P17.14.b phase i trial of dnx-2401 oncolytic adenovirus combined with a short course of dose-dense temozolomide for recurrent glioblastoma

Abstract BACKGROUND Oncolytic virotherapy is emerging as a novel therapeutic strategy for glioblastoma (GBM). DNX-2401, an oncolytic adenovirus with selective replication and enhanced infectivity in tumor cells, showed anti-tumor effect in a previous clinical trial for recurrent GBM. The combination of DNX-2401 and Temozolomide (TMZ) has shown a synergistic anti-glioma effect in preclinical models. MATERIAL AND METHODS We conducted a phase I open-label single-center study to investigate the safety and efficacy of this therapeutic combination in patients with first recurrence of GBM. Following tumor biopsy or resection, 3x10e10 viral particles of DNX-2401 were injected intratumorally or into the post-resection cavity, respectively. Approximately 2 weeks after DNX-2401 injection, patients were treated with up to two 28-day cycles of oral 150 mg/m2/day TMZ in a 7 days on/7 days off schedule. RESULTS Thirty-one patients (13 [42%] female, 18 [58%] male) with confirmed recurrent GBM were enrolled and treated with DNX-2401 followed by a median of 1.5 cycles of TMZ (range, 0-2). Median age was 54 years (range, 25-78) and median KPS was 70 (range 70-90). Surgery consisted of biopsy in 14, partial resection in 15 and complete resection in 2 patients. IDH1/2 mutation was confirmed in 1 patient. MGMTP was methylated in 9 and unmethylated in 21 patients (1 patient, unknown). Best response according to RANO criteria was partial response in 1 patient, stable disease in 21 subjects and progressive disease in the remainder. Median PFS was 51 days (95% CI, 43-81). Median OS was 282 days (95% CI 202-344) with 6-month and 12-month OS rates of 72.5 (95% CI 52.4-85.2) and 27.5 % (95% CI 12.4-45.0), respectively. Four patients survived more than 18 months with 2 long-term survivors exceeding 4.5 years. Treatment was generally well tolerated. The safety profile was as expected for subjects treated with TMZ alone. Except one subject who experienced grade 2 brain edema possibly related to DNX-2401, no additional toxicity was considered attributable to DNX-2401. The most frequent reported adverse events were lymphopenia (54.8%), asthenia (48.4%), constipation (41.9%), headache (29%) and pyrexia (22.6%). Ongoing correlative analyses evaluating immune response are ongoing. CONCLUSION Our data suggest that treatment with DNX-2401 followed by a short-course of dose-dense TMZ is feasible, can be safely administered with expected adverse events related to chemotherapy, and appears to render a clinical benefit in a subset of patients with recurrent GBM. Further assessment of this therapeutic approach is warranted.