Phase 0 trials can reveal valuable data on experimental drugs for glioblastoma (GBM), a notoriously tough-to-treat brain cancer. But so far, pharma has been reluctant to adopt.

In a Phase 0 study in neuro-oncology, also known as a “window of opportunity” trial, patients receive therapeutic dosing of a drug candidate for a few days prior to tumour resection surgery. Patients only continue treatment if resection samples show that the drug penetrated the blood-brain barrier or achieved target modulation.

While the Phase 0 study design has advantages, pharma companies have historically shown limited interest in this approach, owing to concerns that Phase 0 studies may prolong the drug development process. Nevertheless, there has been a slight recent uptick in Phase 0 studies in GBM as more sponsors get on board.

“Many drug companies and their leadership are starting to understand that developing drugs in the central nervous system is a lot harder than developing them in the rest of the body because of the unique issue of drug delivery,” explains Dr Michael Vogelbaum, PhD, Chief of Neurosurgery at Moffitt Cancer Center. “We are starting to see some more interest in Phase 0 trials, and that is fortunate.”

According to GlobalData’s Clinical Trials Database, there were no Phase 0 trials for GBM initiated in 2012, compared to 20 Phase I and 12 Phase I/II trials. A decade later, 2021 saw five Phase 0 trials in GBM, accounting for 17% percent of the 28 early-phase trials initiated. GlobalData is the parent company of Clinical Trials Arena.

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Institutions ahead in Phase 0 glioblastoma trials

In the limited Phase 0 trials for GBM, institutions have been leading the charge. Institutions have run 84% of all Phase 0 GBM trials in the past 10 years, compared to 58% of Phase I studies and just 39% of Phase I/II trials, the database shows.

The Ivy Brain Tumor Center, a non-profit institution with the largest GBM Phase 0 program in the world, has successfully worked with pharma through agreements posing limited risk to sponsors, explains COO Shwetal Mehta, PhD. Under these contracts, sponsors provide the drug for a Phase 0 trial but keep intellectual property rights, in exchange for agreeing that the center will publicly publish all data, she adds.

Moffit’s Vogelbaum says he usually has to approach drug companies about pursuing Phase 0 designs, but there have been some recent exceptions. For example, Celgene, a subsidiary of Bristol Myers Squibb, recently approached Vogelbaum’s team about pursuing a window-of-opportunity trial for one of the company’s drugs.

In addition to industry sponsors, Phase 0 trials need to garner support from neurosurgeons to make the design more prevalent, Vogelbaum adds. It’s a matter of training neurosurgeons to understand that performing surgery in the context of drug development is both safe and valuable in the overall care of a patient, he explains.

New Phase 0 designs in glioblastoma

Almost any GBM drug can be studied in a window-of-opportunity trial, as long as it is safe to do surgery, Vogelbaum says. Drugs with anticoagulant properties or drugs that interfere with healing, for example, would not be good candidates, he notes.

As for Phase 0 dosing, it can vary based on the half-life of the drug, ranging from a few days to a few weeks, adds Dr Patrick Wen, neuro-oncologist at Brigham and Women’s Hospital. But patients only enter Phase 0 trials when they have an immediate need for a surgery, so they cannot be dosed for a month or longer, he notes.

Shwetal Mehta, PhD, COO of Ivy Brain Tumor Center

Because most Phase 0 trials in GBM are for drugs with established Phase II doses, these window-of-opportunity trials can be combined with Phase II designs. Most Phase 0 trials at the Ivy Brain Tumor Center give patients the opportunity to continue dosing post-surgery in an expansion Phase II component if the drug delivers positive Phase 0 data, Mehta says. Currently, the center is running a Phase 0 trial with an undisclosed CDK 4/6 inhibitor for meningioma that could move directly into a randomised Phase II or Phase III trial, pending forthcoming data, she notes.

Alternatively, a Phase I or Phase II GBM trial can have a separate cohort for window-of-opportunity arms, as seen in some more recent trials, Vogelbaum notes. In this model, a conventional Phase II trial would have a subset of patients that underwent pre-surgical dosing, serving as a reference for the biological impact of the experimental therapy, he explains.

As one example, Vogelbaum is working with OncoSynergy for a Phase I trial (NCT04608812) in GBM involving elements of this approach. The trial studies OS2966, a monoclonal antibody targeting integrin beta1.

What happens next?

Looking ahead, Vogelbaum wants Phase 0 approaches to become more routine, and not just for drugs. This approach could apply to immunotherapies, including checkpoint inhibitors, determining how they act on solid tumour tissue and the brain’s resistance mechanisms, he says. Even though these therapies are unlikely to penetrate the blood-brain barrier, they could still alter aspects of physiology that in turn impact tumours in the brain, he notes.

The Ivy Brain Tumor Center is getting involved in liquid biopsy approaches to monitor patients’ cerebral spinal fluid (CSF) regularly while they are on therapeutic dosing in Phase 0 studies, Mehta says. This could bolster Phase 0 trials and help determine why some drugs that do successfully penetrate the blood-brain barrier have not translated to clinical effectiveness, she explains.

Both Mehta and Vogelbaum agree that the field is likely to see a considerable increase in Phase 0 window-of-opportunity trials in the coming years. However, Wen notes future advances in brain imaging could spell a decline in window-of-opportunity trials in the long term.

Sophisticated molecular imaging, Wen says, could determine whether drugs penetrate the blood-brain barrier and achieve target modulation in a non-invasive way, but these advances are likely around 10 years away, and Phase 0 trial use will likely rise in GBM until then, he adds.

In the end, experts see Phase 0 designs as a tool to help patients get better treatment options for a devastating disease. GBM has a median survival of just 12–16 months, and no widely effective treatments, leaving a glaring need for new clinical trial strategies.

“Brain tumours, and especially glioblastoma, are a big challenge for the clinical field,” Mehta says. “We haven't changed the survival rate for three or four decades.”


  • Despite advantages to a Phase 0 trial design, especially in GBM, uptake of this approach has been low. Institutions are mainly responsible for initiating most recent trials.
  • Phase 0 trials in GBM can combine Phase I or Phase II elements, using novel designs ranging from Phase II expansion cohorts, Phase 0 subsets in traditional trials, or even combinations with large-scale, randomised Phase II or Phase III studies.
  • Phase 0 GBM trials could extend to immunotherapies, even though they are unlikely to cross the blood-brain barrier. Advances in liquid biopsies could strengthen Phase 0 trial use in the short term but advances in non-invasive imaging could cause them to decline in the longer term.