Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors
Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death liga...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e009336.full |
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| author | Dmitriy Zamarin Diwakar Davar Adel Samson Kevin J Harrington Siddharth Sheth Eric Tu Mitesh J Borad Grace K Dy Evanthia Galanis Fernanda Arnaldez Sandip P Patel Nicholas Durham Benedito A Carneiro Sonia Agrawal Zhongying Chen Chunling Fan Maozhen Gong Jenny Burton Kevin Laubscher |
| author_facet | Dmitriy Zamarin Diwakar Davar Adel Samson Kevin J Harrington Siddharth Sheth Eric Tu Mitesh J Borad Grace K Dy Evanthia Galanis Fernanda Arnaldez Sandip P Patel Nicholas Durham Benedito A Carneiro Sonia Agrawal Zhongying Chen Chunling Fan Maozhen Gong Jenny Burton Kevin Laubscher |
| author_sort | Dmitriy Zamarin |
| collection | DOAJ |
| description | Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors.Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395.Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively.Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors.Trial registration number NCT03889275 |
| format | Article |
| id | doaj-art-9b8ca43a8d514a34aab835d920738e15 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9b8ca43a8d514a34aab835d920738e152025-08-20T01:52:21ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-009336Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumorsDmitriy Zamarin0Diwakar Davar1Adel Samson2Kevin J Harrington3Siddharth Sheth4Eric Tu5Mitesh J Borad6Grace K Dy7Evanthia Galanis8Fernanda Arnaldez9Sandip P Patel10Nicholas Durham11Benedito A Carneiro12Sonia Agrawal13Zhongying Chen14Chunling Fan15Maozhen Gong16Jenny Burton17Kevin Laubscher18Early Drug Development, Memorial Sloan Kettering Cancer Center, New York, New York, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USALeeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research / The Royal Marsden NIHR Biomedical Research Centre, London, UKDivision of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USATranslational Medicine, Cell Therapy and Oncolytic Viruses, BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAMayo Clinic, Phoenix, Arizona, USA5Roswell Park Comprehensive Cancer Center, Buffalo, NY, USAMayo Clinic Rochester, Rochester, Minnesota, USAClinical Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAMoores Cancer Center, University of California San Diego, La Jolla, California, USATranslational Medicine, Cell Therapy and Oncolytic Viruses, BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USALifespan Cancer Institute, Legorreta Cancer Institute at Brown University, Providence, Rhode Island, USAOncology Data Science, Research and Early Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAIntegrated Bioanalysis, Clinical Pharmacology and Safety Sciences (CPSS), BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAClinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences (CPSS), BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAAstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USAOncology R&D, AstraZeneca PLC, Cambridge, Cambridgeshire, UKOncology Data Science, Research and Early Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USABackground MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors.Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395.Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively.Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors.Trial registration number NCT03889275https://jitc.bmj.com/content/12/11/e009336.full |
| spellingShingle | Dmitriy Zamarin Diwakar Davar Adel Samson Kevin J Harrington Siddharth Sheth Eric Tu Mitesh J Borad Grace K Dy Evanthia Galanis Fernanda Arnaldez Sandip P Patel Nicholas Durham Benedito A Carneiro Sonia Agrawal Zhongying Chen Chunling Fan Maozhen Gong Jenny Burton Kevin Laubscher Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors |
| title_full | Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors |
| title_fullStr | Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors |
| title_full_unstemmed | Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors |
| title_short | Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors |
| title_sort | phase i study of a recombinant attenuated oncolytic virus medi5395 ndv gm csf administered systemically in combination with durvalumab in patients with advanced solid tumors |
| url | https://jitc.bmj.com/content/12/11/e009336.full |
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