Expanded phase I study of intratumoral Ad-RTS-hIL-12 plus oral veledimex: Tolerability and survival in recurrent glioblastoma

2044 Background: Glioblastoma (GBM) is an aggressive brain tumor affecting ~74,000 people worldwide annually. Recurrent GBM patients have a median OS (mOS) of 6-7 months. OS in patients who have failed temozolomide, bevacizumab or equivalent salvage chemotherapy, is ~3-5 months. New therapies are urgently needed. Ad-RTS-hIL-12 (Ad) is a novel gene therapy expressing IL-12 under the control of an oral activator ligand, veledimex (V), through the RheoSwitch Therapeutic System. Intratumoral administration of Ad results in targeted tumor cytotoxicity and induction of systemic T cell memory. Ad + V is a treatment strategy to extend the IL-12 therapeutic window. Methods: In a multicenter Phase I dose escalation trial and expansion cohort, subjects with recurrent or progressive Grade III or IV glioma undergoing resection were injected intratumorally with Ad 2 x 1011 viral particles and daily oral V for 15 doses, beginning prior to surgery. The primary endpoint is safety and tolerability of Ad + V; secondary endpoints include OS. Results: 25 subjects were dosed in 3 dose escalation cohorts: 20 mg (n = 7), 30 mg (n = 4), and 40 mg (n = 6) and an expansion cohort of 20 mg (n = 8). Results show V crossed the blood brain-barrier with 35±5% of plasma levels detected in the brain tumor. The 20 mg dose (n = 15) had better drug compliance (86%) than the 30 mg (63%) or 40 mg (52%) cohorts and the 20 mg cohort shows better survival (mOS 12.7 months) compared to other cohorts. The frequency of related ≥Grade (G)3 AEs in the 20 mg cohort was significantly lower: 20% in 20mg, 50% in 30mg and 40 mg. In the 20 mg cohort, the most frequent AEs were transient mild flu-like symptoms seen in 12/15, G3 cytokine release syndrome in 2/15, G3 elevated ALT/AST in 1/15 and G3 lymphopenia in 3/15. All AEs reversed promptly upon discontinuing V. Conclusions: Overall, Ad + 20 mg V is well tolerated; toxicities were predictable and reversible upon discontinuing V. There is a correlation between V dose, BBB penetration and drug related AEs. The tolerability and encouraging survival observed to date warrant further investigation in a pivotal trial. A stereotactic arm and a pediatric trial in diffuse intrinsic pontine glioma patients are planned. Clinical trial information: NCT02026271.