HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
April 10, 2019
4 min read

Phase 0 trials ‘quickest route’ for development of glioblastoma treatments

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Photo of Nader Sanai
Nader Sanai

Ivy Brain Tumor Center at The Barrow Neurological Institute has launched a program that offers phase 0 trials to accelerate the drug approval process for patients with glioblastoma.

“Phase 0 trials are the quickest route to identify individualized strategies for treating glioblastoma, and our approach demands only a fraction of the time and costs associated with traditional drug research and development,” Nader Sanai, MD, neurosurgeon at Barrow Neurological Institute and director of the brain tumor center, said in a press release.

In phase 0 trials, nontoxic drug doses are administered for short periods to a small cohort of patients. The goal is to obtain pharmacokinetic and pharmacodynamic data at the initial stage of the clinical trials process.

In addition, molecular profiling of tumors in phase 0 trials may offer insight to refine or accelerate development of drugs for patients with glioblastoma.

HemOnc Today spoke with Sanai about the origin of phase 0 trials, how they work, what they are designed to accomplish and why this may be a worthwhile strategy for glioblastoma.


Question: How did the concept of phase 0 trials come about?

Answer: The FDA developed phase 0 trials in 2004. We needed ways to test new drugs earlier and not allow certain drugs to go through subsequent phases when they clearly had challenges that were not going to be overcome. At the same time, we needed to identify promising drugs and accelerate their development. Our focus has been to translate this new phase 0 mechanism to patients with malignant brain tumors.


Q: How do they work?

A: In a traditional trial, patients qualify based on clinical or biological characteristics of their tumors, then enroll in a study and are treated with a drug for several weeks, months or longer. Then we look at imaging to see how patients are faring. In a phase 0 clinical trial, we look for the biological context. Before a planned operation to remove a brain tumor, for example, the patient is matched to an investigational drug and receives a very small exposure to the drug. This exposure is enough that when we remove the tumor, we can ask two important questions. Did the drug penetrate the tumor, and did it modulate the intended target based on how it was designed for this specific tumor and patient? These are the top two reasons investigational drugs fail, particularly for patients with malignant brain tumors. If the answer is ‘yes’ to both of the questions, the patient receives the drug therapeutically for a longer period of time, so we can see the clinical effects in the context of what we know to be its biological effects.


Q: Why might this be a worthwhile strategy for glioblastoma?

A: Glioblastoma and other malignant brain tumors are widely considered to be the deadliest tumors. At the same time, they are the most challenging tumors for developing new drugs. During the past 30 years, the FDA has approved only five drugs for malignant brain tumors. When comparing this to the 60-plus agents approved for lung cancer, we can see the different track records.

There are two primary barriers. The first is that most new drugs have an extremely difficult time getting into the brain tumor. The second is that drug development usually relies on laboratory studies to see which drugs hold the most promise. Those that do go on to be tested in humans. But in neuro-oncology, we have very limited animal models and preclinical systems to test a drug’s effectiveness that reliably give us an indication for what is going to happen in human disease. Phase 0 trials effectively humanize the preclinical models and allow us to ask critical questions because we know that each tumor can be slightly different from another. This heterogeneity is not something that can be easily modeled in a laboratory.


Q: How many patients have undergone treatment with this approach, and w hat results have been observed?

A: To date, we have enrolled more than 120 patients in phase 0 trials investigating new agents for malignant brain tumors. These trials have been for glioblastoma, aggressive meningiomas and brain metastases. They have all used first-in-class agents to try and target these tumors. For some of these agents, we have learned that in spite of other correlative data suggesting the drug penetrated the brain, we see definitive evidence that it has not. We published those results and communicated to the scientific community that the agent is not likely to have promise within the malignant brain tumor population. For other agents, however, the exact opposite has been true. In contrast to recent preclinical data, our phase 0 study of the Wee1 inhibitor AZD1775 (AstraZeneca) in recurrent glioblastoma, published in Clinical Cancer Research, showed good human brain tumor penetration, provided the first evidence of clinical biological activity in human glioblastoma, and confirmed the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma.


Q: Is there anything else that you would like to mention?

A: Phase 0 trials are very resource-intensive and require a high degree of coordination at the clinical trial level. In medical oncology, a phase 0 trial can include a patient with lung cancer who gets a needle biopsy Monday, a single pill of an experimental drug Tuesday, and another needle biopsy Wednesday. This can provide the information that is needed, but for patients with brain tumors, it is far more complicated. This is why we needed to create a center dedicated to this type of pharmacodynamics-driven clinical trial mechanism. The Ivy Brain Tumor Center in Phoenix is the highest-volume operative brain tumor center in the United States. With approximately 1,300 brain tumor operations per year, and because we have an infrastructure customized for this type of work, we can open multiple trials in parallel and go through as many new drug actions as possible, avoiding redundancies with previous studies. This is an exciting new direction for the field and for patients with brain tumors. – by Jennifer Southall


Sanai N, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-17-3348.

For more information:

Nader Sanai, MD, can be reached at Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013; email: nader.sanai@barrowbrainandspine.com.

Disclosure: Sanai reports no relevant financial disclosures.