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Phillip Koo: Welcome to UroToday and our special feature on practical aspects of starting a theranostics clinic. And we are very fortunate to have with us today, Dr. Kendra Harris, who is Chair of Radiation/Oncology at Tulane, and also Charlotte Manogue, who is the GU Program Manager at the Tulane Cancer Center. So thank you, guys, for joining us today.

And one of the biggest goals that we have with this program is to really demystify what seems like an insurmountable task with regards to creating a theranostics program locally. So, first off, I kind of wanted to open it up by talking about the regulatory hurdles, and that in and of itself at work creates a lot of fear in people, but wanted to ask you guys what steps are needed to first overcome those issues.

Charlotte Manogue: So the first thing I think that everyone kind of needs to be aware of is that this needs to be on your actual radioactive materials license for your hospital. For us, it actually has to be on there twofold because Tulane, as a university, has a radioactive materials license and so does the hospital. And so as for samples, if you are going to take blood samples from place to place, for us, they need to transfer and all of that good stuff.

The application is not inherently difficult and actually, our RSO handled a lot of it, but you make an application to the state with how much you are going to keep on-site at a time and then the kind of practical measures of what it is going to be bound to, so you don't just have lutetium on your license. You have lutetium-PSMA-617 as that piece. So if I wanted to attach it to a different antibody or something else, I would have to go back and kind of add that on as well. Some places have broad licenses, so you don't have to do those specific pieces. For us, we had to do it piece by piece.

The second is getting through the radiation safety committee at our hospital which, for us, was kind of explaining that these targeted radiopharmaceuticals are different than getting a CT scan or things that are going to hit kind of your whole organ system differently or [crosstalk 00:02:43].

Kendra Harris: Even like radium.  

Charlotte Manogue: Right. So kind of getting that piece and that clearance through that safety committee was another one.

And then as these are not FDA-approved right now, for us, it was going to the IRB which was a standard IRB application with a consent form development and a protocol and HIPAA releases and any materials that we would be giving to the patients. So we give discharge instructions, all of those have to go through the IRB. And mostly what they are looking for is that this is at a reading level and a comprehension level that people can understand what we are doing and why we are doing it and what the alternatives and their options are as well.

And then I think just teaching the patients that we are accessible and that you can talk to us and that no question is really stupid because it's a new kind of thing that they have never experienced before. It's very different from having a pill or even going to get chemotherapy which they've kind of heard about in some movie or from friends or something. This is a different kind of can of worms for them.

Phillip Koo: Great.

So that pathway, I guess, oftentimes you had to follow a lot of rules for the research and clinical trials, and then you guys sort of shifted into this next phase of expanded access which, to my knowledge, Tulane is the only site in the US that is currently offering this under expanded access. Can you talk a little bit about that transition and what it took to be able to offer that in that setting?

Kendra Harris: I mean, I think the first place to start is that we are offering it because patients want it, and patients need it.

I think you should talk about the front end.

Charlotte Manogue: So Novartis has set up a really user-friendly portal in which any physician or their representative in which case for us, it's me, makes an account. You register the physician once. You upload their CV and their medical license and information about where we would ship the drugs to, accessibility like phone numbers and fax numbers, all of that kind of stuff. And once you kind of have that account in their portal, it's a very simple four-step kind of application to Novartis to get access to the drugs.

So one piece is kind of informing the patient, what drug are you asking for? How many doses? Is this COVID related, unfortunately, is one of the questions that are on there? Why are we giving it to them? What is the disease? And then basically, the justification or additional information, they've progressed on multiple lines of therapy, they still have good blood counts and performance status, but that they're not qualified for clinical trials or it is not appropriate for them at this time.

And then once that application goes into Novartis, they have been really excellent at turning things around in, I'd say, within a week. As we kind of put in more, they've gotten a little slower, but generally, we've heard from them in about three days or so.

