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Clin Cancer Res. 2017 Apr 15;23(8):1929-1936. doi: 10.1158/1078-0432.CCR-16-1272. Epub 2016 Oct 18.

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

Author information

1
Memorial Sloan Kettering Cancer Center, New York, New York.
2
Indiana University Simon Cancer Center, Indianapolis, Indiana.
3
Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
5
Clinica Universidad de Navarra, Pamplona, Spain.
6
The Angeles Clinic and Research Institute, Los Angeles, California.
7
Aarhus University Hospital, Aarhus, Denmark.
8
Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France.
9
Istituto Oncologico Veneto, Padua, Italy.
10
Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy.
11
University Hospital of Siena, Siena, Italy.
12
Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
13
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
14
Bristol-Myers Squibb, Princeton, New Jersey.
15
Stanford University School of Medicine, Stanford, California.
16
Yale Comprehensive Cancer Center, New Haven, Connecticut.
17
Stanford University School of Medicine, Stanford, California. levy@stanford.edu.

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.

PMID:
27756788
DOI:
10.1158/1078-0432.CCR-16-1272
[Indexed for MEDLINE]
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