Modified Poliovirus Therapy Receives Breakthrough Designation for GBM

The breakthrough therapy designation is meant to expedite the development of promising medications that have shown preliminary signs of clinical efficacy, typically in phase I or II trials. Under the program, the FDA will be more accessible, in order to provide advice on the design and conduct of the clinical development program.

“Breakthrough status means that we can work with the highest levels in the FDA to develop the most efficient clinical trial and pathway to fully evaluate the safety and efficacy of the genetically modified poliovirus for treating recurrent glioblastoma,” said lead investigator Darell Bigner, MD, PhD, director of the Preston Robert Tisch Brain Tumor Center at Duke. “Ultimately, we hope the therapy will one day obtain FDA approval.”

The phase I study that was the basis for the designation enrolled adult patients with a Karnofsky performance status of ≥70%. Patients in the trial received a poliovirus immunization booster 2 weeks prior to treatment with PVS-RIPO. Treatment was administered directly into the tumor via catheter, which was implanted utilizing stereotactic guidance.

In the trial, treatment was administered in the Neuro-Surgical Intensive Care Unit or neuro step down unit, for safety purposes, at a delivery rate of 0.5 ml/hr over the course of 390 minutes. The study identified a viral load of 5.0 x 107 TCID50 as the ideal dose for PVS-RIPO. Higher doses required prolonged steroid use, according to the ASCO report.

According to a poster presentation during the 2015 ASCO Annual Meeting, the median age was 57.5 years (range 20-70). The KPS was most commonly 90% (62.5% of patients). Prior therapies included radiation (100%), temozolomide (100%), and bevacizumab (41.7%).

At a data cutoff of May 19, 2015, the median OS across all doses of PVS-RIPO was 12.5 months (95% CI, 6.3-19.8). The 12-month OS rate was 56% (95% CI, 28.7-56.3%), the 18-month rate was 32% (95% CI, 10.4-56.3%), and the 24-month OS rate was 24%. At this analysis, 11 patients had failed treatment with PVS-RIPO.

The longest survival durations were seen with 2 doses that were not selected for further investigation. In these groups, two patients continued to live for more than 35 months, with an additional patient living for more than 23 months. At the recommended dose, 8 of 9 patients (89%) remained on treatment at the time of the analysis. The longest duration of response was 7+ months. According to a statement from Duke on May 16, 2016, 3 patients remained alive 36 months following treatment.

The most common grade 3 adverse events (AEs) were hyperglycemia (12.5%), lymphopenia (20.8%), and hemiparesis (14.3%). There was one case of grade 4 lymphopenia, and 1 dose-limiting grade 4 AE (intracranial hemorrhage during catheter removal). There were no grade 5 events.

PVS-RIPO, which is manufactured at the NCI’s Frederick facility, consists of a genetically modified nonpathogenic version of the oral poliovirus Sabin type 1. In the therapy, the internal ribosomal entry site (IRES) on the poliovirus was replaced with the IRES from human rhinovirus type 2 (HRV2), thus eliminating neurovirulence. Once administered, the therapy enters and begins duplicating within cells that express CD155/Necl5, which is common across solid tumors.

The phase I study exploring PVS-RIPO continues to enroll participants with recurrent GBM, with a phase II/III study being planned, according to Duke. Additionally, given the availability of CD155/Necl5 on solid tumors, trials are anticipated across other types of cancer.

Desjardins A, Sampson JH, Peters KB, et al. Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination. J Clin Oncol. 2015;33 (suppl; abstr 2068).