Baptist Health Miami Cancer Institute is leading a groundbreaking clinical trial that is studying the use of a new medication combined with stereotactic radiosurgery to combat metastatic brain cancer. The aim is to unveil innovative therapies capable of diminishing tumors and preventing the brain inflammation that can follow radiation therapy, as well as potentially protecting neurocognitive function.

At the forefront of this trial is a promising agent, azeliragon. It’s hoped that the oral drug will inhibit cancer cell growth and help overcome resistance to radiotherapy.

“The study is the first of its kind in the world,” says radiation oncologist Rupesh Kotecha, M.D., chief of radiosurgery and director of the Central Nervous System Metastasis Program at the Institute. Dr. Kotecha is the trial’s principal investigator (PI). “This is an exciting new combinatorial regimen. In patients with brain metastasis treated with radiotherapy, it has the potential to overcome cancer’s resistance pathways and improve response rates. Importantly, it also has the promise of protecting against inflammation.”

Each year, between 200,000 and 300,000 patients are diagnosed with brain metastases in the U.S. It occurs when cancer cells from a patient’s primary tumor site travel through the blood or lymphatic system to the brain. The most common primary cancers that metastasize to the brain are lung, breast, melanoma and kidney cancers.

A particularly challenging disease entity to treat, brain metastasis is typically treated with a combination of therapies meant to extend life and improve quality of life while managing the disease - rarely curing it. Patients may undergo surgery, chemotherapy, stereotactic radiosurgery, whole-brain radiation therapy, molecular targeted therapies and immunotherapies, or, often, a mixture of therapies.

Azeliragon was originally researched for its benefits in treating Alzheimer’s disease. While the drug was well-tolerated by patients, it did not slow cognition loss and studies were halted. In several preclinical cancer trials, researchers have determined that the drug may help mediate against radiation resistance, protect against neuroinflammation and preserve neurocognitive function.

In 2023, the FDA approved azeliragon for the treatment of glioblastoma, the deadliest and most common brain cancer in adults. “It was never tested, however, in combination with radiosurgery, Dr. Kotecha explains. “We are investigating this as a new drug application in our Phase I/II study.” 

Yazmin Odia, M.D., chief of neuro-oncology at Miami Cancer Institute and co-PI of the trial, states, “Whether the well-tolerated oral medication azeliragon has the potential of simultaneously protecting normal brain while enhancing cancer response to brain-directed stereotactic radiosurgery is of great importance to patients and treating physicians alike.”

The rapid development of stereotactic radiosurgery in the past decade has made it possible for patients to receive a high dose of radiation precisely to the tumor in one sitting, sparing important nearby brain structures. The non-invasive procedure can be completed in less than one day for many patients.

The study, “A Phase I/II Study to Assess Safety and Preliminary Evidence of a Therapeutic Effect of Azeliragon Combined with Stereotactic Radiation in Patients with Brain Metastases,” (ADORATION), requires patients to take two doses of azeliragon a day for six days prior to radiation therapy. Following radiation, patients take one pill a day for at least eight weeks but may continue on the medication longer if well-tolerated. Patients are regularly assessed and visit the Institute for routine surveillance throughout the study.

The phase I trial will help determine the maximum dosage of the medication to be given with radiosurgery safely, while also tapering corticosteroids, while the phase II trial is designed to determine effectiveness in terms of protecting against neuroinflammation, lessening a tumor’s chance of becoming resistant to radiation, reducing tumor size and maintaining or improving quality of life.

Doctors are also hopeful that with the protection of azeliragon, they can lower the dose of corticosteroids most patients receive. Corticosteroids can have side effects such as high blood pressure, diabetes, mood changes and osteoporosis, and can make some people more vulnerable to infection.

“Another benefit of this drug is that it can be used as an addition to a patient’s systemic therapy,” Dr. Kotecha says. “This means that if they are receiving chemotherapy, immunotherapy or targeted therapy, for example, it can also be used. That’s important because patients with brain metastases often progress from one therapy to another. We won’t have to stop treatment if other medications change.”

Lissette Gonzalez of Coral Gables was the first patient enrolled in the trial. Diagnosed with lung cancer in 2022, she soon found out that the cancer had spread to her brain. “I love to help people, so if what I do now helps other patients in the future, I am happy,” said Ms. Gonzalez, an optimist with a big heart. She has experienced no side effects from treatment and hopes that her next MRI shows that her tumors are shrinking.

Miami Cancer Institute participates in and leads a number of clinical studies for patients with brain metastases. “We are much better able to tailor treatment to the individual now, based on the molecular makeup of their tumor,” Dr. Kotecha says. “The more we learn, the more we are able to move the needle on survival and on improving quality of life for our patients.”