{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:17:39Z","timestamp":1792019859101,"version":"4.4.0"},"reference-count":35,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T00:00:00Z","timestamp":1602201600000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,8,23]]},"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and\/or palliative radiation therapy (RT) for advanced solid tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Patients and methods<\/jats:title>\n                  <jats:p>Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005\u20130.055\u2009mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012\u2009mg plus durvalumab 1500\u2009mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037\u2009mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012\u2009mg in combination with durvalumab 1500\u2009mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade \u22653 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease \u22658 weeks.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>IT MEDI9197 was feasible for subcutaneous\/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.<\/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=\"NCT02556463\">NCT02556463<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001095","type":"journal-article","created":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T17:45:20Z","timestamp":1602265520000},"page":"e001095","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and\/or palliative radiation therapy in patients with advanced solid tumors"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct02556463","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Lillian","family":"Siu","sequence":"first","affiliation":[{"name":"Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Brody","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, United 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