Once that's approved, they kind of approve you for one of two pathways. One is a single patient IND and one is the Managed Access Program. For the single patient IND, you need to put in an FDA Form 3926 and submit it back to them. They grant you a letter of authorization to reference their drug master file with the FDA, and then I make an application to the ONC Project Facilitate at the FDA in order to get access to a single patient IND. They have been excellent in a 24-hour turnaround, hearing from the FDA that we can have clearance to kind of get this patient enrolled in and add an active treatment.

After you get access from the FDA and they grant you permission, we go to the IRB and say, "We have a single patient IND. Here's the number." And then it's a straight IRB process, just like it would be normal for any kind of expanded access use.

For the MAP, it's a little bit different, the Managed Access Program, in that we make the application to the IRB once. So all of the same application in terms of what I just said with the Novartis piece, eliminate the FDA piece entirely. You don't have to do that at all. Instead of granting you an LOA, they grant you access to their suggested protocol, their consent form. All of the reporting requirements go back to Novartis's team in terms of their FDA clearance. And then basically, you go to the IRB with everything that they give you and go through your IRB process, and then it's a two-week lead time in terms of getting the drug.[crosstalk] 

Kendra Harris: Which is to say, I think it's important that none of the documents for the Managed Access Program were generated by me or by her. So Novartis has done all that work already. And so getting signed up to work on getting the program opened at your site, you would take these completed documents, review them if there are some changes that are needed that are site-specific, and submit them to the IRB. You do that one time. And then each man that you see in consideration of this therapy has to meet the original...

Charlotte Manogue: Criteria.

Kendra Harris: ... criteria, patient selection criteria of the VISION trial, and this sort of handy, easy-to-use website with Novartis are how you signal that you are sending them a candidate for consideration, for inclusion in the cohort.

Charlotte Manogue: I mean, in that, [inaudible 00:08:27] does everything from the initial application to, "Yes, I've gotten IRB approval. I want to initiate a drug, an initial shipment for a drug, and then also for subsequent doses, how to initiate a resupply," so it's all in one piece. And just like if they were on a trial, they have an ID number that is linked to that specific patient, so you continue to use that as a reference with the Novartis team for who you are asking for things for.

Phillip Koo: So I think what people have thought is really complicated, there seems to be a great deal of support to help facilitate that process, so it doesn't quite... it's not quite as insurmountable as what I think it was what people thought.

So I think oftentimes, the question of PSMA imaging comes into play here. And though we have PSMA PET agents that are approved, none that are really widely available as of today, can you talk about how you've been able to manage that obstacle in order to get your patients qualified for lutetium therapy?

Charlotte Manogue: With Dr. Sartor's support and his contacts and everything, we were able to open a protocol here at Tulane. We put in an expanded access IND with the FDA and got clearance to run that through, so we are currently able to image patients on a very small kind of study here in which it consists of four kinds of contact points, most of which can be done over the phone other than actually getting the scan.

But we will take a PSMA scan from anywhere. So if... and there doesn't seem to be a timeframe in which you had to have had the scan, so it's not like you needed to get the scan 30 days before your first dose. They've been accepting scans from the last couple of months, prior year. So if someone has gotten a scan for something else... to be fair, if someone got the scan on the VISION trial and was randomized to the standard of care arm which is true of a couple of patients, I was able to go back and get the information from that scan that was done then and grant them access to the therapy now.

Phillip Koo: Great. So I'll ask both of you, any last piece of advice that you have for the listeners out there who obviously want to bring this to their patients, but oftentimes find it too difficult to sort of navigate?

Kendra Harris: Yeah, so I would say that the regulatory piece on the front end if you've never done it before, it's a lot. However, this is not a one-trick pony. PSMA-targeted radioligand therapy and all these variations, from my perspective, is the next five years of new agents that are going to be approved. And one of the beautiful things about this is that patients are advocating for themselves and want this therapy.

