By Maxine Bookbinder

April 2, 2015 | The Phoenix-based Translational Genomics Research Institute (TGen) and Barrow Neurological Institute at Dignity Health St. Joseph’s Hospital and Medical Center are undertaking innovative Phase 0 trials, incorporating drug candidates, surgery, and genomic sequencing to test new therapies to treat glioblastoma brain tumors.

“Glioblastoma multiforme (GBM) is one of the top three fastest-killing cancers and affects people of all ages,” says Catherine Ivy, founder and president of The Ben & Catherine Ivy Foundation, formed in 2005 after Ben Ivy died from GBM. “It is critical that we fund research that will help patients live longer so we can study and treat brain cancer.” The Foundation has contributed more than $50 million to glioma research in North America.

Because of the limited number of diagnosed patients yearly – approximately 11,000 -- no drugs have been developed specifically for glioblastoma. Dr. Michael Berens, PhD, deputy director of research resources and professor of the Brain Tumor Unit at TGen, a non-profit medical research institute focused on treating patients with cancer, neurological disorders, and diabetes through translational research, hopes to change that.

Phase 0, also called exploratory Investigational New Drug (IND) studies or micro-dose trials, are early-phase I clinical trials designed to use single, low dose investigational drugs to accelerate the drug approval process, and to provide new therapies for future patients. The concept began as a result of the FDA’s 2004 Innovation or Stagnation, Challenge and Opportunity on the critical Path to New Medical Products,  which called for new tools to streamline the initial process of differentiating promising vs. failing products. Then, in 2005, the agency published Guidance for Industry, Investigators, and Reviewers, which states that IND trials are less extensive than traditional trials, will reduce time and money spent on drugs unlikely to succeed, and will enable sponsors to move more efficiently with promising drugs. 

Phase 0 trials can be used for any illness and sometimes use healthy participants. The primary purposes are to test drug efficacy rather than therapeutic benefit and to determine if a drug’s pharmacodynamics merit further testing.  Since Phase 0 trials use low doses, the drugs pose no lethal harm to patients. Early in the testing process, phase 0 trials can eliminate drugs that don’t meet basic requirements, saving time and money.

All experimental drugs in Dr. Berens’ study have already been proven safe in other cancers and are FDA-approved, but have not yet reached market. All protocols have been approved and no IRB challenges have been raised. “We have a very strong team in place,” says Dr. Berens. His study patients all have brain tumors and would have had surgery regardless of trial participation.

In the TGen study, tumor analysis reveals whether the drug reaches the tumor, how long the drug remains in the body, and whether the cancer cells respond to the drug. “The end point is, does the drug get to the tumor?” says Dr. Berens. “How fast? How long does it stick around? Does it stay in the tumor the right amount of time? And, is there evidence the tumor is responding to the drug?”  

Trial participants are given a drug. Then, within 2-24 hours, neurosurgeons at Barrow Neurological Institute remove and test their tumors to determine if the drug crossed the blood brain barrier, reached the tumor and if so, to what effect. If the drug results in tumor activity, the patient then moves to Phase II. If not, the patient can enter other trials. 

Surgery allows investigators to access tumors, which is necessary to determine whether they are vulnerable to specific drugs and at what dosage. “We can take the tumor and profile it,” says Dr. Berens. For example, investigators can home in on cancer cell response to WEE1 inhibitors and at what specific dosage.

Each phase 0 clinical trial tests one drug, says Dr. Berens.  “The goal is to run multiple Phase 0 clinical trials in succession, and eventually in parallel, in hopes of finding an effective drug that works on individual patients in “real-time” for use in treatment after the tumor is removed.”

Genomic information on the patient’s tumor is evaluated once all tumor specimens have been collected.  Certain cancer-associated genes will be sequenced in both the patient’s blood and tumor DNA.

Dr. Berens’ research does not exclude other trial designs, but centers around Phase 0 because “they bring new agents into use for brain tumor patients.”  A problem in brain tumor treatment is finding drugs capable of penetrating the blood-brain barrier, which buffers the brain from the blood circulatory system, protects the brain from rapid changes in metabolic conditions, and minimizes exposure to molecules that are toxic to brain neurons.  This study tests drugs that travel behind the blood-brain barrier. “No other clinical trials are designed to do that. We are encouraged by what we have seen so far.”

TGen’s successful Phase 0 trials may accelerate the pace of bringing new drugs to glioblastoma patients from five years to approximately six months, reducing costs in the process, says Dr. Berens.

It is anticipated the full Phase 0 trial will include a total of 24 patients to study dosage effects and the persistence of the drug in the tumor. But research is not limited to Phoenix; glioblastoma drug development can accelerate if additional institutes, “either through imitation or collaboration,” expand Phase 0 studies nationwide. Successful teams will include a convergence of dedicated neurosurgeons, genomic scientists, pharmaceutical companies willing to put drugs into testing, and funding sources, including philanthropic donors. 

Dr. Berens is particularly encouraged by increased interest in genomics and individualized therapies. “When President Obama announced his Precision Medicine Initiative in January, I said, ‘Hallelujah!’ Another voice in the wilderness. TGen has been saying it for nine years.”