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

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.

Conflict of interest statement

J.d.B.: consultancies for Astellas, AstraZeneca, Boehringer Ingelheim, Carrick, Daiichi, Genentech/Roche, GSK, MSD, Merck, Menarini, Serono, Sanofi Aventis, Shattuck and Taiho; received research grants from Astex, AstraZeneca, Daiichi, Genentech, GSK, Merck, MSD, Sanofi, and Serono. C.H.H.: consultancies for Bristol-Myers Squibb, Eli Lilly, MSD, Merck Serono, Novartis, Ono Pharmaceutical; received remuneration from Bristol-Myers Squibb, MSD, and Ono Pharmaceutical; received research funding from AstraZeneca, Bristol-Myers Squibb, Genentech, MSD, Merck Serono, Ono Pharmaceutical, and Taiho Pharmaceutical. A.A.: consultancies for Ono Pharmaceuticals and Advanced Accelerator Applications. S.B., R.F., U.S., R.G.G., D.C.L.H., N.S. and T.B.: employees of Boehringer Ingelheim. T.B.: owns stock in Roche, Seattle Genetics, Immunogen, Gilead, and Celgene. C.T.: consultancies for Pfizer, Nektar, and Daiichi; received remuneration from Pfizer, Roche, and Daiichi. J.C.H.Y.: consultancies for Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Takeda, and Hansoh Pharmaceuticals. L.T.C.: consultancies for Ono Pharmaceutical, BMS, MSD, Eli Lilly, PharmaEngine, Five Prime, Novartis, and Astra Zeneca; received patent royalties/licensing fees from HuniLife; received remuneration from Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Eli Lilly, PhamaEngine, TTY, SyncoreBio, Five Prime, Novartis, Astra Zeneca, and Ipsen; received research funding from Novartis, Pfizer, Merck Serono, Polaris, TTY, SyncoreBio, Celgene, and BMS; Board Member of ScinoPharm Taiwan, Ltd. A.L.C.: consultancies for Novartis, Merck Serono, Eisai, Merck Sharp & Dohme (I.A.) Corp., Exelixis, Bayer HealthCare Pharmaceuticals Inc., Bristol-Myers Squibb Company, and Ono Pharmaceutical Co., Ltd.; received remuneration from Bayer, Eisai, Novartis, Eli Lilly, and MSD. The remaining authors declare no competing interests.

Figures

Fig. 1. PK and PD effects of xentuzumab in study 1280.1 (weekly xentuzumab).

Mean plasma concentration–time profiles after IV infusion of xentuzumab in part I course 1 (a; semi-log scale), and after the first (course 1) and repeated (course 2 and 3) weekly IV infusions of 1000 mg xentuzumab in part II (b; semi-log scale). Mean total IGF-1 absolute change from baseline–time profiles after repeated weekly xentuzumab infusions in part I (c). Comparison of individual and arithmetic mean AUEC0-840 values of absolute change from baseline of total IGF-1 after weekly xentuzumab infusions of 10–1800 mg (d). Individual and arithmetic mean total IGF-1 absolute change from baseline–time profiles after weekly IV infusion of 1000 mg in part II (e; linear scale; filled circles indicate the mean values). Median bioactive IGF effect–time profiles after repeated weekly infusions of xentuzumab in part I (f), and after weekly IV infusion of 1000 mg in part II (g; linear scale). AUEC0–840 area under the biomarker effect versus time curve between 0 and 840 h after the start of the first infusion, gMean geometric mean, IGF(-1) insulin-like growth factor(-1), IV intravenous, PD pharmacodynamics, PK pharmacokinetics.

Fig. 2. Probability that RBD is reached for weekly dose levels (pooled data from both studies).

Mean probability that RBD is reached for xentuzumab 1000 mg/week is shown in bold. Horizontal lines represent the median, diamonds represent the mean, and boxes represent the 25th and 75th percentiles. Whiskers represent the 2.5th and 97.5th percentiles. EVT extreme value theory, RBD relevant biological dose.