Early Phase Clinical Trial Program - Cleveland Clinic's Children’s Cancer Innovative Therapy Program

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Matteo Trucco, a pediatric hematologist-oncologist at Cleveland Clinic Children's, who's leading the Cleveland Clinic Children's Cancer Innovative Therapy Program. He's here today to talk to us about that program. So welcome.

Matteo Trucco, MD: Thank you for having me.

Dale Shepard, MD, PhD: So maybe to start, you can tell us a little bit about what's your role here at Cleveland Clinic?

Matteo Trucco, MD: So my role at Cleveland Clinic is I'm kind of the pediatric version of Dale Shepard, honestly. I see sarcoma patients and I run clinical trials on the pediatric side, everything from the phase 1 trials where we're trying to figure out whether drugs are safe to a little bit more advanced clinical trials, where we're trying to see if new drug combinations or new drugs are actually efficacious in treating certain cancers.

Dale Shepard, MD, PhD: The Cleveland Clinic Children's recently launched this new early phase initiative. It's this Cleveland Clinic Children's Cancer Innovative Therapy Program. Tell us a little bit about what that program is about.

Matteo Trucco, MD: So that program was designed to try to kind of more formalize how we develop new ideas, new treatments for kids with cancer. I mean, we certainly had been doing clinical trials before my coming here, but it was an attempt to kind of bring a little more innovation to it, bring a little more structure to it and build kind of a platform where other researchers can also come with their clinical trials, their ideas. It's really a three-pronged approach. One, there's industry-sponsored trials. So a drug company comes up with the newest, greatest drug, and certainly we want to make that available for kids. And with some of the recent changes at the FDA, more drug companies are interested in seeing if their drugs are helpful for treating childhood cancers.

The second prong is partnering with consortia in the pediatric oncology field. So Children's Oncology Group is the big one. We've been a member of that consortium for a long time. And certainly those trials are important, but we also partnered with some smaller consortia that are a little more agile and a little more innovative. They're willing to kind of try something a little more out there, a little different to see if maybe some of the tried and true approaches that we've been using for years and years and years, maybe they need to change. Maybe we need to attack these cancers in a different way, look at them in a different way. So some of these smaller consortia are doing that.

And then we have investigator initiated trials, where it's someone here at the Cleveland Clinic has come up with a new approach, a new drug, a new way of treating childhood cancer. And it's kind of in the early phases, and so we kind of have it available here to see if it works. And then with our partners, either in industry or in the consortia, we can expand that. And again, kind of building that infrastructure with the research coordinators, the managers, research nurses, to be able to bring these trials efficiently and effectively to our patients.

Dale Shepard, MD, PhD: So when you mentioned the industry trials, are these a primarily the approach to be more inclusive and have the adult trials go down into younger ages? Are these specifically pediatric trials?

Matteo Trucco, MD: We've got both. So the FDA, at the end of 2019, kind of did a 180. Where it used to be that you had to have a pretty darn good argument for including pediatric patients on an adult trial without having established safety first, now they realized that that approach kind of left pediatric cancer patients behind. A lot of drugs weren't made available to them. So now it's, you have to come up with a compelling argument to not have at least a pediatric arm on a clinical trial. Right now we have a couple clinical trials that are just drugs that have been used in adults, and now it's an exclusive pediatric trial kind of mirroring the adult trial. But I foresee in the near future, some trials coming down the pike where there's going to be at least a cohort for pediatrics or a separate arm for pediatrics built into the adult trial.

Dale Shepard, MD, PhD: Oh, that's great. It's the only way things get better. Now, the program you're working with, is this primarily focusing on any particular cancers? Is this more on the solid side, the heme side? What are we focusing on?

Matteo Trucco, MD: So since my clinical focus is sarcomas, there's a slight preponderance of clinical trials aimed at sarcomas. But the vision is for it to make trials available for brain tumors, for hematology, for leukemia, heme malignancies, let's call them. And we'd have those trials through the Children's Oncology Group, through some other industry sponsors and some investigator-initiated trials. But my interest, what I kind of partnered with, is a little more on the solid tumors and the sarcomas, just because that's where my clinical interest lies, and we tend to have a large referral base for those patients. We also have my colleague in office, Dr. Neha Patel, who's working on pediatric brain tumor trials. And some of the consortia we work with are starting to get a little more interested in brain tumors also. Then we also have bone marrow transplant trials in pediatrics that we have several trials open. And again, we're working on more moving forward.

Dale Shepard, MD, PhD: When you look at those groups of solid or heme malignancies or brain tumors, historically one of those groups been underrepresented?

Matteo Trucco, MD: I jokingly say that I aspire to be a leukemia doc because they're the poster child for success in cancer, not just pediatric cancer. Because they went from the 1950s where the most common cancer we see in kids is acute lymphoid leukemia was almost universally fatal, and now we cure 80, 85, 90-plus percent of those. So they really pioneered combinatorial chemotherapy and are really a success story in medicine. Sarcomas, for example, kind of always lag a little bit behind. A localized sarcoma, we're looking at about a 70% cure rate, which is not bad, but could obviously be better, and we have very toxic chemotherapies that we use. Metastatic sarcomas, we really haven't made a significant difference in them in 40 years. And we're using chemotherapy that was first developed 30, 40 years ago. So clearly, those are areas that we need to improve. And that's part of why I got drawn to sarcomas and part of why I got drawn to clinical trials, specifically wanting to bring forward new treatments and better treatments for sarcomas.

