Background <p>Oral melanoma is one of the most devastating cancers in dogs. We previously developed a novel agent extracted from Japanese butterbur shoots and its petasin derivatives demonstrated anti-proliferative activity in canine oral melanoma cells. The aim of this study was to evaluate the safety and clinical efficacy of the butterbur shoot extract (BSE) in dogs with oral melanoma as a combined phase 1 and 2 study.</p> Results <p>All enrolled dogs underwent radiation therapy or surgery as local therapy before BSE administration. We enrolled nine dogs in the phase 1 study, and BSE was orally administered at doses escalating from 50 to 200&#xa0;mg/kg. Grade 1 alanine aminotransferase elevation and diarrhoea were observed in each dog. We determined that 200&#xa0;mg/kg BSE was safe to administer. We subsequently administered it to sixteen dogs with stage 3 oral melanoma in the phase 2 study. Their progression-free survival and overall survival were compared with those of the historical controls, and adverse events were assessed. BSE administration significantly extended overall survival but did not prolong progression-free survival. No dose-limiting toxicities were observed.</p> Conclusions <p>These results indicate that 200&#xa0;mg/kg of BSE is safe to administer and may improve the outcome of canine oral melanoma.</p>