https://scholars.lib.ntu.edu.tw/handle/123456789/487251
標題: | Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours | 作者: | de Bono J. CHIA-CHI LIN Chen L.-T. Corral J. Michalarea V. Rihawi K. Ong M. JIH-HSIANG LEE CHIH-HUNG HSU CHIH-HSIN YANG Shiah H.-S. Yen C.-J. Anthoney A. Jove M. Buschke S. Fuertig R. Schmid U. Goeldner R.-G. Strelkowa N. Huang D.C.-L. Bogenrieder T. Twelves C. ANN-LII CHENG |
公開日期: | 2020 | 出版社: | Springer Nature | 來源出版物: | British Journal of Cancer | 摘要: | Background: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. Methods: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. Results: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ?450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. Conclusions: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. Clinical trial registration: NCT01403974; NCT01317420. ? 2020, The Author(s). |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081903238&doi=10.1038%2fs41416-020-0774-1&partnerID=40&md5=fabcf29e57328e2c7c94d7fc09dddfe5 https://scholars.lib.ntu.edu.tw/handle/123456789/487251 |
ISSN: | 0007-0920 | DOI: | 10.1038/s41416-020-0774-1 | SDG/關鍵字: | biological marker; drug antibody; neutralizing antibody; somatomedin; somatomedin B; somatomedin C; xentuzumab; IGF1 protein, human; monoclonal antibody; neutralizing antibody; somatomedin B; somatomedin C; xentuzumab; acute respiratory failure; adult; advanced cancer; aged; anemia; antineoplastic activity; area under the curve; Article; aspiration pneumonia; biological activity; central nervous system metastasis; clinical outcome; cohort analysis; colitis; constipation; decreased appetite; diarrhea; dose response; drug dose escalation; drug efficacy; drug safety; drug tolerability; drug withdrawal; dyspnea; fatigue; female; gastrointestinal disease; half life time; human; hyperglycemia; hypersensitivity; immunogenicity; infusion related reaction; lethargy; logistic regression analysis; lung hemorrhage; major clinical study; male; maximum concentration; maximum tolerated dose; metastasis; nasopharynx carcinoma; nausea; neuroectoderm tumor; neutropenia; open study; optimal drug dose; pharmacodynamics; phase 1 clinical trial; plasma concentration-time curve; pneumonia; priority journal; protein blood level; relevant biological dose; solid malignant neoplasm; subdural hematoma; thrombocytopenia; thrush; treatment response; vomiting; clinical trial; genetics; immunology; middle aged; neoplasm; pathology; young adult; Adult; Aged; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Dose-Response Relationship, Drug; Female; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Young Adult |
顯示於: | 腫瘤醫學研究所 |
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