{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:37:46Z","timestamp":1787017066145,"version":"build-2736575974"},"reference-count":24,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,7,13]]},"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I\/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with\/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients (aged \u226518 years) with advanced\/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of \u22642 were included. GWN323 (10\u20131500\u2009mg) or GWN323+spartalizumab (GWN323 10\u2013750 mg+spartalizumab 100\u2013300\u2009mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500\u2009mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300\u2009mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade \u22653) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T\u2009cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-\u03b3 or natural killer-cell signatures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GWN323, as a single agent and in combination, was well tolerated in patients with relapsed\/refractory solid tumors. The MAD was 1500\u2009mg q3w for single-agent and GWN323 750 mg+spartalizumab 300\u2009mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02740270\">NCT02740270<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-002863","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T12:50:22Z","timestamp":1628859022000},"page":"e002863","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["First-in-human phase I\/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02740270","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-1660","authenticated-orcid":false,"given":"Sarina A","family":"Piha-Paul","sequence":"first","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravit","family":"Geva","sequence":"additional","affiliation":[{"name":"Division of Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tira J","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, National Cancer Centre Singapore, Singapore"},{"name":"Department of Medicine, Division of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren WT","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, National Cancer Centre Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinta","family":"Hierro","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall D\u2019Hebron University Hospital, Universitat Aut\u00f2noma de Barcelona, Barcelona, Spain"},{"name":"Molecular Therapeutics Research Unit (UITM), Vall d\u2019Hebron Institute of Oncology (VHIO), Universitat Aut\u00f2noma de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshikiko","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"Rahma","sequence":"additional","affiliation":[{"name":"Center for Cancer Therapeutic Innovation, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lesokhin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA"},{"name":"Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-4908","authenticated-orcid":false,"given":"Jason John","family":"Luke","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, University of Chicago, Chicago, Illinois, USA"},{"name":"Department of Hematology\/Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Otero","sequence":"additional","affiliation":[{"name":"Translational Clinical Oncology, Novartis Institutes for BioMedical Research Inc, East Hanover, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Nardi","sequence":"additional","affiliation":[{"name":"Translational Clinical Oncology, Novartis Institutes for BioMedical Research Inc, East Hanover, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angad","family":"Singh","sequence":"additional","affiliation":[{"name":"Oncology Data Science, Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandros","family":"Xyrafas","sequence":"additional","affiliation":[{"name":"Early Development Analytics-Statistics, Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Oncology Therapeutic Area-Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research Inc, East Hanover, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Mataraza","sequence":"additional","affiliation":[{"name":"Oncology Translational Research, Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe L","family":"Bedard","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"2025100304474850000_9.8.e002863.1","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti-PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"N Engl J Med"},{"key":"2025100304474850000_9.8.e002863.2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"2025100304474850000_9.8.e002863.3","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","article-title":"Ipilimumab plus dacarbazine for previously untreated metastatic melanoma","volume":"364","author":"Robert","year":"2011","journal-title":"N Engl J Med"},{"key":"2025100304474850000_9.8.e002863.4","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/bs.ai.2015.12.005","article-title":"Combinatorial cancer immunotherapies","volume":"130","author":"Hellmann","year":"2016","journal-title":"Adv Immunol"},{"key":"2025100304474850000_9.8.e002863.5","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1053\/j.seminoncol.2015.05.014","article-title":"Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS","volume":"42","author":"Sanmamed","year":"2015","journal-title":"Semin Oncol"},{"key":"2025100304474850000_9.8.e002863.6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/2051-1426-2-7","article-title":"Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy","volume":"2","author":"Schaer","year":"2014","journal-title":"J Immunother Cancer"},{"key":"2025100304474850000_9.8.e002863.7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1100\/tsw.2007.106","article-title":"GITR-GITRL system, a novel player in shock and inflammation","volume":"7","author":"Krausz","year":"2007","journal-title":"ScientificWorldJournal"},{"key":"2025100304474850000_9.8.e002863.8","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.cytogfr.2013.12.003","article-title":"Cell-Specific