Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma. - Université de Lille Accéder directement au contenu
Article Dans Une Revue Oncotarget Année : 2021

Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.

P. Boyé
  • Fonction : Auteur
E. David
  • Fonction : Auteur
F. Serres
  • Fonction : Auteur
Q. Pascal
  • Fonction : Auteur
F. Floch
  • Fonction : Auteur
K. Geeraert
  • Fonction : Auteur
V. Coste
  • Fonction : Auteur
L. Marescaux
  • Fonction : Auteur
S. Cagnol
  • Fonction : Auteur
J. Y. Goujon
  • Fonction : Auteur
M. Egorov
  • Fonction : Auteur
R. Le Bot
  • Fonction : Auteur

Résumé

Purpose: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans. Experimental Design: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design. Dogs received three cycles of 12b80 intravenous injection at 4 mg/kg (n = 1), 6 mg/kg (n = 2), 8 mg/kg (n = 3), and 10 mg/kg (n = 4). Endpoints included safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT). Results: The MTD of 12b80 was 8 mg/kg (i.e., equivalent dose of doxorubicin of 110 mg/m2, range: 93–126). Most adverse events included grade ≤ 2 gastrointestinal disorders and hypersensitivity reactions. No hematological or cardiac DLT were observed at any dose tested. Conclusions: In dogs, 12b80 is overall well tolerated and expends the MTD of doxorubicin up to four times the standard dose of 30 mg/m2. These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.
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hal-04413195 , version 1 (23-01-2024)

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P. Boyé, E. David, F. Serres, Q. Pascal, F. Floch, et al.. Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.. Oncotarget, 2021, Oncotarget, 11, pp.4281-4292. ⟨10.18632/oncotarget.27801⟩. ⟨hal-04413195⟩

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