Use of Epothilone B (Patupilone) in Refractory Lymphoma and advanced solid tumors in dogs

Background: The epothilones are microtubule-stabilizing agents with promising antitumor effect in refractory and metastatic tumors in humans. The toxicity profile is considered more favorable than in taxanes. The safety of epothilone B (patupilone) has not been evaluated in tumor-bearing dogs. Objectives: To evaluate the inhibition of proliferation in canine tumor cells after patupilone treatment. To assess toxicity profile and maximally tolerated dose of patupilone in dogs with refractory tumors. Animals: Twenty client-owned dogs with various malignancies. Methods: The inhibition of proliferation was assessed with a proliferation assay in vitro in canine hemangiosarcoma and lymphoma cell lines. In the prospective clinical study, dogs received patupilone intravenously once a week for two treatments (= one treatment cycle). Dose was escalated with three dogs per cohort and 20% increments. Adverse effects were graded according to the VCOG-CTCAE v1.0. Results: Both canine cell lines were sensitive to patupilone with approximately 50% decrease of proliferative activity at 0.2-1 nM. In vivo, dose-limiting adverse effects occurred at 3.3 mg/m2; main adverse effects were diarrhea, anorexia, vomiting, and nausea. Neither neutropenia nor peripheral neuropathy was observed. Maximally tolerated dose for two patupilone administrations once weekly IV is 2.76 mg/m2. 3/11 dogs receiving more than one treatment cycle showed partial remission in the short period of observation. Conclusions and Clinical Importance: Canine tumor cells show inhibition of proliferation to patupilone in vitro. Clinically, a dose of 2.76 mg/m2 IV is well tolerated in dogs with spontaneously occurring tumors