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

BACKGROUND: The 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. RESULTS: Dogs 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. CONCLUSIONS: Doses 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.

A retrospective review of cats with suspected false positive results in point-of-care feline leukemia virus tests and concurrent immune-mediated anemia.

OBJECTIVE: To describe clinical findings, diagnosis, treatment, and survival in 18 cats with anemia of suspected immune-mediated origin (ASIMO) and conflicting results using FeLV diagnosis tests, and to suggest an accurate way to assess their FeLV diagnosis. ANIMALS: 18 cats. PROCEDURES: Medical records from 5 veterinary institutions were retrospectively reviewed to identify cats with ASIMO, positive results on p27 SNAP ELISA, and negative results on pro-virus PCR testing in peripheral blood, in the absence of other identified triggers. Follow-up was recorded from diagnosis to the time of writing, and survival analysis was performed to assess similarities with previous published data. RESULTS: 18 cats were enrolled from referral centers in Spain, Italy, and the United Kingdom. Both peripheral immune-mediated hemolytic anemia (IMHA; 12/18) and precursor targeted immune-mediated anemia (PIMA; 6/18) were described. When the SNAP ELISA test was rechecked in patients with disease control, SNAP ELISA positive results had become negative. Two cats had a relapse of the ASIMO, and the FeLV SNAP ELISA tested positive again. Other signs of FeLV disease did not appear in any of these patients despite immunosuppression. 14 cats (14/18 [78%]) were alive at the time of writing, and the mean estimated survival time was 769 days. CLINICAL RELEVANCE: This study describes incongruent FeLV results in cats with ASIMO. It supports the necessity to confirm FeLV SNAP ELISA positive results using additional tools, such as pro-virus PCR testing, as different p27 point-of-care and external serological tests may be inconsistent.

Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.

BACKGROUND: The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. METHODS AND FINDINGS: Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. CONCLUSIONS: This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.