Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. Academic Article uri icon

Overview

abstract

  • Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma.Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs.Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses ≥1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines.Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of ≥1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents. Clin Cancer Res; 23(8); 1929-36. ©2016 AACR.

authors

  • Segal, Neil Howard
  • Logan, Theodore F
  • Hodi, F Stephen
  • McDermott, David
  • Melero, Ignacio
  • Hamid, Omid
  • Schmidt, Henrik
  • Robert, Caroline
  • Chiarion-Sileni, Vanna
  • Ascierto, Paolo A
  • Maio, Michele
  • Urba, Walter J
  • Gangadhar, Tara C
  • Suryawanshi, Satyendra
  • Neely, Jaclyn
  • Jure-Kunkel, Maria
  • Krishnan, Suba
  • Kohrt, Holbrook
  • Sznol, Mario
  • Levy, Ronald

publication date

  • October 18, 2016

Research

keywords

  • 4-1BB Ligand
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Neoplasms

Identity

Scopus Document Identifier

  • 85018841234

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-16-1272

PubMed ID

  • 27756788

Additional Document Info

volume

  • 23

issue

  • 8