A phase I dose-escalation study to assess the oncolytic virus VCN-01 safety and efficacy in refractory retinoblastoma patients.

10046 Background: Preclinical work demonstrated antitumor activity of VCN-01 (oncolytic adenovirus targeting the E2F pathway and expressing hyaluronidase) for retinoblastoma. We report this first-in-children study aiming to assess its safety and efficacy. Methods: Patients with intraocular retinoblastoma who failed conservative therapy facing imminent enucleation were eligible for this phase I, dose-escalation study (NCT03284268) with two dose levels of VCN-01 intravitreal injection (2E+9 vp/eye per dose for the first patient) and 2E+10 vp/eye dose in two doses every two weeks for the remaining 8. Dose limiting toxicity (DLT) was defined as ≥ grade IV ocular toxicity or ≥ grade III systemic toxicity according to CTCAEv04. Response assessed by RB-RECIST criteria and toxicity were evaluated at day 42 of the first injection. Results: Thirteen patients (4 screening failures) were enrolled. Out of the 9 treated patients, five had bilateral retinoblastoma. There was no DLT. 7/9 patients experienced adverse reactions. being uveitis the most common (7/9 patients, G3 in four). From the second patient onwards, all patients received pre-emptive oral and/or topical steroids to prevent uveitis. Uveitis was improved or resolved at day 42 in 7 patients. One patient with G3 uveitis did not receive the second dose because of medical decision and also experienced glaucoma requiring treatment. No systemic toxicities occurred. VCN-01 caused reversible changes in electroretinograms due to turbidity. Viral particles were not found in the healthy retina in enucleated eyes. No VCN-01 genomes in peripheral blood were detected in any case. At 42 days of the first injection, 5 patients achieved partial response, 3 stable disease and one progressive disease. Subsequent eye-conservative treatment was administered to 5 patients and 3 eyes are preserved with vision (follow-up 12-49 months). The remaining 6 eyes were enucleated because of refractory tumor. No extraocular relapse occurred. Conclusions: VCN01 was safe, being uveitis the most common adverse effect. VCN-01 did not cause retinal toxicity. The response in these heavily pre-treated eyes was encouraging. Clinical trial information: NCT03284268 .