PT - JOURNAL ARTICLE AU - Rocio Garcia-Carbonero AU - Miriam Bazan-Peregrino AU - Marta Gil-Martín AU - Rafael Álvarez AU - Teresa Macarulla AU - Maria C Riesco-Martinez AU - Helena Verdaguer AU - Carmen Guillén-Ponce AU - Martí Farrera-Sal AU - Rafael Moreno AU - Ana Mato-Berciano AU - Maria Victoria Maliandi AU - Silvia Torres-Manjon AU - Marcel Costa AU - Natalia del Pozo AU - Jaime Martínez de Villarreal AU - Francisco X Real AU - Noemí Vidal AU - Gabriel Capella AU - Ramon Alemany AU - Emma Blasi AU - Carmen Blasco AU - Manel Cascalló AU - Ramon Salazar TI - 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 AID - 10.1136/jitc-2021-003255 DP - 2022 Mar 01 TA - Journal for ImmunoTherapy of Cancer PG - e003255 VI - 10 IP - 3 4099 - http://jitc.bmj.com/content/10/3/e003255.short 4100 - http://jitc.bmj.com/content/10/3/e003255.full SO - J Immunother Cancer2022 Mar 01; 10 AB - 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 7 days 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 1×1013 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 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-γ, soluble lymphocyte activation gene-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-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.Trial registration number NCT02045602.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.