In an open-label phase III trial (ASPECT) reported in Lancet Oncology, Manfred Westphal, MD, of University Hospital Eppendorf in Hamburg, and colleagues assessed the effects of locally applied adenovirus-mediated gene therapy with sitimagene ceradenovec followed by IV ganciclovir after surgical resection in patients with newly diagnosed resectable glioblastoma.1 They found that the sitimagene ceradenovec treatment plus standard care significantly improved the composite endpoint of time to reintervention or death but not overall survival compared with resection plus standard care.
The trial involved 38 European sites with recruitment between November 2005 and April 2007. In total, 250 patients aged 18 to 70 years with newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection and a Karnofsky performance score ≥ 70 were randomized to surgical resection of the tumor and intraoperative perilesional injection of sitimagene ceradenovec (1 × 10¹² viral particles) followed by ganciclovir (postoperatively, 5 mg/kg IV twice a day) in addition to standard care (n = 124) or resection and standard care alone (n = 126).
Temozolomide was not a standard treatment in all participating countries at the time of the study and was allowed at the discretion of the treating physician. The primary endpoint was the composite of time to death or reintervention, adjusted for temozolomide use.
Patients in the sitimagene ceradenovec group and the standard care group were generally well matched for age (median, 58 and 57 years), sex (59% and 65% male), histopathology diagnosis (glioblastoma multiforme in 94% and 95%), location of tumor (right in 60% and 51%), ventricular opening (23% and 15%), time since clinical diagnosis (median, 7 and 8.5 days), Karnofsky score (90–100 in 66% and 71%), estimate of resection during surgery (radical in 83% and 81%), and estimated extent of resection from postoperative MRI (≥ 90% in 67% and 68%). For those with available data, 65% of patients in the sitimagene ceradenovec group and 76% in the control group had nonmethylated MGMT (the DNA repair gene O6-methylated-DNA methyltransferase).
Temozolomide was used by more patients in the control group overall (65% vs 49%) and among those with nonmethylated MGMT (67% vs 45%).
Time to Death or Reintervention
Median time to death or reintervention was significantly longer in the sitimagene ceradenovec group (308 vs 268 days, hazard ratio [HR] = 1.53, P = .006). The effect of sitimagene ceradenovec was greater among the subgroup of patients with nonmethylated MGMT (HR = 1.72, P = .008). Sitimagene ceradenovec also increased time to death or reintervention among patients who never used temozolomide (HR = 1.58, P = .0398).
There was no difference between groups in overall survival (median, 497 vs 452 days, HR = 1.18, P = .31). There was evidence of a better effect of sitimagene ceradenovec treatment on overall survival among patients with nonmethylated MGMT, but the effect was not significant (HR = 1.40, P = .112). Two-year overall survival was 25% in sitimagene ceradenovec group and 21% in the control group.
An analysis of outcome by baseline antiadenoviral antibody status suggested a greater effect of sitimagene ceradenovec treatment in patients with higher titers of neutralizing antibodies. Among patients with titers > 100, the hazard ratio for time to death or reintervention was 2.17 (P = .047) vs the control group. Among patients with antibody titers > 0, the hazard ratio for time to all-cause mortality was 1.79 (P = .025) vs the control group. The proportion of patients who were antibody-positive and antibody titers initially increased in the sitimagene group and then declined over time.
More patients in the sitimagene ceradenovec group had one or more treatment-related adverse events of any grade (71% vs 41%), treatment-related severe adverse events (23% vs 3%), treatment-related adverse events of grade 3 or higher (43% vs 9%), and serious adverse events (60% vs 43%). The most common grade 3 or 4 adverse events were hemiparesis (6.5% vs 2.4%) and aphasia (4.8% vs 1.6%).
Seizure was more common in the experimental group during days 5 to 19, but the overall incidence was similar in the two groups (31% and 35%). Overall, 87% of patients in the experimental group and 86% of patients in the control group experienced nervous system disorders, 53% and 44% had gastrointestinal disorders, and 41% and 34% had infections. Treatment was discontinued due to an adverse event in 2% of sitimagene ceradenovec patients.
The investigators concluded, “Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or reintervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy.” ■
Disclosure: Dr. Westphal reported no potential conflicts of interest.
1. Westphal M, Ylä-Herttuala S, Martin J, et al: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncol 14:823-833, 2013.
The ASPECT study,1 a randomized, open-label, phase III trial examining adenovirus-mediated gene therapy with sitimagene ceradenovec followed by IV ganciclovir for patients with operable high-grade glioma, is an important achievement for both neuro-oncology and gene therapy. As vector engineering...