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.

Autor:	Garcia-Carbonero R; Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain., Bazan-Peregrino M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Gil-Martín M; Medical Oncology Department, Institut Catala d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Álvarez R; Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain., Macarulla T; Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Riesco-Martinez MC; Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain., Verdaguer H; Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Guillén-Ponce C; Hospital Ramon y Cajal, Madrid, Spain., Farrera-Sal M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; ProCure Program, Institut Catala d'Oncologia, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Moreno R; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; ProCure Program, Institut Catala d'Oncologia, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Mato-Berciano A; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Maliandi MV; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Torres-Manjon S; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; ProCure Program, Institut Catala d'Oncologia, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Costa M; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; ProCure Program, Institut Catala d'Oncologia, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Del Pozo N; Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre-CNIO, Madrid, Spain., Martínez de Villarreal J; Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre-CNIO, Madrid, Spain., Real FX; Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain., Vidal N; Department of Pathology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain., Capella G; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain, Spain., Alemany R; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; ProCure Program, Institut Catala d'Oncologia, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Blasi E; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Blasco C; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Cascalló M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Salazar R; Medical Oncology Department, Institut Catala d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain RamonSalazarSole@iconcologia.net.; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain, Spain.; University of Barcelona, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Mar; Vol. 10 (3).
DOI:	10.1136/jitc-2021-003255
Abstrakt:	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 1×10 ¹³ viral particles (vp)/patient (Part I), and 3.3×10 ¹² vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10 ¹³ vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10 ¹³ vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10 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-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. Competing Interests: Competing interests: MB-P, MF-S, AM-B, MVM, EB, CB and MC are employees, and RS is consultant for VCN Biosciences. MC and RAle are co-inventors of one patent application concerning the expression of hyaluronidase by oncolytic adenoviruses and both have ownership interest in VCN Biosciences. RG-C has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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