharmacokinetic pharmacodynamic as well as sheer toxicological effects on the human body. It's - there's a level of safety and concern and risk there, right, so that to me is first and foremost, what separates and creates a very distinct space when you're talking about early-phase oncology. Then you throw in the fact that these patients that become brave participants on these trials are immunocompromised, severely sick, heavily pre-treated - you have a scenario that just is fraught with potential complications and unclear increased risks. So, I mean, and increased scrutiny, right. And rightly so. An increased responsibility on behalf of the sponsors as well as the sites and the investigators as well.

JENN WEINBERG:

Things can change by the day. And you just have to really stay on top of everything with regards to safety. And again, because of the population you're dealing with are so sick and they need the decisions made quickly. You don't have a lot of time to waste really, but you have to be sure quality and safety is, of course, most important. And it's just I think really, it's so important to have good communications within, I mean, any trial, of course. But just because of the speed in which things happen in these early-phase trials, I think it's just really important to have a plan in place in order to share those updates. You know, anything from cohorts being, you know, opened to cohorts being closed and where enrollment stands and of course any safety or toxicity issues too, and at a site, you really need to feel confident that you have the most current information at hand and that you're aware of, you know, what's going on the sponsor side and what's pending and what's coming your way so that you can appropriately, you know, assess and treat your patients. And then from the sponsor side, it's just as important to feel confident that your sites are so busy, and they have so much information coming to them, not only for your study, which I think is always important to remember, but for many studies. And so, it's really important for them to know that they have the latest information, and they know where to go find it and who to reach if they do have questions and when the answers are needed really fast to make those decisions at the point of care.

HANNAH LIPPITT:

Thank you for sharing those insights. It's really interesting. I've spoken to a couple of people on this very podcast about the pressure on site staff, and one guest, Chelsea, was actually discussing how keeping on top of all the amendments and remembering dozens of portal passwords can be so tricky because there are many different studies to manage. Do you have any thoughts on how oncology trials can be managed more effectively to reduce the pressure?

JENN WEINBERG: I think managing passwords is quite a task and something we've heard very widely from many, if not all of the sites. And I'm aware that I'm obviously a big fan of Teckro. But I do think we do a really good job of keeping this simple at Teckro meaning it's easy to log in and stay logged in and know where to find the most important documents to be successful in your study as well as, you know, keeping training simple. I think that much of what we're doing

at Teckro is going to help streamline the communications in the early- phase as well. We've had such good success in working with study teams to work towards doing a better job of targeted messaging, particularly as it applies to master protocols with multiple cohorts and lots of different populations or arms. And I think that as long as we continue to listen to what sponsors need and what sites need, we can also continue to play a part in the change for the better. And in working with some of the key institutions involved in early research, we've been able to hear what would make their lives easier and some of that communication piece and knowing who to contact and having study updates readily available is part of that change.

DAN OTAP: To dovetail actually what Jen mentioned, I think there is a really good opportunity to look at Teckro’s capabilities in regard to communication between sponsors, CROs and sites that I think there's a lot of leverage potential there. I know that you guys have messaging, you know, opportunities and it really is valuable, especially in the early- phase space to be able to, even from your phone, connect to the medical monitor or whoever at a timely and in a timely fashion.

DAN OTAP: Hannah to your question about thinking about solutions, SCRS convened a working group with thought leaders across industry, across vendors, across CROs as well as sites. And they've written up a white paper that kind of is a best practices and advice proposals as far as how to build out units in institutions. So first and foremost, as far as dilutions, I think that's going to be a resource for sites that are interested - investigators, research managers that may not be as familiar with the Phase 1 nuances. The other thing that you know, again, I'm not trying to advertise

for SCRS, but I think that their summits are also a place where a lot of people can convene and talk solutions. Not just talk. I mean, I think all of us sometimes get a little bit tired of pontification and just simply talking for the sake of talking - or even worse, complaining for the sake of complaining. These spaces like the oncology summit for SCRS that's going to be in Austin in March, April of this year is really a space where sites and industry sponsors and vendors and tech provider solutions, etc, can really convene and really discuss these kinds of topics on ok, there's some difficulty here. What can we do to minimize? I don't think we're ever going to get away from working in a very complex industry. I think that's part of the time...part of the reason why I love of the industry that we're in is it's exciting, it's complicated, it's hard.

