Abstract
BackgroundXentuzumab, 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.MethodsThese 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.ResultsStudy 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.ConclusionsXentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity.Clinical trial registrationNCT01403974; NCT01317420.
Highlights
Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling
Xentuzumab (BI 836845) is a fully humanised IgG1 monoclonal antibodies (mAbs), which binds IGF-1 and IGF-2 with high affinity and potently neutralises proliferative and pro-survival signalling triggered by both ligands
In study 1280.2, the 3-weekly schedule did not show a similar level of target engagement at equivalent doses to the weekly schedule; as such, xentuzumab 1000 mg weekly was assessed in the expansion part in both trials
Summary
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. Xentuzumab (BI 836845) is a fully humanised IgG1 mAb, which binds IGF-1 and IGF-2 with high affinity and potently neutralises proliferative and pro-survival signalling triggered by both ligands.. Xentuzumab (BI 836845) is a fully humanised IgG1 mAb, which binds IGF-1 and IGF-2 with high affinity and potently neutralises proliferative and pro-survival signalling triggered by both ligands.4 This ligand-binding approach offers advantages over IGF-1R-targeted therapies, as it inhibits the proliferative/anti-apoptotic effects of IGF-2 signalling through insulin receptor isoform A (INSR-A).. This ligand-binding approach offers advantages over IGF-1R-targeted therapies, as it inhibits the proliferative/anti-apoptotic effects of IGF-2 signalling through insulin receptor isoform A (INSR-A).5 These authors contributed : Johann de Bono, Chia-Chi Lin The insulin-like growth factor (IGF) signalling axis plays a role in carcinogenesis and is associated with cancer progression, prognosis, and treatment resistance. therapeutic targeting of the IGF axis has been investigated in various human cancers, with early strategies targeting the IGF type 1 receptor (IGF-1R)
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