The investigator-initiated study, funded by the Ben & Catherine Ivy Foundation and Barrow Neurological Foundation, has successfully used Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD1390 in recurrent glioblastoma in combination with radiation therapy, provided by AstraZeneca.
The institute announced initial results from a phase 0/1 clinical trial of AZD1390 in recurrent glioblastoma in combination with radiation therapy. The study demonstrated, for the first time in human, that AZD1390 may be a potent radio-sensitizer in patients with glioblastoma.
A study in the National Library of Medicine revealed that several approaches of optimizing radiation-effectiveness using radiosensitizers have been made in the past as part of the search for glioblastoma treatment. Tissue-selectiveness and penetration of the blood-brain barrier seem to have been the major roadblocks but as in this study, modern strategies continue to try and circumvent these obstacles.
Well-tolerated in GBM patients
The analysis from the Ivy Foundation study shows that AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in gadolinium non-enhancing tumor tissue, and substantially suppressing activation of ATM target, pRAD50, in response to radiation.
Nader Sanai, director of the Ivy Brain Tumor Center and director of neurosurgical oncology at Barrow Neurological Institute, will present the findings during a mini oral session on CNS tumors at the European Society for Medical Oncology Congress in Madrid, Spain today (Saturday October 21).
“Exploring ATM as a target for brain tumor precision medicine is an important priority for our field and our patients,” says Dr. Sanai.
“Our data indicates that AZD1390 is brain penetrant and generates tissue effects consistent with radiosensitization in recurrent glioblastoma patients.”
Brain tumor surgery
Initial data is based on 12 recurrent glioblastoma patients who enrolled in the clinical trial and received the study drug for three days prior to brain tumor surgery.
Tumor tissue, cerebrospinal fluid and blood were collected. All patients exceeded a predefined threshold for brain tumor drug penetration, qualifying them for continued therapeutic dosing with AZD1390 plus radiotherapy.
In parallel, excised tumor tissue was also radiated ex-vivo, demonstrating that pRAD50 expression was significantly suppressed in AZD1390-treated patients compared to untreated.
MGMT-unmethylated glioblastoma
This study is still accruing and a Phase 0/1 clinical trial of AZD1390 in newly diagnosed MGMT-unmethylated glioblastoma is now underway.
AZD1390 is a highly potent, brain penetrant ataxia telangiectasia mutant (ATM) kinase inhibitor that blocks ATM-dependent signaling and repair of DNA double strand breaks in the genome. It therefore exhibits powerful activity in combination with agents such as irradiation that induce those breaks. AstraZeneca supplied AZD1390 to the study investigators, as well as provided scientific collaboration in study design and implementation.
Ivy Brain Tumor Center at Barrow Neurological Institute in Phoenix is a tertiary care and nonprofit translational research program that employs bold, early-phase clinical trial strategies to identify new treatments for aggressive brain tumors, including glioblastoma.