First-in-human Study to Determine Effectiveness of Novel, Non-invasive Therapy for Brain Cancer

Featured Image: Nader Sanai, MD, (right) the director of the Ivy Brain Tumor Center and a neurosurgical oncologist who has been internationally recognized for his clinical expertise and research efforts dedicated to the treatment of brain tumors. Photo courtesy: The Ivy Brain Tumor Center at the Barrow Neurological Institute.
Featured Image: Nader Sanai, MD, (right) the director of the Ivy Brain Tumor Center and a neurosurgical oncologist who has been internationally recognized for his clinical expertise and research efforts dedicated to the treatment of brain tumors. Photo courtesy: The Ivy Brain Tumor Center at the Barrow Neurological Institute.

The Ivy Brain Tumor Center at the Barrow Neurological Institute and SonALASense have signed an strategic agreement to jointly test a new and non-invasive drug-device combination, called sonodynamic therapy or SDT, for the treatment of recurrent glioblastoma.

The study, announced during the annual meeting of the Society for Neuro-Oncology (SNO) being held November 20 – 24, 2019 in Phoenix, AZ, is a first-in-human phase 0/2 clinical trial to assess safety and effectiveness of a new, non-invasive drug-device combination for the treatment of recurrent glioblastoma.[1]

Sonodynamic therapy (SDT) is a proposed form of treatment using drugs that only become cytotoxic upon exposure to ultrasound. This approach was developed as a novel promising noninvasive approach derived from photodynamic therapy (PDT). The major difference between SDT and PDT is the energy source used to activate the sensitizers (ultrasound versus light).[2]

In addition to the sonodynamic therapy (SDT) study, results from two other clinical trials will be presented by Nader Sanai, MD, the director of the Ivy Brain Tumor Center and a neurosurgical oncologist who has been internationally recognized for his clinical expertise and research efforts dedicated to the treatment of brain tumors.

Phase 0/2 Clinical Trial
SonALAsense, a clinical-stage pharnaceutival company, and the Ivy Brain Tumor Center, a non-profit translational research program employing early-phase clinical trial strategies to identify new treatments for aggressive brain tumors, including glioblastoma, are collaborating with Insightec®, the innovator of Magnetic Resonance-Guided focused ultrasound (MRFUS), to adapt its technology for use at non-thermal energy levels in combination with SonALAsense’s proprietary formulation of 5-aminolevulinic acid (ALA) for the treatment of glioblastoma.

By adapting the Ivy Center’s Phase 0/2 clinical trial model, SonALAsense’s ALA drug will be administered intravenously, metabolized exclusively by glioblastoma cells, and accumulated as a fluorescent metabolite protoporphyrin IX. This tumor metabolite is then stereotactically activated using Insightec’s MR-guided focused ultrasound which results in reactive oxygen species that are lethal to every tumor cell.

This combination of metabolic targeting by ALA and activation by non-invasive focused ultrasound represents an innovative potential new therapeutic modality for glioblastoma patients. This novel technology is called ALA sonodynamic therapy.

Early development
Preclinical studies of ALA sonodynamic therapy have shown promise and, by evaluating this therapy through the Ivy Center’s Phase 0/2 clinical trial design, investigators will rapidly assess safety and biological and clinical efficacy in a first-in-human clinical trial. The clinical trial is scheduled to open for enrollment in 2020.

“Our goal at the Ivy Brain Tumor Center is to live at the forefront of first-in-human and first-in-class therapies for glioblastoma, which is why this collaboration with SonALAsense makes so much sense,” Sanai said.

“New modalities are desperately needed in brain tumor therapy. As we evolve our approaches through Phase 0/2 clinical trials, we are committed to developing non-invasive interventions that deliver results to patients as quickly as possible,” he added.

“SonALAsense’s vision is for sonodynamic therapy to change glioblastoma from a deadly cancer into a chronic disease, and glioblastoma patients into long-term cancer survivors. I look forward to working with Sanai and his experienced team at the Ivy Brain Tumor Center to determine if our vision can become a reality through our planned Phase 0/2 clinical study,” said Stuart Marcus, MD, PhD, founder, chief executive officer and chief medical officer of SonALAsense.

“We are very grateful for the financial support of the Ivy Foundation to conduct the clinical study,” he added.

Ribociclib
During the annual meeting of the Society for Neuro-Oncology Sanai will also share the results of a new Ivy Center Phase 0/2 clinical trial of a CDK4/6 inhibitor in recurrent aggressive meningioma patients. Meningiomas are the most frequently reported primary Central Nervous System (CNS) tumors.

According to the American Brain Tumor Association, meningiomas are considered a type of primary brain tumor, they do not grow from brain tissue itself, but instead arise from the meninges, three thin layers of tissue covering the brain and spinal cord. These tumors most commonly grow inward causing pressure on the brain or spinal cord, but they may also grow outward toward the skull, causing it to thicken. Most meningiomas are benign, slow-growing tumors. Some contain cysts (sacs of fluid), calcifications (mineral deposits), or tightly packed bunches of blood vessels.[1]

The Ivy Center Phase 0/2 study demonstrates that ribociclib (Kisqali®; Novartis), a recently U.S. Food and Drug Administration (FDA-) approved drug to treat aggressive breast cancer, has the ability to penetrate the blood-brain barrier and target the brain tumor cell mechanisms – providing the first evidence of biological activity in meningioma patients.

Ribociclib is an inhibitor of cyclin D1/CDK4 and CDK6, and, in addition to treating certain kinds of breast cancer, the drug, developed by Novartis and Astex Pharmaceuticals, is studied as a treatment for other drug-resistant cancers.

Based on the results of this study, investigators at the Ivy Center are now working to test new drug cocktails deploying ribociclib for multiple brain tumor types.

Ceritinib
Researchers at the Ivy Brain Tumor Center will also underscoring the importance of a Phase 0/2 clinical trial of ceritinib in brain metastases and recurrent glioblastoma.

Ceritinib (Zykadia®; Novartis) is an orally bioavailable, small molecule inhibitor of several cancer cell signaling pathways highly expressed in glioblastoma and brain metastases. The trial assessed the pharmacokinetics and pharmacodynamics of ceritinib in recurrent glioblastoma and brain metastasis patients.

The study results demonstrated that ceritinib is highly bound to plasma proteins and was ineffective in penetrating the human CNS in patients with glioblastoma. The trial’s negative results exemplify how the Ivy Center’s Phase 0/2 clinical trial design can rapidly identify drug development strategies to accelerate as well as flag new drugs that should be de-emphasized for specific brain tumor indications.

Radio interview
A Bold Approach to Identify New and Effective Therapies for Malignant Brain Tumors (Interview with Nader Sanai, MD, the director of the Ivy Brain Tumor Center) [Listen] [Download]

Reference
[1] Meningioma. American Brain Tumor Association (ABTA). Online. Last accessed November 20, 2019.
[2] Wan GY, Liu Y, Chen BW, Liu YY, Wang YS, Zhang N. Recent advances of sonodynamic therapy in cancer treatment. Cancer Biol Med. 2016;13(3):325–338. doi:10.20892/j.issn.2095-3941.2016.0068 [Pubmed][Article]