Nader Sanai, MD, Director of the Ivy Brain Tumor Center, Neurosurgical Oncology at the Barrow Neurological Institute, talks about new brain tumor trials.
Interview conducted by Ivanhoe Broadcast News in September 2018.
Can you give us an overview of the collection of trials that you’re doing?
Dr. Sanai: Sure. For most patients with malignant brain tumors they run out of standard of care options really quickly. So for most of these patients they really are at the point where they need to find trials and trial medications that can work for them. We have a collection of clinical trials within what’s called the Ivy Brain Tumor Center that we call pharmacodynamics, or pharmacokinetic, driven studies. Another word for them is Phase Zero clinical trials. These are clinical trials that focus on new drugs targeting new classes of mechanisms for patient with malignant brain tumors including gliomas, atypical malignant meningiomas and other rare but aggressive tumors of the brain.
Because these patients don’t have time to be messing around trying all kinds of different medications, tell us how you’re speeding it up?
Dr. Sanai: For most patients entering a clinical trial, it usually involves some screening process hopefully at the genetic level. Then, getting a drug or a placebo and taking it for several weeks or months or even longer with the hope that it’s going to do something. At some point there will be an assessment, often times with imaging, to see whether or not there’s an effect or not. The challenge with that approach of course is that there are a lot of assumptions being made and if a drug is working or not working, it doesn’t necessarily tell you whether the imaging is going to get better or worse. In fact, in patients that do have a response, it’s still not clear if that’s due to the drug directly or not. We have a system in place where patients will get a very, very small dose of the drug before a planned operation. In doing so, we can then take the tumor that we remove in the operation, test it and answer two basic questions… Did the drug get there and did the drug do what it is supposed to do to this individual patient’s tumor? We then get those answers within seven to ten days of the operation. So essentially, while the patient is recovering from surgery and getting back to baseline we can really make a decision for them individually whether they would benefit from this drug or not. Most drugs for brain tumors fail because of those two things… the drug did not get to the brain because the blood brain barrier is a protective layer that protects things from getting to your brain, or because the drug did not do what it was supposed to do based upon animal studies and laboratory studies.
How do you pick the drug to test on the tumor before the surgery for a patient?
Dr. Sanai: We have an extensive array of relationships with small and large drug companies. What we do is collect a portfolio of drugs, usually combinations of drugs that cover a spectrum of genetic variations in the tumors. Then we put the patient’s tumors through some pretty intensive sets of analysis to look at genes and gene products to see what parts of the tumor are actually abnormal and how those would fit with different drugs in our portfolio. We try to make our best estimate match between the genetics of the patient’s tumor and the genetics of the drug. Then we go one step beyond that and actually test the drug in that patient and see whether or not our hypothesis is correct and whether or not for this patient there’s real cause for them to be in the trial or not.
So, the initial testing is for a biopsy of the tumor?
Dr. Sanai: The initial testing is typically from the first operation or a prior operation. Almost all patients that have recurrent brain tumors have had a previous operation somewhere and have had standard of care therapy. So we use that tissue as a baseline analysis of the patient’s tumor. And then, of course, we compare that to the tissue that we get from the operation that occurs during the course of the clinical trial.
Is this all for recurrent patients?
Dr. Sanai: Correct. Almost every patient with a malignant brain tumor at recurrence enters or should enter some clinical trial.
How do you know if these individual drugs are going to get through the blood brain barrier?
Dr.Sanai: For the protection of our brain, we have a blood brain barrier that protects it from allowing most agents to come in. This is why most of the things we ingest during the course of our daily activities don’t actually affect us neurologically in a negative way. But it works against us when we have disease that’s hiding behind the blood brain barrier in your brain or spine. Most drugs never make it in at any sort of significant quantities. We have our specialized laboratory called Pharmacokinetics laboratories whose job is really to take individual drugs, figure out the right way to test it within tissue behind the blood brain barrier, and in fact even understand the different conformations of the drugs. As the drugs enter your body, they change in form, shape and function, and we have to be able to detect all of these variations, measure them in important quantities and do it in real time. This is something that’s really been one of the leading edge technologies that we’ve developed here and one of the reasons we can even do these types of trials.
The program is a couple years old, is that right?
Dr. Sanai: The program was initially started in 2017 and the Ivy Center was formed just a few months ago.
So then you really don’t have anything measurable as far as patients coming through the program yet?
Dr. Sanai: We’ve completed three trials to date, approximately fifty patients overall. Each of these trials is with different combinations of agents and different patient populations. In two of those trials we identified drugs that really were valuable and had effect and need to be further developed in larger scale Phase II and Phase III studies. I know one of the studies we identified a drug that we had anticipated would penetrate the brain well, but in fact didn’t. That emphasizes an important point of these studies which is that a negative study and negative information is just as valuable as positive. Many times, drugs are inappropriately developed and expanded to larger scale trials when a study like this can demonstrate that there’s really no value to doing that and the drug has no hope of making it beyond the blood barrier into the tumors.
