Two Novel Studies Seek to Improve Outcomes in Children with Malignant Fourth Ventricular Brain Tumors

Prakash Chandran (Host): Advancing health. Personalizing care. At Memorial Hermann, this is our mission. This podcast shares the science and stories behind those efforts. Today, we're interviewing Dr. David Sandberg. He's the Director of Pediatric Neurosurgery at McGovern Medical School at UTHealth Houston and Children's Memorial Hermann Hospital. And he's going to be sharing with us how new pediatric brain tumor trials are improving outcomes by moving past historic treatments that expose children to considerable toxicity and often result in low survival rates despite treatment.

This is Advance, the podcast from Memorial Hermann. My name is Prakash Chandran. So, Dr. Sandberg, really great to have you here today. Thank you so much for your time. I'd love to jump right in and ask you all about the UTHealth Houston studies for children with reoccurring brain tumors at Children's Memorial Hermann Hospital.

Dr. Sandberg (Guest): Thank you so much for this invitation and for asking this question. It's my honor to be here with you. We are trying to push the envelope and offer hope to families who don't have hope. When children have recurrent malignant brain tumors in the brain, the current treatments are inadequate, and most children die of their disease.

The treatments that are given are often very toxic. You know, the brain is very good at protecting itself. The brain has something called the blood-brain barrier, which prevents things from getting into the brain. That's great if you're trying to prevent an infection or a toxin from getting into the brain. But when you want to get a drug into the brain, it makes it much harder.

So, when we give drugs via a vein or orally via pill, you have to give such high drug levels that you can cause considerable toxicity. Our idea is to infuse drugs directly into the brain, into a spot where nobody's ever done it before which is called the fourth ventricle, which is the location of the most common malignant brain tumors in children.

We're focused on two diseases especially, ependymoma and medulloblastoma. And we have two very exciting open clinical trials in which we're infusing different drugs into the fourth ventricle of the brain, specifically to treat children with recurrent malignant brain tumors in this area who don't have any other great options.

Host: So, you touched on this earlier around these studies and trials being there to offer hope, but can you talk more specifically about the purpose of these trials?

Dr. Sandberg: So, the purpose of these trials, you know, first and foremost, is of course to show that it's safe to do something that nobody's ever done, which is infusing drugs in these areas. We showed in animal trials that you can get extremely high drug levels exactly in the site of disease and the site of recurrence which is what you want without getting high drug levels in the bloodstream, which is great because these tumors, unlike many other cancers, don't spread throughout the bloodstream.

So, you know, we're trying to show safety, but of course, you know, families don't sign up for a clinical trial to show safety. They want a disease response. They want the tumor to melt away. And we've had some success in some of our prior trials. And we're hopeful that we'll have even more success in the current trials in actually making a difference in the disease process and extending the lives of children without causing extensive toxicity.

Host: So, what's been the history of treating these types of cancers? And what were the outcomes of the previous studies?

Dr. Sandberg: So, the history, you know, there are different trials of various different types around the country. I started doing these trials. Our first one was in 2013. Our very first patient was a patient who came from Alabama. We infused the standard chemotherapy drug called methotrexate, which has been around for decades, but nobody had ever infused it in this site in the brain.

We had a dramatic response. The patient had tumors all over the brain and the spine. The tumor essentially melted away. He had a very poor prognosis at the time, was given less than three months to live by the doctors treating him in Alabama with nothing else to offer. He wound up surviving two years and his tumor melted away and it stayed away for over a year until it finally came back. During that year, he had an amazing year. He wound up going on trips, his neurological status improved. He was walking better, talking better. His eyes were better. So, it was really, truly amazing to watch. I'd never seen anything like that.

Since then, we've had several different trials trying different drugs and different concentrations of those drugs. The key we're working at is figuring out what is the right drug to infuse in this space where the tumors start and typically recur. And it's a process. So, we've had some failures and some successes. Our latest trials, we're very hopeful that we're going to really make a difference.

Host: So, you know, in the trials, there are different types of cancers being treated and, you'll have to forgive me if I pronounce these wrong, but there's the medulloblastoma, the ependymoma and ATRT. How can the treatment impact these different diseases?

Dr. Sandberg: So ATRT is the rarest of those, and we've only enrolled a few patients with that disease process. In terms of the other two, ependymoma is a great target for this particular approach because standard chemotherapy drugs almost invariably don't work. The success rate with standard chemotherapy given orally or by vein has almost no impact on the majority of kids with recurrent ependymoma. And these tumors are relentless, they keep coming back and coming back.

We have preliminary success with a drug called 5-azacytidine, which causes shrinkage of some of the tumors we treated in our last trial, but it wasn't enough. It didn't cure children. So, we've added a second drug called trastuzumab, which is active against ependymoma. And we're hoping that the combination of these drugs has an even greater impact.

