title: Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody.
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.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Segal
authors.affiliation: Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: McDermott
authors.affiliation: Clinica Universidad de Navarra, Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, California.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Istituto Oncologico Veneto, Padua, Italy.
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.affiliation: Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: University Hospital of Siena, Siena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Gangadhar
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Satyendra
authors.initials: S
authors.lastname: Suryawanshi
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Neely
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Suba
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Holbrook
authors.initials: H
authors.lastname: Kohrt
authors.affiliation: Yale Comprehensive Cancer Center, New Haven, Connecticut.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Stanford University School of Medicine, Stanford, California. levy@stanford.edu.
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D053330:4-1BB Ligand / Q000819:agonists*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C505974:TNFSF9 protein, human; C000620833:urelumab