HANNAH

LIPPITT: It's pretty evident that communication, conversations between the three - sites sponsors and CROs is invaluable. Do you think there is anything else that sponsors and CROs could do to help to ease the burden on sites during Phase 1 oncology trials?

DAN OTAP: I was having a conversation earlier today about the idea of site augmentation and that being something that sponsors can do for sites. We all know that resourcing is an issue, and we want to try to back fill as much as possible. But I really actually kind of focused on something different. From the sponsor side, when we're talking about early phase oncology, I think it's all about Occam's Razor. And I think I think it's honestly about taking an approach, leveraging a principle of parsimony, right? Like keeping the main thing in the main thing and not extending our reach. And inadvertently, unbeknownst to us as the sponsors and we have our clinical scientists, they are well-intentioned and brilliant, right, that's why I work where I work. But without knowing it, inadvertently increasing site burden for things that are quote unquote “nice-to-have data” - a like nice-to-have data points and assessments and completions - like do we need

that 12-hour PK? Do we really need that 18-hour PK, etc.? So, we were so immersed in the science work - I mean, our company, ultimately, that's one of the things we really strive for is being driven by the science, like pretty much every other sponsor, right but I think that we really need to focus, and I think there's a zeitgeist right now that actually is going in this direction. And honestly, when you're talking about patient participant centricity and you're talking about site centricity, I honestly, truly feel as if we're at an inflection point in our industry where sponsors are taking heed on what's being said to where - and I know that some would actually retort saying, “well, damn, look at the literature, actually our complication, for the complexity of oncology trials, even from an NCI- sponsored perspective, from things like SWOG and others have actually been studied and we see the complexity and number of assessments do nothing but increase” - right? But I honestly feel like we're at a tipping point here where we have sponsors that are starting to slow down and listen and being like, “OK, what do we need to have?”

Being mindful of the participant burden and the site impact burden amidst also being scientifically and data-driven in the way that we design our trials and schedule assessments, etc., I think is extremely important. And when it comes to us sponsors, you know, responsibility is in this overall discussion of clinical trial resourcing and burdens and doing more with less, etc. I think that's where we have a responsibility to really take a hard look at what we're doing and be very purposeful and question everything.

JENN WEINBERG: It actually just reminded me one of those great mentors that I worked with at a site was a study coordinator. And I remember as a CRA, again, coming from early Phase 1 healthy volunteer trials where they're all in a controlled environment. I remember asking why they kept missing a blood draw. And I mean, I went through all my checks as a CRA, like, oh, I have to retrain you, you're missing this. This is the multiple times we've skipped this. And honestly, I still remember her setting me down exactly where we were. And she said, “do you understand what it means when they come off of this trial and then having to

tell them that they have to go to a different floor and wait to have a blood draw done?” And it really put things into perspective. And it really made me think in the day-to-day, the questions that I was asking, you know, and it helped me bring back to the study team to say, “hey, they're missing this because it's not logical to ask the patients to go and do this at the site, you know.” Again, I can't agree with you more about the nice-to-haves versus the need-to-haves. And I think this is where it's really important for sponsors to continue to engage with the sites directly. It's a real opportunity to get it right and to I think a lot of times sites share feedback with whoever is in front of them at the time, you know, and this information or feedback, while everyone might have the best intentions, sometimes it gets lost in the noise, right? And just the day to day of what everybody's job is. And I just think that it's a great opportunity for sponsors to do better by the sites and by the patients by engaging again directly with them and really listening to what's happening on, you know, on the front line.

