Clinical Trials for Brain & Spine Tumors: Challenges & Opportunities

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Clinical trials play a vital role in advancing evidence-based medicine, while also offering hope to many patients and their families. However, for rare conditions such as brain tumors and spine tumors, developing successful clinical trials comes with many inherent challenges.

In today's episode of Neural Pathways, we are discussing those challenges as well as the opportunities and how they both influence clinical trial design. I'm your host Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Mark Malkin, fellow Canadian, join me for today's conversation.

Dr. Malkin is a neurologist, neuro-oncologist in the Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center within Cleveland Clinic's Neurological Institute. Mark, welcome to Neuro Pathways.

Mark Malkin, MD:

Thank you for having me, Glen.

Glen Stevens, DO, PhD:

So Mark, why don't we just start off where you can share with us a little bit about your background and how you found your way to the Cleveland Clinic.

Mark Malkin, MD:

Sure. So as you mentioned, I'm originally from Canada, maintain my Canadian citizenship, although I'm now a dual citizen. Born in Ottawa, grew up in Toronto, which is where I went to college and medical school and where I completed my neurology residency training. And then I moved to New York to do the fellowship in neuro-oncology at Memorial Sloan Kettering Cancer Center. And the original plan was to come back to Toronto because in 1987, '88, Toronto didn't have a neuro-oncologist. Now they have excellent neuro-oncology.

And so I stayed on for what was going to be another year on staff at Memorial Sloan Kettering, and one year turned into 15 or 16 more. And so that's where I really learned the ropes in neuro-oncology, how to care for patients, how to do clinical trials, how to teach the fellows and residents and medical students, and I took on a fair bit of administrative duties as well.

In 2004, I moved to Milwaukee and helped build an already excellent established neuro-oncology program at the Medical College of Wisconsin. In 2013, I was offered the opportunity to come to Richmond, Virginia, Virginia Commonwealth University and Massey Cancer Center to create a neuro-oncology program. And that's where I was for eight years until seven months ago when Dr. Gene Barnett, the director of the Brain Tumor and Neuro-Oncology Center here, recruited me to do three things.

First, to care for brain tumor patients, and I do that two and a half days a week, to help increase the portfolio and enrollment of clinical trials for neuro-oncology patients and to mentor the junior faculty. And so it's the clinical trials and the mentorship that I do 50% of the time.

Glen Stevens, DO, PhD:

Great. With your experience, it's really great having you here. And already seven months seems like you've been here a longer period of time, but we're already so happy to have you here. The Human Genome Project generated the first sequences of the human genome that they looked at from the nineties to early 2000s. And then in 2005, the NCI initiated the Human Cancer Genome Project to obtain a comprehensive understanding of all the major genomic alterations that underlie all major cancers. It was really going to be the answer to solving the riddle of cancer.

Several months later, the NIH launched the Cancer Genome Atlas, and in 2008, relevant to both you and I, glioblastoma was sequenced. And they defined three critical signaling pathways. And again, the thought and hope was that nirvana would be the end of this. Unfortunately that's not been the case. In 2015, Bo Biden succumbed to what is thought to be high grade glioma, and in 2016, President Obama with Vice President Biden, now President Biden, we had the development of Moonshot where they were going to eliminate cancer, not just brain tumor but cancer in general.

So I guess that moves us today. A lot of stuff going on 20 years ago to try and get us to the answers and the clinical trials that will get the answers. So I know we can't sum up in 30 minutes all the work and the trials that have been done to sort of lead us to where we are now, but talk about clinical trial development since that period of time. We know an awful lot about what's mutated, what we have too much of, what's not working, and where have we gone?

Mark Malkin, MD:

So there are a number of challenges to the development of clinical trials and ultimately we hope translating those genetic discoveries into therapeutic options for patients, and personalizing the options which may differ in one patient compared to another.

So the first challenge is that primary brain tumors, and glioblastoma is the most common primary malignant brain tumor, are rare. In the US each year, approximately 10,000 people are diagnosed with a glioblastoma each year. That is dwarfed by the number of patients with newly diagnosed breast cancer, lung cancer, colon cancer, or prostate cancer. Each of those four cancers is diagnosed in approximately 200,000 patients per year. So finding the patients is the initial problem. It is less of a problem at an institution like Cleveland Clinic where we have a endowed brain tumor center where we have six neuro-oncologists, where we have neuropathology, molecular pathology, neurosurgery, radiation oncology, folks who are full-time dedicated to this.

But it is still a challenge to attract enough patients to evaluate them fully, and then to enter them into clinical trials. How do we meet that challenge? We collaborate with other folks at similar designated and comprehensive cancer centers. And in fact, we collaborate with folks around the world. I'm traveling to Orlando to attend the semi-annual meeting of the NCI sponsored cooperative group called NRG. And that is a North American effort, it's the US and Canada. And sometimes there are collaborations between cooperative groups such as Alliance, such as ECOG-ACRIN, such as SWOG, to get enough patients to test an idea. First challenge.

Second challenge is we don't know the cause of glioblastoma compared to other cancers. Smoking doesn't cause it, it rarely runs in families, so not dissimilar from pancreatic cancer we are often discovering this when the disease is well advanced. Rarely we discover it incidentally, someone falls off their motorbike, comes to the emergency department, gets a scan because they hit their head and there's a brain tumor there. But usually a patient is presenting with symptoms, we do a scan and there's an awfully large, terrible tumor there. And so we don't have the opportunity to prevent, we are in a reactive mode, and that limits our options. Surgical options, radiation options, chemotherapy options, and clinical trial options.

The third challenge is, yes, we know a lot about the genetic makeup of glioblastoma. The old name for glioblastoma was glioblastoma multi forming, which describes for us not only how heterogeneous it looks under the microscope within a patient, let alone between patients, but the molecular genetic alterations can differ from patient to patient. And so our knowledge of the mutations in tumor suppressor genes and oncogenes is way ahead of the drugs or devices or techniques that we have available to test and to target those mutations.

Years ago when I attended a meeting of the Brain Tumor Cooperative Group, which was one of the original cancer specific cooperative groups, after a day of listening to scientists and representatives from pharma, several of us went to the bar in the hotel and we pulled out a napkin and we were able to identify a failed drug for every letter of the alphabet. I still have that napkin in my file cabinet. And here we are at least 20 years later with, as you mentioned, a much more comprehensive understanding of the genetic abnormalities, but not yet a penicillin or an insulin for this disease. And it's not for lack of trying, and thousands of scientists around the world coming up with brilliant ideas.

The other challenge is folks have tried to mimic glioblastoma in the lab, taking glioblastoma from a patient and putting it into a mouse and testing for mutations and drugs against it. Understanding the genetic mutations and trying to create those by gene editing in an animal. Trying to recreate the immune system in the human brain around a tumor in a lab. And so sometimes what happens is there looks to be a blockbuster drug or technique in a lab based on one of these models that when you apply it to patients in a clinical trial doesn't work. And it's because the model doesn't faithfully recapitulate what's going on in the patient's brain. So these are all the challenges we face.

Glen Stevens, DO, PhD:

So with Covid, one thing that we all learned was that it mutates, and we have a vaccine and I recently got my bivalent vaccine, the next one. I think this is something we didn't really appreciate enough early on in the treatment of high grade gliomas, that we would give a treatment and that the tumor would mutate. And that the tumor if somebody was alive two years later wasn't really necessarily the same tumor that it was two years before. I think we've moved a lot more to re-biopsying patients to really determine, but we didn't really do this a lot before. This is really a change as time goes on.

So I think we continue to learn, but it is a difficult foe to say the least. Why don't you just go through quickly for those individuals that are listening that aren't involved a lot in research, and maybe just briefly mention the function of a phase zero, one, two and three, maybe even four, clinical trial?

Mark Malkin, MD:

Sure. So working backwards, phase four is typically a trial that is done once the drug has received FDA approval and there is a post-marketing study typically in a very large number of patients. We don't see those often.

Phase three is a study which is done in a prospective, randomized, controlled, sometimes blinded or double blinded fashion, where one is comparing the current standard of care to standard of care plus the experimental drug or device or standard of care versus the experimental paradigm. Those trials to obtain statistical validity, to have the power to make a decision, yes, this is an advance, no, this is no different than what we've been doing, require typically hundreds of patients. Not thousands like were used in the development of the Covid vaccines, but typically hundreds of patients. And those are done within the context of cooperative groups and sometimes even internationally if we're talking about a rare primary CNS tumor like Oligodendroglioma for example, that's an international effort.

Phase two is a study that's done sometimes in a single institution which sees a lot of patients, like the Cleveland Clinic, or in several institutions. In a phase two study, which is typically done in patients whose tumor has failed standard therapy, a drug or device is used in a dose which is believed to be safe, and one is looking for what we call an efficacy signal. What proportion of patients with this condition, given this drug or device, have a response? However one measures a response. Overall survival, progression-free survival, shrinkage on an MRI, diminution of the metabolism on a PET scan.

And a phase one study is a study which is done to determine that phase two dose. The prime purpose of a phase one study is to determine safety and typically beginning at a very low dose and then if safe in a fixed number of patients ramping up the dose till you get what's called a maximum tolerable dose, or maybe if you're lucky you don't reach maximum tolerability and your top dose becomes the dose for phase two.

Phase zero is often incorporated within a surgical context where one has a drug and one gives it before diagnostic surgery in a situation where the MRI scan looks like a glioblastoma for example. And then at operation one is taking out tissue and one is measuring drug kinetics and drug dynamics and blood and spinal fluid levels. That helps give information to determine what should be the lowest dose in the phase one study.

Glen Stevens, DO, PhD:

The other benefit of that is, as we know, which we haven't really discussed, is the blood-brain barrier, and it can help us understand better is the drug getting to the brain, assuming that we can measure something that would be a byproduct of the drug itself. Because if a drug will not cross this blood-brain barrier, going to be hard for it to work.

Mark Malkin, MD:

Right. And so for decades literally folks have argued back and forth, is the problem developing more successful drugs, the blood-brain barrier, the thing isn't getting through, or is the problem intrinsic or acquired resistance to the drug, going to your point about how mutations happen over time. And I think the truth probably is a bit of both.

Glen Stevens, DO, PhD:

And I think you and I have probably both seen in our careers many times, we've both put many patients on clinical trials over the years that have unfortunately turned out to be negative trials. But what I always tell patients, and I think it's important for the listeners to understand, is that even if a drug isn't moved forward and found to be for a group of people, sometimes for given individuals within that clinical trial, it would appear that that drug was a really good drug for them. And I have many patients in my practice that I have followed for decades that we have treated on a clinical trial that for whatever reason it worked well for them. So I think that's kind of the carrot that dangles there at times, that you will have opportunity to have a treatment that you can't otherwise get. You can do the standard things out there, but you're going to have an opportunity to get something and it may work for you.

Mark Malkin, MD:

Right. And an excellent example of that is the discovery by a couple of Canadian colleagues of ours, Greg Cairncross and Dave McDonald who were looking in London, Ontario at their series of glioma patients who had been given chemotherapy over the years. And although overall there was no survival advantage to the group, there was a subgroup who clearly demonstrated a radiographic improvement and a clinical improvement that translated into very long survival when they were given alkylating agents. Back in the day, BCNU and CCNU. And those were the oligodendroglioma patients.

And then subsequently they with David Lewis at Massachusetts General figured out that this was due to an abnormality in the chromosome complement of those tumors, specifically co-deletion of the short arm of chromosome one and the long arm of chromosome 19. And that led to prospective randomized clinical trials that showed that if you added chemotherapy to radiation therapy in this subgroup, you doubled survival. Median survival went from seven to 13 years.

And so that's a prime example of how sometimes, yes, inexperience or in clinical trials, that the overall result of the trial may be negative, but there can be a subgroup in there with a specific mutation that gives us a clue how to at least pull them out and treat them specifically. And so the hope with the data from the Cancer Genome Atlas is meticulously and really pedantically one goes through mutation after mutation and try to find a subgroup that is going to respond to something.

Glen Stevens, DO, PhD:

Yeah, I'm really glad you brought up the oligodendroglioma story because it's the one that helps all of us brain tumor people continue to move on because they do so much better. And as you know, I did some of my training in London with Greg and David at the London Regional Cancer Center, and it's just fascinating to work with them.

It's also really interesting too, it's a good lesson if you look at their data of their anaplastic gliomas that some of them had chromosomal deletions and some of them didn't. And probably some of them were really glioblastoma patients. But when they tracked those patients out and they separated out the patients that had the 1P19Q code deletion from the other group, the graphs really on the Kaplan Meier survival curves coursed very similar up until about seven years or so. And then that's when they dispersed.

And the lesson there is that if we just stopped following patients at seven years, we never would've figured it out. We would've said no difference. And that's the break point and the inflection point. And it's interesting that you mentioned the 13 years, because they've continued to publish on that old RTOG trial that then went to 15 years. And as they continue to follow, 15 will become 16, 16 will become 18, who knows where the endpoint is in these patients as it goes through. So I think it's fascinating and keeps us all going.

Mark Malkin, MD:

Right. And I tell my patients when I first meet them that we're never going to stop following you. They need the care, their caregivers need the care, and we really need to know what the natural history is. One doesn't learn natural history as a medical student or as a resident coming to do an elective for a week, or even as a fellow for one or two years. You need to be doing this as long as we've been doing this to see that.

