Radiotherapy/Histone Deacetylase Inhibitor Combination Safe, Effective in High-grade Gliomas
Adding panobinostat to radiotherapy appears safe, tolerable, and has preliminary efficacy for treating recurrent high-grade gliomas, according to a phase 1 clinical trial published in the Journal of Neuro-Oncology. The trial combined fractionated stereotactic re-irradiation therapy (FSRT) with panobinostat.1
"We saw synergy between radiotherapy and the agent, panobinostat. Our findings suggest panobinostat makes radiotherapy much more effective," said Yaacov R. Lawrence, MD, of the Department of Radiation Oncology at Thomas Jefferson University Sidney Kimmel Medical College in Philadelphia, Pennsylvania, and senior author of the study.
Although radiotherapy damages brain tumors, cancer cells can repair themselves and continue to survive. The purpose of adding panobinostat to FSRT was to shut down that ability of the cells to repair themselves.
The study enrolled 12 patients with high-grade gliomas that had recurred after initial radiotherapy. Among the patients, 8 had recurrent glioblastoma and 4 had recurrent anaplastic astrocytoma. These 2 forms of aggressive brain cancer represent almost 70% of newly diagnosed gliomas, which occur in an estimated 10 000 patients annually. Despite response to initial radiation, most patients relapse within 2 years and overall survival is then limited to a year or less.
"There is no standard treatment for recurrent high grade gliomas. At Jefferson, we have a lot of experience with offering a second course of radiation after a patient relapses, in order to increase survival, but we are excited by the promise of a targeted agent that makes initial and repeat radiotherapy more effective," said Adam Dicker, MD, PhD, FASTRO, chair and professor of Radiation Oncology, Pharmacology and Experimental Therapeutics at the Sidney Kimmel Medical College, and coauthor of the study.
Panobinostat was approved by the FDA in 2015 to treat multiple myeloma and is being tested in other cancers. It inhibits histone deacetylase, and so it modifies the expression of approximately 8% of RNA molecules that are produced from genes. This affects protein production and thus cancer growth. In addition, panobinostat turns off the DNA repair enzyme known as RAD51.
The trial tested panobinostat at 10, 20, and 30 mg. The 30-mg dose was well tolerated.
"The intent of this study was not to demonstrate benefit of the combination therapy, but to test safety. Still, we did note promising activity, which must be validated in further studies," Lawrence said.
The researchers concluded that a phase 2 trial is warranted to assess efficacy further.
1. Shi W, Palmer JD, Werner-Wasik M, et al. Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas [published online ahead of print January 29, 2016]. J Neurooncol. doi:10.1007/s11060-016-2059-3.