Introduction

12b80 is a new antineoplastic compound, combining doxorubicin to a bone targeting hydroxybisphosphonate vector with a pH-sensitive linker, designed to specifically trigger doxorubicin release in acid bone tumor microenvironment. Preclinically, 12b80 displays in vivo stronger antitumor effects on rodent orthotopic osteosarcoma compared with doxorubicin/zoledronate combination. This phase I study was 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.

Materials and Methods

Client-owned dogs with untreated osteosarcoma were evaluated in an accelerated dose titration design followed by 3+3 design, to determine the safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of 12b80 given intravenously, every three weeks for three cycles.

Results

Ten dogs were enrolled and treated at 4 mg/kg (n=1), 6 mg/kg (n=2), 8 mg/kg (n=3), and 10 mg/kg (n=4). The MTD of 12b80 was 8 mg/kg (i.e., equivalent calculated dose of doxorubicin of 110 mg/m², range: 93–126). No DLT was observed at this dose level. Most adverse events included grade 1 or 2 gastrointestinal disorders and hypersensitivity reactions. No hematologic and cardiac DLT were observed at any dose level tested.

Conclusions

This study showed that 12b80 is overall well tolerated in dogs, expanding the therapeutic index of doxorubicin up to four times the standard dose of 30 mg/m² of doxorubicin.

The results show potential translational relevance for further clinical development of 12b80 in dog and human osteosarcoma.