Glen Stevens, DO, PhD:

Yeah, and I tell my patients the same thing. The cowboy analogy that you maybe have heard before is all hat and no cattle, and we need to get the treatments that are going to be more effective. Right now, we're all hat. We understand so much about the molecular, we can draw it out. We can show all the mutations. The problem is there's so many, if you block one pathway, they go down one of 32 other pathways.

Mark Malkin, MD:

Right, it's whack-a-mole.

Glen Stevens, DO, PhD:

Yeah, it's whack-a-mole. It has been the process as we go through. So you've talked about a lot of the challenges. You've talked about some of the difficulties with the treatment of these tumors. Where do we go?

Mark Malkin, MD:

So we start with collaboration. Lots of individual smart people with what appear to be brilliant ideas haven't individually been able to crack this nut. And so we need to build teams of teams. We need within our institutions for clinicians to be taking problems from the bedside to the bench, to our lab science colleagues, and them bringing something back that we can test in clinic.

We need to also involve and take advantage of the discoveries of our colleagues in pathology and the molecular pathology and the mutations. And also of the huge advances in imaging and big data and artificial intelligence. We are getting to the point that my colleague Phil Gutin, who was the chair of neurosurgery at Memorial Sloan Kettering Cancer Center when I was there, stated now more than a decade ago, almost 15 years ago, which is neurosurgery will become a specialty that puts things into the brain and not just taking things out of the brain.

And we are getting to the point with advanced imaging and artificial intelligence that we can tell on an MRI scan whether a tumor is IDH wild type or IDH mutated. And that's important, because the IDH mutated tumors tend to have a better prognosis. Being able to diagnose without a biopsy is very cool, and presumably one can follow response to therapy without a biopsy. One needs supercomputers and big data to look at the genome of an individual tumor to try to pick out what mutations might be driver mutations, what we call trunk mutations from all of the other background noise. That will help focus the laboratory effort on important mutations and not be distracted from the other stuff, the secondary stuff.

We need more advocacy for patients with brain tumors. We need advocacy on the level that the breast cancer community has advocacy. They've figured this out with the Susan Coleman Foundation really, really well. And yes, it really helps that the tragic circumstances that surround the Biden family with Bo are leveraged by someone who's now our president, who has the ability because of his position to move things forward like the Moonshot initiative. More advocacy means more visibility and ultimately means more funding.

And doing clinical trials costs a lot of money. So I'll give you an example. When I was at Virginia Commonwealth University Massey Cancer Center, we did a phase one study in recurrent malignant glioma repurposing a multiple sclerosis drug, dimethyl fumarate. Why? Because the microglia that surrounded glioblastoma are themselves malignant, just as they are inflammatory in relapsing remitting MS. And we thought that a higher dose, actually, than the MS dose might be effective.

And so we did a very simple over 17 months, 12 patient study of low dose, medium dose, and high dose dimethyl fumarate and showed that it was safe, and we didn't have any funky infectious complications by lowering the lymphocyte count. It cost $250,000 just to do the study, let alone the cost of the drug, which was supplied to us by Biogen, the manufacturer. And that's a 12 patient study. So in order to get to those phase three studies, when you have an effective drug, it costs a lot of money. If we had gone forward with, let's say your standard 40 patient phase two study, because we determined the drug was safe, it would've been two to 3 million. Lot of money for a single drug.

Glen Stevens, DO, PhD:

Well, Mark, two old Canadians are sitting here gabbing, and our time seems to be gone. I'll just close with two better stories. One, just recently did a podcast with Dr. Lobas. And again, these are different types of tumors, but in the neuro-oncology field. And the FDA released the first drug for treating plexiform neurofibroma, selumetinib, which is a MEK inhibitor, with some very nice responses. So this is great news.

And the other one, which is the bane of a lot of the neurosurgeons is belzutifan, a drug used for treating hemangioblastomas in patients with Von Hippel-Lindau disease. And these patients get exhausted by surgeries, and this drug is showing a nice benefit. So some of the other types of cancers I want the listeners to understand, we are making strides. The efforts are not for loss. But we all need to work harder. I love your point about the grassroots initiatives, and it really takes the community to move forward to really drive the funding for these types of things. So I'm really happy to have you here today and share with our audience your thoughts, and look forward to continuing to work with you.

Mark Malkin, MD:

Thank you. Thank you.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.