So all the work that we did at the beginning that felt hard, was hard, was new. It was just a process we learned, right? And now that we've got nearly a dozen trials open and we are looking at a year where there are more men who want this therapy at Tulane than we could possibly take care of, the actual delivering, once you've done it one time, is very straightforward. It can be integrated into a radiation oncologist's workflow, into a nuclear med physician's workflow. The whole process today took 20 to 30 minutes of my time max, start to finish. We are doing three or four doses a day integrated into a full clinic schedule and a full [inaudible 00:12:24] schedule with SBRTs.

So whenever physicians or groups think about how hard this application is, I think what they should instead be considering is how this type of therapy is really going to grow in the armamentarium. And whether they do the work for this or they do it for the next agent or the next, that first application is going to seem harder than it actually is.

So we are happy to be resources to share. We've sent out documents, we're happy to take phone calls because that's the idea. We want patients to have access to this.

So that's what I would ask them to consider, that it's not like it's going to be easier in six months when they want the next agent. Just bite the bullet, reach out, go through it one time, and it's really much more straightforward and easier than even we thought it would be.

Charlotte Manogue: Once you know what you have to do, it's not hard to execute. I think the scarier thing is, "What do we have to do?"

Kendra Harris: It just seems-

Charlotte Manogue: But once you have the pieces of the pie, it's just following it down the road.

Phillip Koo: That's great.

Well, I think you guys have clearly provided that roadmap with regards to how to get this started, and I think the viewers really appreciate your willingness to share this information with the community which we all know is going to have a tremendous impact.

And to your point, this really is a commitment to a new class of therapies, and it's a class of therapies that is not going to go away.

Kendra Harris: ... and it's so fun, right? I mean the first group of men that we brought the expanded access protocol are all the men that got randomized to standard of care and didn't get the lutetium. It is fun to give a therapy that doesn't make people sick, doesn't make them feel bad, allows them to avoid other more toxic therapies for a really significant time period.

Charlotte Manogue: And give them space between doses, right? So when you think about when people get further along, chemo is once every three weeks, sometimes even sooner than that. This is six weeks apart. You can go on vacation. You can still travel. You can go see the grandkids, all of those kinds of things that these guys want to do, but are maybe restricted by their clinic schedule and actually treatment schedule to get that done. We have guys who hop back in their RV and are, "All right, I'll see you in six weeks for the next dose, so..."

Phillip Koo: That's great.

Charlotte Manogue: "... I'll get labs in Idaho."

Phillip Koo: That's a great topic that we haven't touched on yet. What are the radiation precautions that you, instructions that you give patients after their dose?

Kendra Harris: So we've actually... there's a written sheet, right? We also provide them with a card in case they set off a meter somewhere. The questions that are a little bit harder are for these men that are traveling from a distance. We give them precautions about staying a minimum amount of space from people, not sleeping in the same bed as another person. But we have had increased discussions about driving versus flying, right, whereas driving, you can be front seat, back seat, six-foot, no strangers. If they are going to be flying to and from town, then I think we've been having discussions about is it a reasonable thing to stay a couple of nights so that you are not seated next to somebody? Certainly, RVs are plenty of space, but ultimately, the exposure is not very high. It's just about the principle of ALARA, that if you don't stand to benefit, there is no acceptable exposure.

Phillip Koo: Sure. Great.

So there's no inpatient admission.

Kendra Harris:  No.

Phillip Koo:  And the restrictions, at max, might be two days of some sort of distance restriction?

Kendra Harris: So I think we say three days for sleeping and for the toilet.

Charlotte Manogue: And then, I mean, when we talk about exposure to pregnant women or small children, I think we've pushed it out probably closer to five to seven days that first half-life. We'd like to try to have that clear before...

Kendra Harris: But this has been much easier in the time of COVID.

Phillip Koo: Agreed. So that's true.

Charlotte Manogue: And you are used to saying to people, "Six feet apart."

Phillip Koo: And the sort of biologic half-life, the excretion in the urine is, I imagine, really high, so...

Charlotte Manogue: Double flush.

Phillip Koo: ... double flush. That's a good lesson.

All right. Well, thank you very much for your time, and keep fighting the good fight.