Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: A phase I dose-finding study

Mast cell tumors (MCT) are the most common cutaneous tumor in dogs, accounting for 16–21% all skin tumors (1). Several factors are known to be predictive of biological behavior and clinical outcome. Histological grade, clinical stage, location, and growth rate are amongst the most important prognostic factors recognized. (1–11). In an attempt to improve outcome in dogs with high grade or advanced-stage MCT, combinations of local (surgery, radiation) and systemic (chemotherapy) therapy are recommended. Several chemotherapy agents have documented activity against MCT, including single agent vinca alkaloids (vincristine, vinblastine), CCNU, prednisone, hydroxyurea and tyrosine kinase inhibitors (masitinib, toceranib) (3,4,12–23). Multiagent therapy has also been evaluated with varying success (24–26). Medical treatment of macroscopic, advanced-stage disease generally results in modest and non-durable responses; however recent evidence suggests that multiagent protocols may provide higher response rates (27). Currently, most successful cancer chemotherapy regimens in people follow the paradigm of multiple drugs given simultaneously to optimally treat cancer. Several criteria are theoretically requisite for simultaneous use of drugs in combination protocols (27,28). Firstly, individual drugs should have documented single-agent activity for the histology in question. Additionally, the antitumor activity of drugs chosen for use in combination should occur through different mechanisms of action. Further, the combination of drugs that have overlapping toxicities should be avoided. Finally, drugs should be used at their optimal dose and schedule (maximal dose intensity) allowing for the shortest time for recovery of the most sensitive normal target tissue. Chemotherapy using vinblastine, a potent plant alkaloid extracted from the periwinkle plant, has shown to be safe and effective as a single-agent therapy (with or without prednisone) for the treatment of dogs with MCT, and is currently considered a standard of care treatment for this disease in the adjuvant setting or when surgery is not feasible (3,4,12–23). Vinblastine inhibits microtubule formation by binding to tubulin, disrupting the normal mitotic process. The dose-limiting toxicity of vinblastine in dogs is neutropenia, and while gastrointestinal adverse events are possible, they are usually mild and self-limiting. Previous literature suggests that the nadir for neutropenia occurs at 1 week in dogs and that most will tolerate weekly treatments at dosages ranging from 2.0 – 2.6 mg/ m2, and biweekly dosages as high as 3.5 mg/m2 (3, 4,12–23). Toceranib (Palladia®) is a small molecule tyrosine kinase inhibitor (TKI). It is FDA-approved for use in dogs to treat canine cutaneous MCT. Toceranib’s mechanism of action results from competitive blockade of the ATP binding site of several tyrosine kinase receptors (VEGFR, PDGFR and Kit), impairing phosphorylation and downstream signaling (17–20). When evaluated in a prospective, randomized, placebo-controlled study in dogs with nonresectable grade II and III MCT, the overall objective response rate was 42.8%, demonstrating that toceranib has single-agent biologic activity against canine MCTs (20). The dose-limiting toxicity was demonstrated to be gastrointestinal in origin. As vinblastine and toceranib both have documented single-agent activity against canine MCT, possess different mechanisms of action and dose-limiting toxicity profiles; they meet the theoretical requisites for effective simultaneous combination in dogs with MCT. The hypothesis under interrogation in this trial was that toceranib could be safely administered on an every other day schedule simultaneously with a standard weekly protocol of vinblastine, at dosages known to have single-agent activity against MCT in dogs. The aims of the study were two-fold. The primary aim was to determine the maximum tolerated dose of toceranib that can be administered in tumor-bearing dogs, when given concurrently with a standard vinblastine dosing regimen, through the use of a standard phase I dose-finding trial design. A secondary aim was to determine the adverse event profile of toceranib and vinblastine in combination and compare to that of each drug when used alone. While efficacy is not a primary end-point for dose-finding trials, the study did evaluate antitumor activity of the combination protocol.