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

  • Br J Cancer. 2020 Apr;122(9):1324-1332. doi: 10.1038/s41416-020-0774-1.
Johann de Bono  #  1 ,  Chia-Chi Lin  #  2 ,  Li-Tzong Chen  3  4  5 ,  Jesus Corral  6 ,  Vasiliki Michalarea  7 ,  Karim Rihawi  7  8 ,  Michael Ong  9 ,  Jih-Hsiang Lee  2 ,  Chih-Hung Hsu  2 ,  James Chih-Hsin Yang  2 ,  Her-Shyong Shiah  10 ,  Chia-Jui Yen  3 ,  Alan Anthoney  11 ,  Maria Jove  11 ,  Susanne Buschke  12 ,  René Fuertig  12 ,  Ulrike Schmid  12 ,  Rainer-Georg Goeldner  13 ,  Natalja Strelkowa  13 ,  Dennis Chin-Lun Huang  14 ,  Thomas Bogenrieder  15  16 ,  Chris Twelves  #  11 ,  Ann-Lii Cheng  #  2  17
Affiliations
  • 1. Drug Development Unit, Royal Marsden Hospital & Institute of Cancer Research, Downs Road, Sutton, UK. [email protected].
  • 2. Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S. Rd., Taipei, Taiwan.
  • 3. Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan.
  • 4. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou 1st Road, Kaohsiung, Taiwan.
  • 5. National Institute of Cancer Research, National Health Research Institutes, 367 Sheng Li Road, Tainan, Taiwan.
  • 6. Medical Oncology Department, Clinica Universidad de Navarra, Calle Marquesado de Sta. Marta 1, Madrid, Spain.
  • 7. Drug Development Unit, Royal Marsden Hospital & Institute of Cancer Research, Downs Road, Sutton, UK.
  • 8. Azienda Sanitaria Universitaria Integrata di Udine, Via Pozzuolo, 330, 33100, Udine, Italy.
  • 9. The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON, Canada.
  • 10. The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing Street, Taipei, Taiwan.
  • 11. University of Leeds and Leeds Teaching Hospitals Trust, Beckett Street, Leeds, UK.
  • 12. Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riß, Germany.
  • 13. Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, Biberach an der Riß, Germany.
  • 14. Medical Department, Boehringer Ingelheim Taiwan Ltd, 12F, No. 2, Sec 3, Minsheng East Road, Taipei, Taiwan.
  • 15. Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, 1 Geschwister-Scholl-Platz, Munich, Germany.
  • 16. Medicine and Translational Research, Boehringer Ingelheim RCV, 5-11 Doktor-Boehringer-Gasse, Vienna, Austria.
  • 17. National Taiwan University Cancer Center, Taipei, Taiwan.
  • # Contributed equally.
PMID: 32161368 DOI: 10.1038/s41416-020-0774-1
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.

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