[PMID]: | 27756788 |
[Au] Autor: | Segal NH; Logan TF; 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 |
[Ad] Endereço: | Memorial Sloan Kettering Cancer Center, New York, New York. |
[Ti] Título: | Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. |
[So] Source: | Clin Cancer Res;23(8):1929-1936, 2017 04 15. |
[Is] ISSN: | 1078-0432 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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. 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. 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. 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. . |
[Mh] Termos MeSH primário: |
Ligante 4-1BB/agonistas Anticorpos Monoclonais/efeitos adversos Antineoplásicos/efeitos adversos Neoplasias/tratamento farmacológico
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[Mh] Termos MeSH secundário: |
Adulto Idoso Anticorpos Monoclonais/administração & dosagem Anticorpos Monoclonais/farmacocinética Antineoplásicos/administração & dosagem Antineoplásicos/farmacocinética Relação Dose-Resposta a Droga Feminino Seres Humanos Masculino Dose Máxima Tolerável Melanoma/tratamento farmacológico Meia-Idade
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[Pt] Tipo de publicação: | CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (4-1BB Ligand); 0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (TNFSF9 protein, human); 0 (urelumab) |
[Em] Mês de entrada: | 1706 |
[Cu] Atualização por classe: | 171107 |
[Lr] Data última revisão:
| 171107 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 161101 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1158/1078-0432.CCR-16-1272 |
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