Dale Shepard, MD, PhD: Now, some of those successes certainly have been because in the past and even still pediatric trials tend to have much greater enrollment in terms of more patients with pediatric cancers enroll in trials. That's a real problem in adult side. How about early phase trials? Is there the same interest in participating with patients and their parents?

Matteo Trucco, MD: Yeah, I mean, everyone's a little different, obviously. At one point we had 90% of eligible patients go on a trial, and that's upfront trials or trials for relapse were kind of the earlier phase trials. We have a lot of patients that come to us, looking for a trial. And there are certainly kind of standard of care, off the shelf second and third line chemotherapies. But some families say, "Okay, we know those are there and we can use them whenever, but we're looking for something new, something innovative." And what we've also tried to do to make these trials a little more appealing, let's say, to patients and families is try to build them in a way where you're going to get this backbone, which is very similar to the chemo you would get off study, kind of that standard second line chemo. And then we add a new drug or a new therapy that we think would augment the benefit of that trial. So they're not losing anything by coming on clinical trials. I think that that resonates with families, that resonates with doctors.

Dale Shepard, MD, PhD: When we think about the drugs that are being studied, are these primarily new drugs in kids or drugs that have primarily been used in adults being pushed into pediatric trials?

Matteo Trucco, MD: We've got a little bit of all of that. We have a lot of trials where it's... The checkpoint inhibitors, for example, have been very successful for some of the more adult malignancies, melanoma, some lung cancers, stuff like that. We're trying to figure out how to make those work better in pediatrics. It's early, but I'm trying to see how that works. Other things are truly it's, we've done the adult clinical trial for this tyrosine kinase inhibitor and now we're looking to see what the safe dose in pediatrics is. And oftentimes the pediatric dose is actually higher than the adult dose because kids, their organs work better so they are able to tolerate higher doses. So those trials exist.

Then we're doing a lot of repurposing of drugs. We've done some trials using metformin, which is a diabetes drug that we're trying to see if it has anti-cancer activities. I'm in the process of opening a clinical trial using drug called disulfram, which is a drug that's been used for 60 years to treat alcoholism. But there's some evidence that it blocks an enzyme important to help cancer cells survive chemotherapy. And so we're testing to see whether or not that can enhance the chemotherapy. Every once in a while you get a drug that's new to humans, let's say, and is specifically started off in pediatrics for a variety of reasons. There's a couple of drugs like that for Ewing sarcoma, which is a bone tumor that affects adolescents and young adults, where the drug was specifically developed for the mutation that we see in Ewing sarcoma to target that. So those trials started off in pediatrics, maybe not all the way down to the youngest kids, but at least 12 year olds and up. So we have a couple of those trials too.

Dale Shepard, MD, PhD: I guess, maybe take a really brief step back. You just mentioned about really young and 12. And I know some of the adult trials are going down to 12 and above. And when we talk about pediatrics, what population for these trials are we talking? How young is young for these trials? Are we talking months old, years old, six years? Where do these normally start? I mean, there's such a tremendous range you'd see in your clinic compared to what I see on the adult side.

Matteo Trucco, MD: Yeah. I mean, we have trials that go all the way down to essentially newborns. One of the newest drug classes were these NTRK inhibitors, and one of the population that tend to have that mutation more than others is infantile fibrosarcoma. I mean, babies are born with that. So we go that low. And then tumors like Ewing's, as I mentioned, the peak is in the teenage years, but we often end up treating 30 year olds on our trials because they have you Ewing sarcoma, quote unquote, pediatric tumor, if you will. And so if the more promising drug is on a pediatric trial, we usually don't necessarily have an upper limit to many of our trials, or we might cap it at 30 or 40, just somewhat arbitrarily. So I truly do see that range.

As you mentioned, a lot of the adult trials are starting to allow younger patients, and 12 has become kind of a popular number because it's like you're sort of hitting puberty at that age and you're more or less adult sized. Because a lot of dosing is size-based. So we certainly have those trials. And then you have trials where you have one arm that's for 12 and up, and then we have another arm that's 12 and under to try to tease out if the dosing needs to be different for those two different age groups.

Dale Shepard, MD, PhD: So as a phase 1 guy, I have a very, very practical question. Oftentimes these trials are primarily looking at safety. They're looking at toxicity, they're looking at side effects. Helped me out here. How do you do that in a two-year-old?

Matteo Trucco, MD: You rely on the parents a lot. Certain things, you're not going to be able to probably glean as well, like fatigue, but we also have other metrics of fatigue, like our performance scale. We have the pediatric version where instead of saying, "Are you able to care for yourself?" it's more like, "Does the kid play the way they normally do? Or is the kind of playing that the two-year-old is doing not running around like he normally would, but instead they're sitting there playing quietly?" That suggests their performances is lower than normal. So we have those features.

