According to results of a phase I study recently published in <em>Journal of Clinical Oncology</em>, treatment with the investigational agent DNX-2401 resulted in 20% of patients with recurrent malignant glioma surviving more than 3 years from the time of treatment.
Frederick F. Lang, MD
According to results of a phase I study recently published inJournal of Clinical Oncology, treatment with the investigational agent DNX-2401 resulted in 20% of patients with recurrent malignant glioma surviving more than 3 years from the time of treatment.
Patients on the dose-escalation study were enrolled into the treatment-only group A (n = 25) or the treat-resect-treat group B (n = 12). Group A underwent stereotactic biopsy to document recurrence, followed by a single intratumoral injection of DNX-2401 at the assigned dose through the biopsy needle into the contrast-enhancing tumor mass. In group B, stereotactic biopsy and intratumoral injection of DNX-2401 through an implanted catheter was followed 2 weeks later by craniotomy with en bloc tumor resection, and then administration of a second DNX-2401 dose into several locations in the wall of the resection cavity.
Five (20%) of 25 patients in group A survived more than 3 years, including 3 patients who had complete responses (CR, defined as ≥95% reduction in the size of the enhancing tumor) and 2 patients with stable disease. All 3 patients who achieved a CR had progression-free periods of ≥3 years. Two patients (17%) in group B survived for 2 years. Across the overall population, the median survival time was 13.0 months.
“In this dose-escalation study, we show that DNX-2401, a novel tumor-selective adenovirus, is safe and capable of robust viral replication and killing of recurrent high-grade glioma cells,” first author Frederick F. Lang, MD, The University of Texas MD Anderson Cancer Center, Department of Neurosurgery, and colleagues wrote. “Secondary antiglioma immune-mediated responses were observed. Importantly, these biologic mechanisms translated into clinical benefit, including three dramatic responses (≥95% reduction in tumor size) with long progression-free intervals and long-term survival after treatment with DNX-2401.”
DNX-2401 is an oncolytic adenovirus designed to be tumor selective, infectivity enhanced, and replication competent. To evaluate safety and efficacy and define the biologic effect of escalating doses of the virus, investigators recruited 37 patients with recurrent malignant glioma.
Histology across both groups included glioblastoma (89%), gliosarcoma (5%), and anaplastic astrocytoma (5%). Median tumor diameter was 30 mm for group A and 41 mm for group B. Patients were enrolled at first (62%), second (32%), or third recurrence (5%), and had received a median of 2 prior treatment regimens. Three patients in group A (12%) were refractory to prior anti-VEGF therapy.
Lang et al did not observe any dose-limiting toxicities, so a maximum-tolerated dose was not identified. The highest concentration of virus that could be manufactured, 3 × 1010vp in 1 mL, was deemed the maximal achieved dose.
Nearly three-quarters of patients (72%) in group A had tumor reductions. Median overall survival was 9.5 months, regardless of dose.
“In all, these results provide the first clinical correlates that DNX-2401 can induce a direct oncolytic effect followed by an antitumor immune response,” the investigators wrote. “Insofar as DNX-2401 is highly efficient because of expanded infectivity conferred by the RGD motif, and insofar as it is capable of enhancing antigen presentation, we speculate that these effects lead to immune cell infiltration and antitumor activity.”
Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma [published online February 12, 2018].J Clin Oncol.doi: 10.1200/JCO.2017.75.8219.