{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:03:12Z","timestamp":1780596192548,"version":"3.54.1"},"reference-count":26,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Introduction<\/jats:title>\n BI 891065, a second mitochondria\u2010derived activator of caspases mimetic targets the inhibitor of apoptosis (IAP) family member cIAP1. We describe two first\u2010in\u2010human phase 1 trials assessing BI 891065\u2009\u00b1\u2009the anti\u2010programmed cell death protein\u20101 (PD1) antibody, ezabenlimab, in advanced solid tumors.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Trials were conducted in the USA (NCT03166631) and Japan (NCT04138823). Dose escalation of BI 891065 monotherapy (part A) and combined with ezabenlimab (part B) was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoints were maximum tolerated dose (MTD) and number of patients with dose\u2010limiting toxicities (DLTs) in Cycle 1. Other endpoints included objective response (RECIST v 1.1), pharmacokinetics, and changes in peripheral blood mononuclear cell (PBMC) and tumor cIAP1 levels.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Twenty\u2010five patients (USA study) received 5\u2013400\u2009mg daily BI 891065 monotherapy; 12 patients (Japan study) received 100\u2009mg daily, 200\u2009mg daily, or 200\u2009mg twice\u2010daily BI 891065 monotherapy. No DLTs occurred in the USA study; three occurred in the Japan study: grade 3 increased bilirubin (\n n<\/jats:italic>\n \u2009=\u20092) and maculopapular rash (\n n<\/jats:italic>\n \u2009=\u20091). Neither study reached MTD for monotherapy. Treatment\u2010related adverse events (TRAEs) occurred in 52% and 75% of patients, respectively. BI 891065 plus ezabenlimab combination (USA study part B only) was received by 37 patients (50\u2013400\u2009mg daily, 200\u2009mg twice\u2010daily) plus ezabenlimab (240\u2009mg fixed\u2010dose, Day 1 of 21\u2010day\u2009cycles). One DLT occurred (grade 2 pneumonitis). MTD was not reached. TRAEs occurred in 81% of patients. Neither study reported objective responses; 25%\u201340% and 35% of patients achieved stable disease with BI 891065 monotherapy and the combination, respectively. cIAP1 levels were reduced in PBMCs and biopsies.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n BI 891065 was tolerable in patients with advanced solid tumors, demonstrating target engagement as monotherapy and combined with ezabenlimab. Both studies ended early due to efficacy data that were insufficiently promising to justify continuation.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n NCT03166631, NCT04138823<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cam4.71451","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T07:16:03Z","timestamp":1766042163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Second Mitochondria\u2010Derived Activator of Caspases Mimetic\n BI<\/scp>\n 891065 in Patients With Advanced Solid Tumors: Results From Two Phase I Studies"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6836-2364","authenticated-orcid":false,"given":"Manish R.","family":"Patel","sequence":"first","affiliation":[{"name":"Florida Cancer Specialists\/Sarah Cannon Research Institute Sarasota Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika P.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute Nashville Tennesse USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"George","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunther","family":"Kretschmar","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Harada","sequence":"additional","affiliation":[{"name":"Nippon Boehringer Ingelheim Co., Ltd. Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Graeser","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany"},{"name":"Astra Zeneca Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Eleftheraki","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4279-3172","authenticated-orcid":false,"given":"Yoshifumi","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Nippon Boehringer Ingelheim Co., Ltd. Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60958-2"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758835921992968"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.2217\/imt-2017-0185"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020406"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010207"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098231"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040599"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0475"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-015-2709-8"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.52.3993"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.29783"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.4161\/23723548.2014.964622"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2017-2330"},{"key":"e_1_2_13_16_1","unstructured":"I.Tirapu M. A.Impagnatiello D.Zach et\u00a0al. \u201cIn Vitro Characterization of Immunogenic Cell Death Induced by BI 891065 a Novel SMAC Mimetic \u201dPresented at the 3rd CRI\u2010CIMT\u2010EATI\u2010AACR International Cancer Immunotherapy Conference in Mainz Germany on 6\u20139 Sep 2017."},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2018-4558"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy374.041"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.08.1064"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2020.38.15_suppl.3054"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e31822722b6"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/2168479014524582"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250902800153"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.2174\/1574884714666190408125206"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.221"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP38053"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1990.111"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71451","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T11:26:07Z","timestamp":1766748367000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.71451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":26,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/cam4.71451"],"URL":"https:\/\/doi.org\/10.1002\/cam4.71451","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-04-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71451"}}