Safety Evaluation of Combination Vinblastine and Toceranib Phosphate (Palladia®) in Dogs: a Phase I dose-finding study

摘要

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities and exert antitumor activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed on the combination in dogs with mast cell tumors. The dose-limiting toxicity for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg/m² every other week) concurrent with toceranib (3.25 mg/kg PO, every other day). This represents greater than a 50% reduction in dose-intensity for vinblastine (compared to single-agent use) and as such does not support this combination based on current drug combination paradigms. While a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.