In a phase I trial, 31 patients with high-grade glioma undergoing resection were treated with an adenoviral vector encoding a regulatable human IL-12 (injected into the resection cavity) and 10-40 mg of veledimex (VDX), an oral activator for hIL-12 transcription (administered post-operatively). Increased dose of VDX correlated with increased IL-12 and IFNγ in peripheral blood, but also with increased frequency and severity of adverse events (reversible with VDX discontinuation). Treatment increased intratumoral CD8+ T cells and IFNγ, and the 20 mg dose of VDX led to 12.7 months median OS. Concurrent administration of corticosteroids decreased survival.
Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-gamma (IFN-gamma) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus