Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

Johann de Bono, Chia Chi Lin, Li Tzong Chen, Jesus Corral, Vasiliki Michalarea, Karim Rihawi, Michael Ong, Jih Hsiang Lee, Chih Hung Hsu, James Chih Hsin Yang, Her Shyong Shiah, Chia Jui Yen, Alan Anthoney, Maria Jove, Susanne Buschke, René Fuertig, Ulrike Schmid, Rainer Georg Goeldner, Natalja Strelkowa, Dennis Chin Lun HuangThomas Bogenrieder, Chris Twelves, Ann Lii Cheng

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1324-1332
Number of pages9
JournalBritish Journal of Cancer
Volume122
Issue number9
DOIs
Publication statusPublished - Apr 28 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    de Bono, J., Lin, C. C., Chen, L. T., Corral, J., Michalarea, V., Rihawi, K., Ong, M., Lee, J. H., Hsu, C. H., Yang, J. C. H., Shiah, H. S., Yen, C. J., Anthoney, A., Jove, M., Buschke, S., Fuertig, R., Schmid, U., Goeldner, R. G., Strelkowa, N., ... Cheng, A. L. (2020). Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours. British Journal of Cancer, 122(9), 1324-1332. https://doi.org/10.1038/s41416-020-0774-1