and context-dependent effects of GITR in cancer, autoimmunity, and infection","volume":"25","author":"Clouthier","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"key":"2025100304474850000_9.8.e002863.9","doi-asserted-by":"crossref","DOI":"10.1136\/esmoopen-2020-000738","article-title":"New emerging targets in cancer immunotherapy: the role of GITR","volume":"4","author":"Buzzatti","year":"2020","journal-title":"ESMO Open"},{"key":"2025100304474850000_9.8.e002863.10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2016.06.028","article-title":"Rationale for anti-GITR cancer immunotherapy","volume":"67","author":"Knee","year":"2016","journal-title":"Eur J Cancer"},{"key":"2025100304474850000_9.8.e002863.11","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1080\/14728222.2018.1512588","article-title":"Glucocorticoid-Induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy","volume":"22","author":"Riccardi","year":"2018","journal-title":"Expert Opin Ther Targets"},{"key":"2025100304474850000_9.8.e002863.12","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/eji.201142162","article-title":"Enhanced GITR\/GITRL interactions augment IL-27 expression and induce IL-10-producing TR-1 like cells","volume":"42","author":"Carrier","year":"2012","journal-title":"Eur J Immunol"},{"key":"2025100304474850000_9.8.e002863.13","doi-asserted-by":"crossref","DOI":"10.1186\/1479-5876-12-36","article-title":"Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs","volume":"12","author":"Lu","year":"2014","journal-title":"J Transl Med"},{"key":"2025100304474850000_9.8.e002863.14","doi-asserted-by":"crossref","first-page":"eaat7061","DOI":"10.1126\/sciimmunol.aat7061","article-title":"Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+ T cell dysfunction and maintain memory phenotype","volume":"3","author":"Wang","year":"2018","journal-title":"Sci Immunol"},{"key":"2025100304474850000_9.8.e002863.15","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-000530","article-title":"A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors","volume":"8","author":"Naing","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2025100304474850000_9.8.e002863.16","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2018.36.15_suppl.6024","article-title":"Phase I\/II study of spartalizumab (PDR001), an anti-PD1 mAb, in patients with anaplastic thyroid cancer","volume":"36","author":"Wirth","year":"2018","journal-title":"Journal of Clinical Oncology"},{"key":"2025100304474850000_9.8.e002863.17","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2016.34.15_suppl.3017","article-title":"First-In-Human phase 1 single-dose study of TRX-518, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody in adults with advanced solid tumors","volume":"34","author":"Koon","year":"2016","journal-title":"Journal of Clinical Oncology"},{"key":"2025100304474850000_9.8.e002863.18","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2017.35.15_suppl.104","article-title":"Preliminary results of a phase I\/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor\u2013related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors","volume":"35","author":"Siu","year":"2017","journal-title":"Journal of Clinical Oncology"},{"key":"2025100304474850000_9.8.e002863.19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s40425-018-0407-x","article-title":"Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor\u2013related protein agonist AMG 228 in patients with advanced solid tumors","volume":"6","author":"Tran","year":"2018","journal-title":"j. immunotherapy cancer"},{"key":"2025100304474850000_9.8.e002863.20","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1158\/1078-0432.CCR-20-0452","article-title":"Safety and clinical activity of MEDI1873, a novel GITR agonist, in advanced solid tumors","volume":"26","author":"Balmanoukian","year":"2020","journal-title":"Clin Cancer Res"},{"key":"2025100304474850000_9.8.e002863.21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s40425-018-0407-x","article-title":"Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors","volume":"6","author":"Tran","year":"2018","journal-title":"J Immunother Cancer"},{"key":"2025100304474850000_9.8.e002863.22","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2018.36.15_suppl.3029","article-title":"First-In-Human phase 1 study of MK-1248, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody, as monotherapy or in combination with pembrolizumab in patients with advanced solid tumors","volume":"36","author":"Geva","year":"2018","journal-title":"Journal of Clinical Oncology"},{"key":"2025100304474850000_9.8.e002863.23","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1001\/jamaoncol.2019.3848","article-title":"Safety, tolerability, and potential clinical activity of a glucocorticoid-induced TNF receptor-related protein agonist alone or in combination with nivolumab for patients with advanced solid tumors: a phase 1\/2A dose-escalation and Cohort-Expansion clinical trial","volume":"6","author":"Heinhuis","year":"2020","journal-title":"JAMA Oncol"},{"key":"2025100304474850000_9.8.e002863.24","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2019.37.15_suppl.9509","article-title":"Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (PTS) with advanced solid tumors","volume":"37","author":"Papadopoulos","year":"2019","journal-title":"Journal of Clinical Oncology"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-002863","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:47:59Z","timestamp":1759492079000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-002863"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8,13]]},"published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1136\/jitc-2021-002863"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-002863","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8]]}}}