1. DiGiulio, Sarah

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The Ivy Brain Tumor Center at the Barrow Neurological Institute is a nonprofit center conducting early phase clinical trials of new therapeutics for brain tumors. More specifically, the center is focusing on phase 0 clinical trials to measure penetration of new drugs and drug combinations to the central nervous system by the blood-brain barrier. "It's widely considered the most significant problem in drug development for brain tumor patients: Is the drug actually hitting the target the way it was envisioned to hit the target based on pre-clinical evidence?" explained Nader Sanai, MD, Chief Scientific Officer and Director of the Ivy Brain Tumor Center.

Nader Sanai, MD. Nad... - Click to enlarge in new windowNader Sanai, MD. Nader Sanai, MD

The center has been open since 2017 and has 17 different molecules and new drug combinations in its pipeline. The center is doing the highest number of brain tumor operations in the U.S. In an interview with Oncology Times, Sanai explained how the phase 0 trials work and why the center is so excited about them.


1 Can you explain how the phase 0 trials for brain tumors work?

"Phase 0 trials are [when] you're exposing the patient to a small amount of the drug prior to a tissue acquisition procedure-or in this case, a craniotomy for a tumor resection. These trials enable you to assess the pharmacokinetics, or drug penetration, of the drug in the brain tumor, as well as the pharmacodynamics or target modulation of the drug.


"So when a patient comes to our center with a recurrent glioblastoma-and in those patient populations there really is no standard of care for how to treat that patient-that patient will get matched to a drug or drug combination in the pipeline. They'll get exposed to that drug or drug combo (about a week) prior to the planned operation. And then within a week after that operation, we will be able to assess whether that drug actually penetrated that patient's tumor and hit the targets in that patient's tumor.


"If the answer is yes, then the patient goes on to get treated therapeutically with the drug. If the answer is no, then the patient has not lost any time and has not been placed into a trial with no potential benefit for them.


"In traditional trials, the patient is in some way identified as a candidate for the trial and they have a discussion with their oncologist and get put on the experimental drug long-term-for brain tumor patients, they get imaging typically every 2 months. If and when that imaging starts to look like tumor recurrence, that's when the determination is made that the drug is no longer effective or was never effective.


"Typically [at this point] at recurrence, patients can measure their expected survival in a matter of months and you're asking them to take a drug on faith and then hope that in 2 months they're getting a positive result. And in most cases they don't.


"So what we're trying to do here is really shorten that window for the patient and try to get them on an agent or a combination of agents where we have some tangible evidence that the drug or drugs are going to do something within their particular tumor."


2 Are the patients getting a drug any earlier in the drug development process? How do you know the drug will work in that short time period and it will be safe?

"When we accept a drug into our pipeline, it's usually after a fair amount of diligence has been done on our part in understanding whether these uses are appropriate for that drug. What if you have a drug where you have to give it theoretically 2 months before you could detect whether it's working? How will that work in a study design where you're only giving it to a patient for several days?


"The answer is those are drugs we don't pursue for these types of trials. A drug that takes a very long time to reach penetration of the brain is not an optimal drug for patients with brain tumors.


"These studies are designed to identify drugs or drug combinations that clearly have clinical potential, drugs that deserve to be accelerated in the drug development space and in this patient population. We have drugs in our pipeline that are first in human. And we have drugs that are already FDA-approved for other indications-other cancer types that we're now re-positioning for brain cancer. So it might be the first time a brain cancer patient has gotten the drug, but it's not the first time a patient has gotten the drug.


"In all our studies, we look at safety and adverse events. With any clinical trial, there's risk to the patient population. We try to minimize that risk in these types of trials because the patients oftentimes are getting one or just a handful of doses prior to surgery. So with such a low exposure to an experimental therapeutic, the risks to the patient are lower than if they were in a study where they had long-term dosing.


"That being said, for patients who demonstrate a pharmacodynamic or pharmacokinetic response, they do go on to long-term dosing. But we feel that's exactly the population where that type of risk you see in every clinical trial is justifiable because those are patients [with] biological evidence that there's drug effect in their particular tumor."


3 What is the takeaway message about the phase 0 clinical trials you're working on?

"What our studies and programs offer patients that is 1) the unique kind of study design where, if you're on an experimental agent in one of our trials, you have the confidence of knowing that you're on that agent because in your particular tumor there is direct evidence that drug is doing something. And 2), our pipeline is growing with new agents and drug combinations that simply haven't been tested in this patient population before.


"We hear a lot about precision medicine and personalized medicine in the oncology space, but that's really predicated on a scenario where you have multiple agents that have been proven effective and you're trying to choose the right one. And for brain tumor patients we're unfortunately not in that position yet.


"So from our perspective, these trials are about as close to precision medicine as you can get within this space, where you identify based on genetic factors a patient's theoretical susceptibility to a drug or drug combination, and then you actually test that proof of principle in the patient themselves before you expose them to the drug long-term. So we think that this is a very effective way to actually test the many hypotheses that are out there in terms of the biology of these tumors and the pharmacology of new drugs.


"The easiest way to bring patients to our attention whether you're a patient or provider is through the website portal ( We enable the physician or provider to upload relevant imaging data and commit to a 48-hour review cycle for any submitted patient candidate, and then we get back to the provider or patient directly about their eligibility for studies."