This is super exciting for people with gliomas and their families because there’s really not a target study out there for this, correct?
Dr. Sanai: For patients with gliomas and glioblastomas, which is the most aggressive variant and also the most common in adults, is a perpetual problem. There is a standard of care that for most patients take with them to approximately sixteen months of median survival but for the vast majority of patients there is inevitable recurrence, inevitable down cycling and a thinning of options. Clinical trials do exist for glioblastoma patients but we’ve been involved in that for decades and the median survival has only improved by several months over the last thirty years. It also has really reflected the emphasis of the drug development in this country which is on larger scale markets than brain tumor patients and their diseases. We use this clinical trial system that we have as a way of repurposing early development drugs that have been designed for other cancers but still have relevance to glioblastoma patients.
So nothing is brand new? All these drugs are already FDA approved or already being used for something?
Dr. Sanai: Most of the drugs are not FDA approved. In fact, about ninety percent of them are not. However, about sixty percent of them have been through some level of Phase I testing in humans. Almost all is for patients with non-brain tumors. So, we effectively are looking for drugs that are first in class, meaning they’re targeting a novel mechanism that hasn’t been targeted before for brain tumor patients. But, drugs where we know there’s some degree of safety data and we don’t have to go through all of the iterations of first in man studies.
Leslie, in her case, is pretty excited about participating in this trial?
Dr. Sanai: Her enthusiasm is emblematic from what we see from a lot of patients. The reason for that is these are personalized therapies. So they know that the drug selections really match the biology of their tumor. They also know that if they’re on the study and they actually graduate to the therapeutic dosing after the surgery, they’re really doing so knowing that there’s some hard evidence connecting their tumors response to the drug. So in that respect, it’s a lot easier to go through the side effects and the trials and tribulations of an experimental therapy when you know that there’s a smoking gun that points to you needing this drug for your tumor.
And she was hoping before she knew if using it or not?
Dr. Sanai: That’s right. Right now we’re performing some genetic analyses on her prior previously resected tumor. Once we have that completed we’ll be able to access whether one of the candidate drugs is appropriate for her. Then she’ll proceed with receiving that drug for several days prior to surgery. Not enough drugs to really cause a lot of side effects, but enough for us to get enough in her system so that when we perform the surgery we can test to see if her tumor is responding to this drug to see if the drug has successfully penetrated her tumor. Then, based upon those results, approximately seven to ten days after surgery we’ll notify her if she’s been graduated to what we call the therapeutic phase of the trial.
This is hope for folks who haven’t had a lot of hope, right?
Dr. Sanai: Absolutely. Hope is the key word here and for patients with glioblastoma with malignant tumors of the brain in general. Hope is a precious commodity. They hear a lot of negative things in the media, on the internet, from patients, families and physicians. They need to understand that every patient is different. There are individualized responses and every tumors’ biology is a little different. So we approach it on a case by case basis. From their perspective, what they know is that they’re getting a drug that no other brain tumor patient has received to date. That drug is only going to be given to them if we really are proving to them that the drug has an impact.
Is there anything else you would like to include in the story?
Dr. Sanai: I think an important question is why do this here and why hasn’t this been done before? Early phase trials like this are challenging to do because you have to coordinate an experimental therapy with a brain tumor operation. The level of complexity to coordinate these two things is fairly intense. At the same time it means that all of your trial patients need to be patients that are operative candidates that are going through surgery. The Barrow is the largest volume operative brain tumor center in the United States. They perform about thirteen hundred brain tumor operations per year which is about thirty or forty percent more than any other center in the U.S. It means that we have a large population of patients that fit this profile. At the same time, we’re one of the only centers in the U.S. performing what are called Phase Zero trials for these patients. We’ve really made an institutional bet on developing the infrastructure for this. And that’s been enabled by a large grant from the Ben Catherine Ivy Foundation. So our entire set of facilities for clinical trialing are specialized to focus on some of these important areas like Pharmacokinetics, the study of blood brain barrier disruption and delivery, and Pharmacodynamics, the study of biological effects of drugs on tumors. It is important to have specialized facilities to be able to do it in a way where you can make decisions clinically in real time and not retrospectively over several months. We think that we’re particularly attuned to this kind of strategy. We’re emphasizing all of our resources on this and our patients are pouring in to it obviously because of the enthusiasm for new drugs, real time evidence and personalized medicine.
END OF INTERVIEW
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