For medulloblastoma, we're focused on a drug called panobinostat. It's manufactured in a formulation called MTX110 by a company that's based out of the United Kingdom. And this drug has shown great activity against medullablastoma in the laboratory. And we're really hopeful that infusing this drug directly into the fourth ventricle is going to have a great impact on the disease process.

Host: Yeah. So, you've mentioned this a couple times, that direct chemotherapy administration into the fourth ventricle. Talk a little bit more about the rationale behind that and just more explicitly when that discovery was made to say, "Hey, you know what? This is really something that we should be considering narrowing in on."

Dr. Sandberg: So almost two decades ago, I was in an operating room, taking out a brain tumor that occurs in the back of the brain in the fourth ventricle. We removed 99% of the tumor. The post-op MRI looked perfect, but I knew we had left disease behind because we had left disease behind on purpose, stuck to the brainstem. You can't remove that disease safely without hurting the child. And at that moment, that's the only disease that was present in that child. And I knew that child was going to go on to get radiation therapy, which has considerable toxicity in children and then chemotherapy, which was going to wreak havoc on this kid's body. And I wondered, "Why are we not treating this disease right here that we're looking at with our own eyes? Why are we not putting a catheter in and infusing drugs to get big-time, high concentrations in this exact spot?" And I asked some colleagues and wise mentors that I trusted, and nobody had a great answer for why we weren't doing it. It had never been done before, but many ideas, you know, are like that. You know, simple idea, never done before.

So, I started working on preclinical trials, first and foremost, to test the safety in large-animal studies in which we infuse drugs. And what we found is we could get incredibly high concentrations over a hundredfold the drug concentration that you would get with a systemic infusion. And the animals were fine, and their MRI scans looked fine and, neurologically, they were fine. So, I did these studies for seven years, first in pigs and then non-human primates until we were ready to try this in humans, and that was in 2013 as mentioned.

Host: So, the studies that we are discussing today are made possible by a team of multidisciplinary specialists at UTHealth Houston and Children's Memorial Hermann Hospital. What exactly can you tell us about the team that's involved and how they care for patients?

Dr. Sandberg: Yeah. I mean, I'm extremely fortunate and blessed to work with extraordinarily talented individuals on our team. We have four pediatric neurosurgeons. We have a combined neuro-oncology program for children with MD Anderson Cancer Center. So, we have access to their specialists who are world-class. I have four physician assistants who help me with these trials, and I have an amazing research manager named Bangning Yu, who is an MD, PhD, who is brilliant and talented and dedicated to our patients. Those are the primary players involved in these studies. And of course, you know, the amazing nursing staff that we have at the hospital in general and the nurses in the infusion suites. It's really a lot of people. It's Child Life specialists. Well, we have an amazing dog that comes and lies down with the patients during the trial, so that as they're getting infusions you know, they can pet the dog and be distracted. I think, you know, the dog, his name is Pilot. He's our most valuable player right now.

Host: Yeah, just helping them navigate the emotional trials as they're going through this, right?

Dr. Sandberg: It's a massive team effort. We're trying so hard for these kids.

Host: Yeah. So, it's really amazing to hear just how far you've come from that kind of initial “light bulb moment” 20 years ago. But what have you learned throughout the trials, and what is your hope for the future of the studies?

Dr. Sandberg: I've learned to be persistent, that this work takes tremendous effort, but it is absolutely worth the effort to provide hope to families. I've learned that families are desperate for new treatments because the current treatments that we've had are inadequate. They cause tremendous toxicity, and they have low cure rates.

And so, you know, for any of you out there who have children, you know, we know how much we love our children. You can only imagine when you have a child, who's not only had a brain tumor, but that brain tumor has failed standard treatments, the desperation and the lack of hope. We're here to try to do better for the kids.

Host: Well, Dr. Sandberg, I think that's a great message to end on, but is there anything else that you wanted to share with our audience before we close here today?

Dr. Sandberg: No, just gratitude for the support of the families who are going through the most challenging time in their lives. Participating in research trials, it's for folks who don't have any other options and it takes a certain bravery for the families and for the children that we take care of and, you know, my love and gratitude to them.

Host: Well, Dr. Sandberg, thanks again for your time today.

Dr. Sandberg: Thanks for yours.

Host: That's Dr. David Sandberg, Director of Pediatric Neurosurgery at McGovern Medical School at UTHealth Houston and Children's Memorial Hermann Hospital. For more information, go to memorialhermann.org/childrens-neuro or call (713) 500-7363. If you found this podcast to be helpful, please share it on your social channels and be sure to check out the entire podcast library for topics of interest to you.

Thanks for checking out this episode of Advance. My name is Prakash Chandran, and we'll talk next time.