Other things we kind of... We use parallel metrics, lab results, weight, things like that kind of give us a better sign of are they tolerating the drugs as well as we hope. And again, largely, these kids... I mean, if you gave your patients the same drugs, the regimens that I give my patients, and we've done this, the adults just fall apart. You have a big, burly 30-year-old who can't tolerate the same chemo that a five-year-old can just because their organs are just in much better shape than then yours or mine, and they're able to clear things and tolerate things a lot better than the adults.

Dale Shepard, MD, PhD: You previously mentioned people coming to look for trials. How much of this program is supporting patients that you and your colleagues are already seeing here at the clinic and how many patients are referrals from the region?

Matteo Trucco, MD: So a little bit of both. We have, just because of my colleagues and the sarcoma team that you're part of, a lot of sarcoma patients come here. Obviously. Cleveland's a relatively big city. Northeast Ohio has a pretty big population. So we get a decent amount of upfront patients with sarcomas or brain tumors, or what have you. And we treat them, and if they were to reoccur and need a clinical trial, or for whatever reason, they're upfront disease, there's a clinical trial that is a good fit for them, we'll treat them. But we also have a very large national and international referral system for second opinions led by Pete Anderson. And with me coming here, I've kind of also joined that second opinion telemedicine referral network. We provide our expertise, our opinion. And then because it's kind of a small world, if there's some trials that I don't have open here, but I know are open down in Columbus, are open in California, or what have you, so we kind of inform them where they can go and where they can get these treatments.

If hopefully we have the best treatments available to them here and if they want, and several patients have wanted, they come to Cleveland specifically to be on the trials. COVID has made that a little tricky, but despite that, we still have a decent amount of patients that come in. So I don't have hard and fast numbers, but for the clinical trials, it might be about a 50/50 split of of internal candidates and external ones.

Dale Shepard, MD, PhD: So has COVID had much of an impact? I know on the adult side, we've had some actually advantages where people can get labs locally instead of having to come here to the clinic. Have you had similar changes in trials or problems with program development thanks to COVID?

Matteo Trucco, MD: It's changed how we need to go about things. I know one trial has been put on hold because it required the tumor to be surgically removed, and then someone from the company has to come pick up the tumor, take it back, process it, bring it back to us. So that one, because of the travel restrictions and access has been put on hold. Other ones, I think we've done a pretty decent job. It's been a burden on the team, but we've tried to not make it a burden on the patients. Patients have flown up here. That's a bit risky for them, but they incur that risk, or maybe they drive to get those treatments. So that certainly has happened without a problem.

Some of the treatments we've been able to do via video instead of in person. So that's been convenient. A couple, yeah, we've been able to lessen the trips to the hospital, just for monitoring and labs. And then it's just bogged down the system, the approval process and the regulatory stuff. Just one, because the system has been inundated with a bunch of COVID trials, rightly so, but that's more burden on the legal team, the IRB, what have you. And then all these groups have people that are getting infected, people that are quarantining and working from home now. And so it's kind of complicated things from that standpoint, but we've tried to not make those headaches the patient's headaches.

Dale Shepard, MD, PhD: So what are the biggest gaps? What's the biggest thing that needs fixed to move forward in this area?

Matteo Trucco, MD: Oh, there's so many. I mean, the biggest challenge we have is that we don't completely understand the biology of a lot of these tumors. So there are certainly people working on that aspect. Two, getting the drugs available for pediatric trials. That's always been a challenge. And as we discussed earlier, hopefully that's turning around. Three, and something that we're looking at in one of the consortium that I'm a part of is are we giving drugs the right way? If you look at something like childhood leukemia, you get four drugs in the first month, then you switch, you get another six drugs in a different pattern, then you switch and you get some of the first drugs again. And it's a very, if you kind of map it out, a very... There's a lot of variability in what drugs you're getting and how you're getting them and how they function and the duration. And that's probably contributing to the 85, 90-plus percent cure rate that we see in those tumors. Plus, we understand the biology of leukemia a lot better.

Something like childhood sarcomas, we give the same two or three drugs every three weeks, over and over and over and over for 40 weeks. And when you map it out, it seems, wow, that's very redundant. And again, it works to some degree. We have a 70% cure rate in localized disease. That's nothing to sneeze at. But maybe that's not the best strategy for the metastatic tumors. Maybe using an approach more similar to what the leukemia regimens look like would be better. But then you look at the drugs we have for leukemia and the drugs we have for sarcomas, and the drugs we have for sarcomas, they kind of fall into two categories. They're either topoisomerase inhibitors or they're alkylating agents, and that's about it. So there's this lack of diversity in the drugs that we have, and then maybe even how we are giving it is not the smartest way. So we're looking at that.

Dale Shepard, MD, PhD: Excellent. Well, thank you very much for your insight here today, Matteo, and we really appreciate you being with us.

Matteo Trucco, MD: Oh, it's been a pleasure being with you guys.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.