Portal de Periódicos da CAPES

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

2020; Impact Journals LLC; Volume: 11; Issue: 46 Linguagem: Inglês

10.18632/oncotarget.27801

1949-2553

Pierre Boyé, Emmanuelle David, François Serres, Quentin Pascal, Franck Floch, Kévyn Geeraert, Virginie Coste, Laurent Marescaux, Sébastien Cagnol, Jean-Yves Goujon, Maxim Egorov, Ronan Le Bot, Dominique Tierny,

Veterinary Oncology Research

// Pierre Boyé 1 , 2 , 4 , Emmanuelle David 3 , François Serres 1 , 2 , Quentin Pascal 1 , Franck Floch 2 , Kévyn Geeraert 2 , Virginie Coste 1 , Laurent Marescaux 2 , Sébastien Cagnol 3 , Jean-Yves Goujon 3 , Maxim Egorov 3 , Ronan Le Bot 3 and Dominique Tierny 1 , 2 1 Oncovet Clinical Research (OCR), Parc Eurasanté, Loos, France 2 Oncovet, Villeneuve d'Ascq, France 3 Atlanthera, Saint Herblain, France 4 Department of Small Animal Teaching Hospital, The Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UK Correspondence to: Pierre Boyé, email: pierre_boye@hotmail.fr Keywords: bisphosphonate; bone targeting; canine; doxorubicin; osteosarcoma Received: September 21, 2020 Accepted: October 27, 2020 Published: November 17, 2020 Copyright: © 2020 Boyé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT 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/m 2 , 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/m 2 . These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.