Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody

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

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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 treatmentrelated and serious adverse events (AEs), as well as treatmentrelated 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.

Original languageEnglish (US)
Pages (from-to)1929-1936
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2017

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Monoclonal Antibodies
Safety
Liver Function Tests
Therapeutics
Nausea
Fatigue
Lymphoma
Neoplasms
Research Design
Cytokines
Antibodies
Liver
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. / Segal, Neil H.; Logan, Theodore; 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.

In: Clinical Cancer Research, Vol. 23, No. 8, 15.04.2017, p. 1929-1936.

Research output: Contribution to journalArticle

Segal, NH, Logan, T, Hodi, FS, McDermott, D, Melero, I, Hamid, O, Schmidt, H, Robert, C, Chiarion-Sileni, V, Ascierto, PA, Maio, M, Urba, WJ, Gangadhar, TC, Suryawanshi, S, Neely, J, Jure-Kunkel, M, Krishnan, S, Kohrt, H, Sznol, M & Levy, R 2017, 'Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody', Clinical Cancer Research, vol. 23, no. 8, pp. 1929-1936. https://doi.org/10.1158/1078-0432.CCR-16-1272
Segal, Neil H. ; Logan, Theodore ; 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. / Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 8. pp. 1929-1936.
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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 treatmentrelated and serious adverse events (AEs), as well as treatmentrelated 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.",
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AU - Logan, Theodore

AU - Hodi, F. Stephen

AU - McDermott, David

AU - Melero, Ignacio

AU - Hamid, Omid

AU - Schmidt, Henrik

AU - Robert, Caroline

AU - Chiarion-Sileni, Vanna

AU - Ascierto, Paolo A.

AU - Maio, Michele

AU - Urba, Walter J.

AU - Gangadhar, Tara C.

AU - Suryawanshi, Satyendra

AU - Neely, Jaclyn

AU - Jure-Kunkel, Maria

AU - Krishnan, Suba

AU - Kohrt, Holbrook

AU - Sznol, Mario

AU - Levy, Ronald

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N2 - 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 treatmentrelated and serious adverse events (AEs), as well as treatmentrelated 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.

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