Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

Abstract

BackgroundThe receptor kinase inhibitor toceranib phosphate (Palladia) was approved for use in dogs in 2009 using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib may be associated with a reduced adverse event profile while maintaining sufficient drug exposure to provide biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors receiving 2.5-2.75 mg/kg every other day and to document the adverse events associated with this dose rate. Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to therapy.ResultsDogs with solid tumors were administered toceranib at an intended target dose ranging from 2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to therapy was assessed using standard RECIST criteria and adverse events were characterized using the VCOG-CTCAE. Toceranib administered at doses between 2.4-2.9 mg/kg every other day resulted in an average 6–8 hr plasma concentration ranging from 100–120 ng/ml, well above the 40 ng/ml concentration associated with target inhibition. Plasma VEGF concentrations increased significantly over the 30 day treatment period indicating that VEGFR2 inhibition was likely achieved in the majority of dogs. The lower doses of toceranib used in this study were associated with a substantially reduced adverse event profile compared to the established label dose of 3.25 mg/kg EOD.ConclusionsDoses of toceranib ranging from 2.4-2.9 mg/kg every other day provide drug exposure considered sufficient for target inhibition while resulting in an adverse event profile substantially reduced from that associated with the label dose of toceranib. This lower dose range of toceranib should be considered for future use in dogs with cancer.

Phase 1 Dose-Escalation Study with LEC/Chtnt-3 and Toceranib Phosphate (Palladia) in Dogs with Spontaneous Malignancies

“…Preliminary evidence of biologic activity of toceranib alone or in combination with metronomic NSAIDs or cyclophosphamide has been demonstrated in non-mast cell tumors with clinical benefit (complete response, partial response, or stable disease) reported in 54-77% of dogs [28,29,31]. In our study, clinical benefit was noted in 68% of dogs over 28 days.…”

“…This trend is also observed when analyzing new or worsening cases of neutropenia and lymphopenia in their relation to escalating doses of LEC/chTNT-3 (Figure 2B). All hematologic toxicities were grade 1 or 2, and neutropenia is a known side effect of toceranib [28,31]. However, neutropenia and lymphopenia could also be due to recruitment of leukocytes to the tumor site [4,5,33], resulting in lower observed circulating leukocyte counts.…”

“…In our study, clinical benefit was noted in 68% of dogs over 28 days. However, it should be noted that the previously quoted studies enrolled cancer patients with life expectancies greater than 6-12 weeks, and only two dogs were euthanized in those studies [28,29,31]. In contrast, the heterogeneity in clinical presentation and advanced stages of our patients were limitations in our study design.…”

“…Clinical toxicities associated with toceranib are primarily gastrointestinal side effects and neutropenia [27-31,38]. While lethargy was reported in 13% (3/23) of dogs during the 5 days of administration of LEC/chTNT-3, no gastrointestinal side effects were noted during this time.…”

“…Concurrent to LEC/chTNT administration on day 1, patients received toceranib orally once every 48 hours with food at doses, 2.1-2.8 mg/kg. This dose is considered sufficient for target inhibition, but has been shown to result in a reduced adverse event profile from that associated with the standard dose, 3.25 mg/kg [31]. …”