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

Bono, J. (Johann) de; Lin, C.C. (Chia-Chi); Chen, L.T. (Li-Tzung); Corral, J. (Jesús); Michalarea, V. (Vasiliki); Rihawi, K. (Karim); Ong, M. (Michael); Lee, J.G. (Jih-Hsiang); Hsu, C.H. (Chih-Hung); Chih-Hsin-Yang, J. (James); Shiah, H.S. (Her-Shyong); Yen, C.J. (Chia-Jui); Anthoney, A. (Alan); Jove, M. (Maria); Buschke, S. (Susanne); Fuertig, R. (René); Schmid, U. (Ulrike); Goeldner, R.G. (Rainer-Georg); Strelkowa, N. (Natalja); Huang, D.C.L. (Dennis Chin-Lun); Bogenrieder, T. (Thomas); Twelves, C. (Chris); Cheng, A.L. (Ann-Lii)

Keywords:

Xentuzumab
Insulin
Biological dose

Issue Date:

2020

Publisher:

Springer Nature

ISSN:

0007-0920

Note:

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

Citation:

Bono, J. (Johann) de; Lin, C.C. (Chia-Chi); Chen, L.T. (Li-Tzung); et al. "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), 2020, 1324 - 1332

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.

URI:

https://hdl.handle.net/10171/67298

DOI:

10.1038/s41416-020-0774-1

Appears in Collections:

DA - CUN - Oncología médica - Artículos de revista

Files in This Item: