Title: Multicenter Phase IB/II Study of AdV-Tk, a Gene-Mediated Cytotoxic Immunotherapy, Adjuvant to Surgical Resection for Patients With Newly Diagnosed High Grade Glioma
Description: Purpose: The prognosis for malignant gliomas is poor, and overall survival remains less than 15 months despite improved diagnostic and treatment techniques, underscoring the need for novel therapeutic options. This multicenter, single-arm Phase Ib/II trial was conducted to assess the safety and efficacy of AdV-TK, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, in patients newly diagnosed with high grade glioma.

Patients & Methods: Patients were recruited between 2005 and 2010 at four clinical sites. In addition to the standard of care (SOC), which included surgery, adjuvant XRT + temozolomide (TMZ), AdV-TK was administered to the tumor bed at the time of resection followed by valacyclovir prodrug. A total of 48 patients completed therapy per protocol, and were stratified based on extent of resection (total vs. subtotal) and pathological diagnosis (GBM vs. AA/AO). Data from 134 matched patients, who underwent similar SOC at a fifth clinical site during the same time period, were used for descriptive comparison.

Results: There were no dose-limiting toxicities or significant adverse events considered related to AdV-TK. Median overall survival (OS) was 17.05 months, with 67% and 35% at 1- and 2- years respectively. Median OS for patients with total resection was 25 months, compared with 13.5 months for patients with subtotal resection. This difference was more pronounced in patients with a pathological diagnosis of GBM (25.05 vs. 10.6 months). In the comparison group median OS was 13.5 months, with 57% and 22% at 1- and 2- years respectively. Median OS for those with total resection was 16.9 months and 12.47 months for subtotal resection. Progression free survival (PFS) was also improved in the AdV-TK group (8.3 vs. 6.43 months).

Conclusions: Results from this multicenter Phase Ib/II trial demonstrate that AdV-TK plus valacyclovir can be safely delivered at the time of surgical resection without added toxicity to patients with newly diagnosed high grade glioma. The median OS and the 1- and 2-year survival rates of AdV-TK study patients compare favorably to historical reports and a matched comparison set. Survival outcomes are significantly better in patients having undergone total resections versus subtotal resections. These data strongly support launching a statistically powered randomized clinical study of AdV-TK for the treatment of high grade glioma.