Toceranib phosphate and piroxicam have individually demonstrated antineoplastic activity. Additionally, non-steroidal anti-inflammatory therapy is often warranted in aged cancer-bearing dogs for management of osteoarthritis comorbidity. As concurrent use may be warranted for a given individual and the adverse event (AE) profile for each can be overlapping (gastrointestinal), a phase I trial was performed in tumour-bearing (non-mast cell) dogs to establish the safety of the combination using a standard 3+3 cohort design. Five dose-escalating cohorts, up to and including approved label dosage for toceranib and standard dosage for piroxicam, were completed without observing a frequency of dose-limiting AEs necessitating cohort closure. Therefore, the combination of standard dosages of both drugs (toceranib, 3.25 mg kg−1, every other day; piroxicam, 0.3 mg kg−1 daily) is generally safe. Several antitumour responses were observed. As with single-agent toceranib, label-indicated treatment holidays and dose reductions (e.g. 2.5–2.75 mg kg−1) may occasionally be required owing to gastrointestinal events.