When the FDA introduced Phase 0 trials in 2006, the goal was to learn more about new drugs without exposing subjects to their full, potentially toxic, effects. In a traditional Phase 0, subjects take a subtherapeutic dose of an experimental drug, usually for no more than a week, prior to a standard Phase I study.

The neuro-oncology field has developed its own type of Phase 0 study, also known as a “window-of-opportunity” trial. Under this design, patients receive a full therapeutic dose of a drug, also typically no more than a week, before a scheduled tumor resection surgery.

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After tumor resection, researchers can measure whether the drug penetrated the blood-brain barrier and reached the desired target, which brain cancer candidates often fail to do. For tough-to-treat conditions like glioblastoma (GBM), window-of-opportunity trials can prove an invaluable tool.

Traditional Phase 0s reveal more data earlier

In a Phase 0 trial, sponsors can more quickly learn about a drug’s pharmacokinetics (PK) in humans with reduced manufacturing and toxicology costs, explains Phase 0 consultant Dr Tal Burt. Phase 0 trials often use micro-doses, so drug sponsors can go straight to gathering PK data in patients rather than healthy volunteers, he adds.

In addition, Phase 0 studies can also gather PK data in more vulnerable populations traditionally excluded from Phase I, such as children and pregnant women, Burt notes.

Clinically speaking, a micro-dose is 100 milligrams or one one-hundredth of the estimated therapeutic dose, whichever is smaller. Phase I trials normally enroll healthy volunteers because they use higher doses than a micro-dose.

Phase 0 trials can help drug sponsors improve their preclinical selection process. If a company is choosing between several preclinical candidates, a Phase 0 trial could gather early human data for all candidates in a relatively cheap way, Burt explains. Similarly, if a drug candidate has conflicting animal data, a Phase 0 trial could provide an early look in humans before a company invests in a full-scale Phase I program, he adds.

Nevertheless, Phase 0 trials could delay the timeline to entering Phase I, prolonging the development of effective drugs, Burt notes. There are also concerns with extrapolating data from micro-dose trials, challenging radiolabeling, and changing analytical standards, Burt’s research has noted.

But overall, Phase 0 studies give companies the chance to eliminate bad drug candidates earlier in the process, which can ultimately save time and money. As Burt puts it: “Kill early, kill cheap.”

A window of opportunity in neuro-oncology?

In neuro-oncology, micro-dosing does not work because most drugs struggle to penetrate the blood brain barrier, explains Dr Michael Vogelbaum, PhD, Chief of Neurosurgery at Moffitt Cancer Center. As a result, the field developed its own version of Phase 0 trials, he says.

In a window-of-opportunity trial, a patient with a scheduled tumor resection surgery receives a therapeutic dose of a drug candidate prior to the surgery, Vogelbaum says. If analysis of the removed tumor indicates the drug did not enter the blood brain barrier or achieve target modulation, the patient stops taking the drug. But if the drug successfully did so, the patient can continue taking the therapeutic agent in a Phase II setting, since brain tumors are almost always recurrent.

Typically, patients are matched to a drug candidate based on their genetics and receive it for three or four days prior to surgery, explains Shwetal Mehta, PhD, COO of Ivy Brain Tumor Center, a non-profit running Phase 0 trials in GBM. Most drug candidates for neuro-oncology Phase 0 trials have previous safety data in other indications, she adds.

In neuro-oncology, animal models are much weaker approximations than for most other cancers, heightening the need for earlier PK data in humans, Mehta says. Phase 0 trials can help bridge that gap, eliminating ineffective drugs earlier in the process for patients with limited time to wait, she adds. If a drug does not work in a patient, the patient can quickly enroll in another trial, she notes.

In GBM, there have been many drugs that cure brain tumors in animal models that do not translate to humans, she adds. There are no widely effective treatments for GBM, and the median survival is an estimated 12-16 months.

In GBM, novel Phase 0/II designs could streamline the drug development process for a notoriously difficult-to-treat disease. But what's stopping sponsors from using this trial design?