Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours
| Autor: | Rainer Georg Goeldner, Li-Tzong Chen, Alan Anthoney, Karim Rihawi, Ann-Lii Cheng, Maria Jove, Susanne Buschke, Jesus Corral, Vasiliki Michalarea, Jih-Hsiang Lee, Thomas Bogenrieder, Her Shyong Shiah, René Fuertig, Michael Ong, Ulrike Schmid, Chia-Chi Lin, Dennis Chin-Lun Huang, Chih-Hung Hsu, Johann S. de Bono, James Chih-Hsin Yang, Chia Jui Yen, Chris Twelves, Natalja Strelkowa |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Maximum Tolerated Dose Cancer therapy medicine.medical_treatment Antibodies Monoclonal Humanized Article 03 medical and health sciences Insulin-like growth factor Young Adult 0302 clinical medicine Pharmacokinetics Insulin-Like Growth Factor II Internal medicine Neoplasms Medicine Humans Insulin-Like Growth Factor I Adverse effect 030304 developmental biology Aged 0303 health sciences Dose-Response Relationship Drug business.industry Oncogenes Middle Aged medicine.disease Antibodies Neutralizing Nasopharyngeal carcinoma 030220 oncology & carcinogenesis Pharmacodynamics Monoclonal Toxicity Biomarker (medicine) Female business |
| Zdroj: | British Journal of Cancer |
| ISSN: | 0140-3974 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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