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 t...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003255.full |
| _version_ | 1827892452288102400 |
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| author | Gabriel Capellá Francisco X Real Marta Gil-Martin Rocio Garcia-Carbonero Rafael Moreno Ramon Alemany Martí Farrera-Sal Ramon Salazar Teresa Macarulla Jaime Martinez de Villarreal Natalia del Pozo Carmen Guillén-Ponce Miriam Bazan-Peregrino Rafael Álvarez Ana Mato-Berciano Emma Blasi Carmen Blasco Manel Cascallo Maria C Riesco-Martinez Helena Verdaguer Maria Victoria Maliandi Silvia Torres-Manjon Marcel Costa Noemí Vidal |
| author_facet | Gabriel Capellá Francisco X Real Marta Gil-Martin Rocio Garcia-Carbonero Rafael Moreno Ramon Alemany Martí Farrera-Sal Ramon Salazar Teresa Macarulla Jaime Martinez de Villarreal Natalia del Pozo Carmen Guillén-Ponce Miriam Bazan-Peregrino Rafael Álvarez Ana Mato-Berciano Emma Blasi Carmen Blasco Manel Cascallo Maria C Riesco-Martinez Helena Verdaguer Maria Victoria Maliandi Silvia Torres-Manjon Marcel Costa Noemí Vidal |
| author_sort | Gabriel Capellá |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T21:39:58Z |
| format | Article |
| id | doaj.art-f20744c4524742ac8290f86ad68345d4 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:39:58Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-f20744c4524742ac8290f86ad68345d42023-07-27T05:15:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003255Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumorsGabriel Capellá0Francisco X Real1Marta Gil-Martin2Rocio Garcia-Carbonero3Rafael Moreno4Ramon Alemany5Martí Farrera-Sal6Ramon Salazar7Teresa Macarulla8Jaime Martinez de Villarreal9Natalia del Pozo10Carmen Guillén-Ponce11Miriam Bazan-Peregrino12Rafael Álvarez13Ana Mato-Berciano14Emma Blasi15Carmen Blasco16Manel Cascallo17Maria C Riesco-Martinez18Helena Verdaguer19Maria Victoria Maliandi20Silvia Torres-Manjon21Marcel Costa22Noemí Vidal2313 Hereditary Cancer Program, Institute of Oncology, Oncobell, Institut d`Investigació Biomèdica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), L`Hospitalet de Llobregat, Barcelona, Spain20 Departament de Medicina i Ciències de la Vida, Universitt Pompeu Fabra, Barcelona, SpainMedical Oncology Department, Institut Català d’Oncologia – IDIBELL, L’Hospitalet-Barcelona, Barcelona, SpainOncology Department, Hospital Universitario 12 de Octubre, Imas12, UCM, CNIO, CIBERONC, Madrid, SpainAff344 grid.418701.b0000000120978389Institut Catalá d’Oncologia Barcelona SpainIDIBELL, Institut Català d`Oncologia, Barcelona, SpainAff1 grid.417656.7ProCure ProgramIDIBELL-Institut Català d’Oncologia, l’Hospitalet de Llobregat El Prat de Llobregat SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain, SpainVall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SpainEpithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain1Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Centre, Madrid, SpainHospital Ramon y Cajal, Madrid, SpainVCN Biosciences, Sant Cugat del Vallès, Barcelona, SpainCentro Integral Oncológico Clara Campal (CIOCC), Oña 10, 28050, Madrid, SpainVCN Biosciences, Sant Cugat del Valles, Barcelona, 08174, SpainVCN Biosciences, Sant Cugat del Valles, Barcelona, 08174, SpainVCN Biosciences, Sant Cugat del Valles, Barcelona, 08174, SpainVCN Biosciences, Sant Cugat del Valles, Barcelona, 08174, SpainOncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, SpainVall d`Hebron University Hospital & Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SpainVCN Biosciences, Sant Cugat del Vallès, Barcelona, SpainProgram in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Barcelona, SpainProgram in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Barcelona, SpainDepartment of Pathology, Hospital Universitari de Bellvitge, L`Hospitalet de Llobregat, SpainBackground 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.https://jitc.bmj.com/content/10/3/e003255.full |
| spellingShingle | Gabriel Capellá Francisco X Real Marta Gil-Martin Rocio Garcia-Carbonero Rafael Moreno Ramon Alemany Martí Farrera-Sal Ramon Salazar Teresa Macarulla Jaime Martinez de Villarreal Natalia del Pozo Carmen Guillén-Ponce Miriam Bazan-Peregrino Rafael Álvarez Ana Mato-Berciano Emma Blasi Carmen Blasco Manel Cascallo Maria C Riesco-Martinez Helena Verdaguer Maria Victoria Maliandi Silvia Torres-Manjon Marcel Costa Noemí Vidal 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 Journal for ImmunoTherapy of Cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/10/3/e003255.full |
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