Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1

Anthony W. Tolcher, John Sarantopoulos, Amita Patnaik, Kyriakos Papadopoulos, Chia Chi Lin, Jordi Rodon, Barbara Murphy, Bruce Roth, Ian McCaffery, Kevin S. Gorski, Brianne Kaiser, Min Zhu, Hongjie Deng, Greg Friberg, Igor Puzanov

Research output: Contribution to journalArticle

243 Scopus citations

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R). Patients and Methods: Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects. Results: Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months. Conclusion: AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.

Original languageEnglish (US)
Pages (from-to)5800-5807
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number34
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tolcher, A. W., Sarantopoulos, J., Patnaik, A., Papadopoulos, K., Lin, C. C., Rodon, J., Murphy, B., Roth, B., McCaffery, I., Gorski, K. S., Kaiser, B., Zhu, M., Deng, H., Friberg, G., & Puzanov, I. (2009). Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. Journal of Clinical Oncology, 27(34), 5800-5807. https://doi.org/10.1200/JCO.2009.23.6745