DAN OTAP: Yeah, I mean, I, I want to actually say that this is the brilliance of these kind of types of podcasts and these kind of discussions. Literally when you were talking about what you were just saying and talking about what does this do and what this means for this patient who's also a participant on these trials? It's like the hair on my arm stood up because I'm like, that's exactly like that's being human. It's almost, you know, it's almost like being human-centric, right? Not like because we forget, or at least I forget since day one I've been involved in oncology research is as far as being in clinical trials and being exposed to this. I've been in I've been involved with medications and drug development where we don't know if it's going to work. Everything leads to that. This thing is going to work in this indication it's going to help either slow tumors, shrink tumors, stop tumor growth, you know, liquid solid tumors, etc. But I still have to recenter myself and come back to this is a clinical trial. It is we don't know the answer to this question. And those patients may benefit, or they may not benefit. And in fact, a lot of the participants may never benefit, but they'll benefit those that come after them. And I know that we say this all the time and we use phrases like patient centricity, etc., but that what you just said kind of hit me like a ton of bricks again. And that's a sobering aspect of saying, “do you know what this means?” Like, I'm like, “oh, well, we need x, y and z and post-progression we want this and this and scientifically it's beautiful and makes sense” but at the end of the day, it's coupled with the fact that somebody with a potentially, if not truly debilitating and life-threatening illness was told, “hey, we tried this. It didn't work. Your cancer is coming back or it's resurging. We got to look at the next thing. And, oh, by the way, for the trial that you were just on, that ultimately failed. We're going to get x, y and z extra.” It's a hard I mean, that's we work in such a brilliant space. And I think it's just Herculean what these participants do.

HANNAH LIPPITT: It's very powerful what you're saying. And I think for many people listening, it will be interesting for them to know what drives people who work in oncology. And I think also it would be interesting to see if sponsors and CROs kind of listen to some of the recommendations made by both of you, discussed by both of you. So, it will be very interesting to see what happens in the future. And if we think about the future, how optimistic are you, both of you, in terms of change? Do you see the situation changing quickly?

JENN WEINBERG: I think that all of us involved in research just need to agree to do our very best to work towards doing things smarter and faster. But again, keeping in mind what we're asking of the patients and in order to do that, you know, the very best we can by those patients who are giving so much of themselves by participating in this important phase of research, but also, you know, making early phase trials more accessible to patients. I think Dan sort of touched on this and that maybe we can be a little bit more flexible around, does a patient have to come into the clinic? You know, a lot of these Phase 1 clinics are the big institutions where it's hard to get patients there and it takes a lot out of them. And is there a better way we can do this, you know, remotely or, you know, in a hybrid approach?

DAN OTAP: For me at least, we're still learning to live in a new normal and work and conduct clinical research in that new normal. So, I am optimistic. So, with that in mind, we have to - Jenn, you had mentioned this – we have to become, you know, the quintessential become faster, leaner, stronger in how we execute things, not only from a business perspective, but from company bottom lines. For those who need the answers to these questions that we're looking at and looking for now, which are basically the patients and those brave - or just those who become involved in our studies, I mean, let's face it and we're talking about early phase oncology here. So, let's be let's be very truthful. We do not know if these new molecules or modalities will work in these extremely devastating and life-threatening cancers. We don't. Again, everything in the pre-clinical space points to it, right? but I remember a mentor of mine saying we brilliantly cure cancer in mice for years. But when it goes into that human space in human subject protection and human subjects research, a lot of stuff changes. But, I mean, I see oncology trial management reshaping the ways that we can conduct feasibility for sites, how we partner with centers of excellence and who we conduct the dose escalation portions of these early phase investigations with as well as more of the community practice-based sites and investigators who can partner with us on the dose expansion phases so that in the event we find a molecule that does have effective targeting against a specific cancer, that we can get that medicine to the actual patients faster upon approval, period, right we have an enormously long way to go. We are in the most fascinating and rewarding industry in the world. Again, I'm biased, and I love being part of this process in whatever small way I can, but I'm OK with being a kind of a small fish in a massive pond and ocean. In this discussion on moving clinical trials and patient centricity, etc forward. Because just being a part of this and hopefully being a part of changing something for the better, I think I'll always be a hopeful cynic when it comes to this stuff. I am optimistic. I am I have to remind myself that. But I am.

HANNAH LIPPITT: A hopeful cynic! I love that. And it's great to end on such a positive note. Thank you so much for being here and sharing your thoughts about early phase oncology trials.

HANNAH LIPPITT: And that's your dose of Totally Clinical. You can download our podcast on Apple, Spotify and Google. Please subscribe and leave a rating and review so more people can find the show. See you on your next visit and remember to bring your friends. Thanks for listening! Goodbye!

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