Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Autor: Carlos Gomez‐Roca, Caroline Even, Christophe Le Tourneau, Neus Basté, Jean‐Pierre Delord, Jerome Sarini, Sebastien Vergez, Stephane Temam, Caroline Hoffmann, Philippe Rochaix, Edith Borcoman, Bruno Gavillet, Elisabeth Rouits, Annick Ménétrey, Franck Brichory, Daniela Purcea, Gregoire Vuagniaux, Claudio Zanna
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Clinical and Translational Science, Vol 15, Iss 1, Pp 55-62 (2022)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.13002
Popis: Abstract Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF‐κB signaling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre‐operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day [D]1–15 +/‐ 2); Debio 1143 (200 mg/day D1–15 +/‐ 2) plus cisplatin (40 mg/m2 D 1 and 8); cisplatin alone (40 mg/m2 D 1 and 8; EudraCT: 2014‐004655‐31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary end point; effect of Debio 1143 on cellular IAP‐1 (cIAP‐1). Levels of cIAP‐1/‐2, X‐linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs), including CD8+ T cells, programmed cell death protein 1 (PD‐1), PD‐ligand 1 (PD‐L1), and gene expression were also analyzed. Twenty‐three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n = 13), mean tumor concentrations of Debio 1143 were 18‐fold (maximum 55.2‐fold) greater than in plasma, exceeding the half‐maximal inhibitory concentration for cIAPs and XIAP by 100 to 1000‐fold, with significant engagement/degradation of cIAP‐1 (p
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