Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors
Background Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-r...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005007.full |
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| author | Christy Ralph Sumati Gupta Matthew Zibelman Brendan D Curti Kevin J Harrington Steven J O'Day Andrew G Hill David C Campbell Gavin M Wright David E Gerber Jonathan E Rosenberg Jaime R Merchan Charles M Rudin Hardev S Pandha Wallace L Akerley Daphne Day Timothy D Clay Ross R Jennens Yixin Ren Emmett V Schmidt Lisa Guttman |
| author_facet | Christy Ralph Sumati Gupta Matthew Zibelman Brendan D Curti Kevin J Harrington Steven J O'Day Andrew G Hill David C Campbell Gavin M Wright David E Gerber Jonathan E Rosenberg Jaime R Merchan Charles M Rudin Hardev S Pandha Wallace L Akerley Daphne Day Timothy D Clay Ross R Jennens Yixin Ren Emmett V Schmidt Lisa Guttman |
| author_sort | Christy Ralph |
| collection | DOAJ |
| description | Background Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed.Results No DLTs occurred in parts A (n=18) or B (n=85). Grade 3–5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35).Conclusions Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy.Trial registration number NCT02043665. |
| format | Article |
| id | doaj-art-07dff5f507bc4d64bce5f819f24c264d |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-07dff5f507bc4d64bce5f819f24c264d2025-01-29T11:45:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005007Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumorsChristy Ralph0Sumati Gupta1Matthew Zibelman2Brendan D Curti3Kevin J Harrington4Steven J O'Day5Andrew G Hill6David C Campbell7Gavin M Wright8David E Gerber9Jonathan E Rosenberg10Jaime R Merchan11Charles M Rudin12Hardev S Pandha13Wallace L Akerley14Daphne Day15Timothy D Clay16Ross R Jennens17Yixin Ren18Emmett V Schmidt19Lisa Guttman20Division of Medical Oncology, Institute of Oncology, St. James`s University Hospital, Leeds, UKHuntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USAFox Chase Cancer Center, Philadelphia, Pennsylvania, USA3Providence Cancer Institute, Franz Clinic, Portland, OR, USADivision of Radiotherapy and Imaging, The Institute of Cancer Research / The Royal Marsden NIHR Biomedical Research Centre, London, UKJohn Wayne Cancer Institute, Providence St John`s Health Center, Santa Monica, California, USATasman Oncology Research, Ltd, Southport, Queensland, AustraliaWestern Health, Sunshine Hospital, St Albans, Victoria, AustraliaDepartment of Surgery, St Vincent`s Hospital Melbourne, The University of Melbourne, Fitzroy, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Parkville, Victoria, AustraliaDivision of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USAMemorial Sloan Kettering Cancer Center, New York, New York, USASylvester Comprehensive Cancer Center, Miami, Florida, USAProfessor of Medicine, Weill Cornell Medical College, New York, New York, USAUniversity of Surrey, Guildford, UKDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USADepartment of Oncology, Monash Health and Monash University, Clayton, Victoria, AustraliaMedical Oncology, St. John of God Subiaco Hospital, Perth, Western Australia, AustraliaEpworth Healthcare, Richmond, Victoria, AustraliaMerck & Co., Inc, Rahway, New Jersey, USAMerck & Co., Inc, Rahway, New Jersey, USAPractical Clinical, Mississauga, Ontario, CanadaBackground Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed.Results No DLTs occurred in parts A (n=18) or B (n=85). Grade 3–5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35).Conclusions Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy.Trial registration number NCT02043665.https://jitc.bmj.com/content/11/1/e005007.full |
| spellingShingle | Christy Ralph Sumati Gupta Matthew Zibelman Brendan D Curti Kevin J Harrington Steven J O'Day Andrew G Hill David C Campbell Gavin M Wright David E Gerber Jonathan E Rosenberg Jaime R Merchan Charles M Rudin Hardev S Pandha Wallace L Akerley Daphne Day Timothy D Clay Ross R Jennens Yixin Ren Emmett V Schmidt Lisa Guttman Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors |
| title_full | Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors |
| title_fullStr | Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors |
| title_full_unstemmed | Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors |
| title_short | Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors |
| title_sort | phase 1 open label dose escalation study on the safety pharmacokinetics and preliminary efficacy of intravenous coxsackievirus a21 v937 with or without pembrolizumab in patients with advanced solid tumors |
| url | https://jitc.bmj.com/content/11/1/e005007.full |
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