Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Background VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1 x10(13) viral particles (vp)/patient (Part I), and 3.3x10(12) vp/patient (Part II). Fourteen patients were included in Part Ill: there were no DLTs and the RP2D was 1 x10(13) vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1x10(13) vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1 x10(13) vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon- r,soluble lymphocyte activation ne-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paditaxel plus gemcitabine to patients with pancreatic adenocarcinoma

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1. VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.Fil: Pascual-Pasto, Guillem. Hospital Sant Joan de Déu; EspañaFil: Bazan-Peregrino, Miriam. No especifíca;Fil: Olaciregui, Nagore G.. Hospital Sant Joan de Déu; EspañaFil: Restrepo Perdomo, Camilo A.. Hospital Sant Joan de Déu; EspañaFil: Mato Berciano, Ana. No especifíca;Fil: Ottaviani, Daniela. Centre National de la Recherche Scientifique; FranciaFil: Weber, Klaus. No especifíca;Fil: Correa, Genoveva. Hospital Sant Joan de Déu; EspañaFil: Paco, Sonia. Hospital Sant Joan de Déu; EspañaFil: Vila Ubach, Monica. Hospital Sant Joan de Déu; EspañaFil: Cuadrado Vilanova, Maria. Hospital Sant Joan de Déu; EspañaFil: Castillo Ecija, Helena. Hospital Sant Joan de Déu; EspañaFil: Botteri, Gaia. Hospital Sant Joan de Déu; EspañaFil: Garcia Gerique, Laura. Hospital Sant Joan de Déu; EspañaFil: Moreno Gilabert, Helena. Hospital Sant Joan de Déu; EspañaFil: Gimenez Alejandre, Marta. No especifíca;Fil: Alonso Lopez, Patricia. No especifíca;Fil: Farrera Sal, Marti. No especifíca;Fil: Torres Manjon, Silvia. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Ramos Lozano, Dolores. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Moreno, Rafael. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Aerts, Isabelle. Centre National de la Recherche Scientifique; FranciaFil: Doz, François. Universite Paris Descartes; Francia. Centre National de la Recherche Scientifique; FranciaFil: Cassoux, Nathalie. Centre National de la Recherche Scientifique; Francia. Universite Paris Descartes; FranciaFil: Chapeaublanc, Elodie. Centre National de la Recherche Scientifique; FranciaFil: Torrebadell, Montserrat. Hospital Sant Joan de Déu; EspañaFil: Roldan, Monica. Hospital Sant Joan de Déu; EspañaFil: König, Andrés. No especifíca;Fil: Suñol, Mariona. Hospital Sant Joan de Déu; EspañaFil: Claverol, Joana. Hospital Sant Joan de Déu; EspañaFil: Lavarino, Cinzia. Hospital Sant Joan de Déu; EspañaFil: De Torres, Carmen. Hospital Sant Joan de Déu; EspañaFil: Fu, Ligia. Hospital Escuela Universitario; HondurasFil: Radvanyi, François. Centre National de la Recherche Scientifique; FranciaFil: Munier, Francis L.. Hopital Ophtalmique Jules Gonin; SuizaFil: Catalá-Mora, Jaume. Hospital Sant Joan de Déu; EspañaFil: Mora, Jaume. Hospital Sant Joan de Déu; EspañaFil: Alemany, Ramón. Instituto de Investigación Biomédica de Bellvitge; EspañaFil: Cascalló, Manel. No especifíca;Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Montero Carcaboso, Angel. Hospital Sant Joan de Déu; Españ