{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T07:16:15Z","timestamp":1794035775360,"version":"4.8.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Invest New Drugs"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n\u2009=\u20098; colorectal, n\u2009=\u20093; ovarian, n\u2009=\u20093; other, n\u2009=\u20098) received IM156 100 to 1,200\u00a0mg either QOD or QD. There were no DLTs. However, 1,200\u00a0mg QD was not well tolerated due to nausea; 800\u00a0mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n\u2009=\u200915; 68%), diarrhea (n\u2009=\u200910; 46%), emesis (n\u2009=\u20099; 41%), fatigue (n\u2009=\u20094; 18%) and abdominal pain, constipation, and blood lactate increased (n\u2009=\u20092 each; 9%). Grade 3 nausea (n\u2009=\u20093; 14%) was the only grade\u2009\u2265\u20093 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC\n                    <jats:sub>0-24<\/jats:sub>\n                    ) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.\n                  <\/jats:p>","DOI":"10.1007\/s10637-022-01277-9","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T07:02:54Z","timestamp":1657263774000},"page":"1001-1010","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors"],"prefix":"10.1007","volume":"40","author":[{"given":"Filip","family":"Janku","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hoon","family":"Beom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Wha","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Won","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young G.","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Seok","family":"Yim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gun Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Song","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Ho","family":"Cheong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Woo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barb","family":"Geiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghee","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archie","family":"Thurston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Welsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S.","family":"Rudoltz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Young","family":"Rha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"issue":"1","key":"1277_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nchembio.1712","volume":"11","author":"SE Weinberg","year":"2015","unstructured":"Weinberg SE, Chandel NS (2015) Targeting mitochondria metabolism for cancer therapy. 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The study was approved by each Institutional Review Board and patients provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors approved the final version of the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All patients provided written informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The study was conducted in accordance with Good Clinical Practice, the International Council for Harmonisation, and guidelines governing clinical study conduct and the ethical principles originating from the Declaration of Helsinki. The study was approved by each Institutional Review Board.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants and\/or animals"}},{"value":"FJ reports research funding paid to the institution from Novartis, BioMed Valley Discoveries, Bioxcel Therapeutics, Bicara Therapeutics, Plexxikon, Deciphera, Piqur, Sanofi, SynthoRx, Merck, Spring Bank Pharmaceuticals, Symphogen, Synlogic, SQZ Biotechnologies, Ideaya Biosciences, Bayer, FujiFilm Corporation, Astex, Asana, Astellas, Agios, and Bristol-Myers Squibb; is or has been on scientific advisory board or provided paid consulting services for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, Ideaya, PureTech Health, Jazz Pharmaceuticals, Cardiff Oncology, Immunomet, Primmune Therapeutics, Sotio, Bicara Therapeutics, Petra Therapeutics; and has ownership interest in Cardiff Oncology. MSR reports stock and ownership interests in Novartis, Kura Oncology, Kronos Bio, Mycovia Pharmaceuticals, ENB Therapeutics, ImmunoMet Therapeutics, FemSelect, Broadspot, Cerus, and Healionics, is or has been in a consulting or advisory role for Blueprint Medicines, Immunomet Therapeutics, Nextcure Inc, Novellus Ltd, Epivax Therapeutics, Premier Research, and Ikena Oncology.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"FJ reports research funding paid to the institution from Novartis, BioMed Valley Discoveries, Bioxcel Therapeutics, Bicara Therapeutics, Plexxikon, Deciphera, Piqur, Sanofi, SynthoRx, Merck, Spring Bank Pharmaceuticals, Symphogen, Synlogic, SQZ Biotechnologies, Ideaya Biosciences, Bayer, FujiFilm Corporation, Astex, Asana, Astellas, Agios, and Bristol-Myers Squibb; is or has been on scientific advisory board or provided paid consulting services for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, Ideaya, PureTech Health, Jazz Pharmaceuticals, Cardiff Oncology, Immunomet, Primmune Therapeutics, Sotio, Bicara Therapeutics, Petra Therapeutics; and has ownership interest in Cardiff Oncology. MSR reports stock and ownership interests in Novartis, Kura Oncology, Kronos Bio, Mycovia Pharmaceuticals, ENB Therapeutics, ImmunoMet Therapeutics, FemSelect, Broadspot, Cerus, and Healionics, is or has been in a consulting or advisory role for Blueprint Medicines, Immunomet Therapeutics, Nextcure Inc, Novellus Ltd, Epivax Therapeutics, Premier Research, and Ikena Oncology.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure of potential conflicts of interest"}}]}}