Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma
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Pierre Boyé1,2,4, Emmanuelle David3, François Serres1,2, Quentin Pascal1, Franck Floch2, Kévyn Geeraert2, Virginie Coste1, Laurent Marescaux2, Sébastien Cagnol3, Jean-Yves Goujon3, Maxim Egorov3, Ronan Le Bot3 and Dominique Tierny1,2
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
Keywords: bisphosphonate; bone targeting; canine; doxorubicin; osteosarcoma
Received: September 21, 2020 Accepted: October 27, 2020 Published: November 17, 2020
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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