Combination vinblastine and palladia for high-grade and metastatic mast cell tumors in dogs.

High-grade and metastatic canine mast cell tumors carry a guarded prognosis because of their unpredictable biologic behavior. An ideal chemotherapy regime is yet to be established. The aim of this study was to review the efficacy and toxicity of combination vinblastine and toceranib for high-grade and metastatic mast cell tumors. Twenty-eight dogs were categorized with either high-grade, lymph node metastasis or Stage IV disease. Demographics, disease, and treatment variables were compared between categories (Kruskal-Wallis test for continuous data and Fisher's Exact test for categorical data). Survival times and progression-free intervals (PFI) were calculated and compared between groups (log rank test). The PFI was 310 d [95% confidence interval (CI): 155 to 1425] and overall survival was 373 d (95% CI: 226 to 1219). There was no difference between disease categories for PFI (P = 0.9) or survival (P = 0.5). The protocol was well-tolerated with increased liver enzyme activity and gastrointestinal toxicity most frequently observed. Progression-free intervals and survival times were similar in dogs with high-grade, metastatic and Stage IV disease.

Combinaison vinblastine et Palladia pour les mastocytomes métastatiques et de haut grade chez le chien. Les mastocytomes canins métastatiques et de haut grade ont un pronostic réservé en raison de leur comportement biologique imprévisible. Un traitement idéal de chimiothérapie n'a pas encore été établi. Le but de cette étude était d'examiner l'efficacité et la toxicité de l'association vinblastine et tocéranib pour les mastocytomes de haut grade et métastatiques.Vingt-huit chiens ont été classés soit avec une maladie de haut grade, des métastases ganglionnaires ou avec une maladie de stade IV. Les variables démographiques, de maladie et de traitement ont été comparées entre les catégories (test de Kruskal-Wallis pour les données continues et test exact de Fisher pour les données catégorielles). Les temps de survie et les intervalles sans progression (PFI) ont été calculés et comparés entre les groupes (test de log-rank). Le PFI était de 310 jours [intervalle de confiance à 95 % (IC): 155 à 1425] et la survie globale était de 373 jours (IC 95 %: 226 à 1219). Il n'y avait pas de différence entre les catégories de maladie pour le PFI (P = 0,9) ou la survie (P = 0,5). Le protocole a été bien toléré avec une augmentation de l'activité des enzymes hépatiques et une toxicité gastro-intestinale les plus fréquemment observées. Les PFI et les temps de survie étaient similaires chez les chiens atteints d'une maladie de haut grade, ceux avec des métastases et ceux de stade IV.(Traduit par Dr Serge Messier).

Recurrent corneal hemangiosarcoma in a cat with subsequent extension into the orbit.

A 7-year-old neutered female Domestic Short-haired cat was presented for evaluation of ulceration and severe vascularization of the left cornea. Ophthalmic examination revealed a large red irregular mass over the whole cornea in the left eye. A lamellar keratectomy was performed. Histopathology revealed a chronic lymphoplasmacytic, histocytic, neutrophilic ulcerative keratitis with fibrosis and vascularization. The tumor recurred within 3 months, and another lamellar keratectomy and sclerotomy were performed. The lesion was diagnosed histopathologically as a hemangiosarcoma with incomplete margins. The mass recurred locally 6 weeks later, and an enucleation was performed. Histopathology revealed infiltration of the limbus and connective tissue beyond the sclera. Seven weeks later, a fluctuant swelling was found in the left orbit. Computed tomography confirmed a soft tissue attenuating mass measuring 33 x 24 mm diameter in the orbit. There was no sign of metastasis. Clinical remission was achieved with combined chemotherapy with doxorubicin and radiation therapy. The patient remained in clinical remission 20 months post-chemotherapy.

Long-term survival in a cat with pancreatic adenocarcinoma treated with surgical resection and toceranib phosphate.

CASE SUMMARY: Primary pancreatic adenocarcinoma is an uncommon neoplasm seen in cats and often has a poor prognosis. We report a case of an 8-year-old male neutered domestic shorthair cat weighing 5.8 kg diagnosed with pancreatic adenocarcinoma treated with surgical resection and toceranib phosphate, which had a progression-free interval of 1148 days and survived for more than 1436 days. The treatment was well tolerated; however, the cat developed generalised coat hypopigmentation. RELEVANCE AND NOVEL INFORMATION: To our knowledge, the cat in our report has the longest progression-free interval and survival time post-surgical resection of pancreatic carcinoma treated with toceranib. Hypopigmentation as a side effect of toceranib has been reported in dogs, but this is the first case reported in cats.

A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma.

BACKGROUND: Effective therapies for transitional cell carcinoma (TCC) are limited, with objective response rates to most chemotherapeutic regimens below 20%. The purpose of this study was to investigate the biologic activity of combined toceranib phosphate and vinblastine chemotherapy for treatment of TCC. A secondary objective was to compare the utility of Computed Tomography (CT) and abdominal ultrasound (AUS) in tumor response assessments. RESULTS: Dogs with TCC received vinblastine at 1.6 mg/m2 every 2 weeks and toceranib at 2.5-2.75 mg/kg on Monday/Wednesday/Friday. Tumor monitoring was achieved through CT and AUS. Five patients completed the 16-week study. Based on AUS assessments, 3 dogs experienced biologic response to therapy including partial responses (PR, n = 2) and stable disease (SD, n = 1). Based on CT, 5 dogs experienced a biologic response (n = 2 PR, n = 3 SD). Both imaging modalities (ultrasound and CT) were found to provide repeatable measurements between operators, however agreement between operator measurements was greater when CT images were used to assess tumor size. CONCLUSIONS: The combination of toceranib and vinblastine did not result in improved response rates. While agreement in tumor volume assessments between both AUS and CT were excellent between operators, this did not extend to assessment of tumor response. The higher rate of concordance between operators when assessing response to treatment with CT suggests that CT should be considered for future clinical trials involving canine bladder TCC to improve the accuracy and repeatability of tumor measurement. The data suggest that response to therapy as assessed by AUS or CT do not predict duration of clinical response.

Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma.

BACKGROUND: Spenic hemangiosarcoma (HSA) in dogs treated with surgery alone is associated with short survival times, and the addition of doxorubicin (DOX) chemotherapy only modestly improves outcome. The purpose of this study was to evaluate the impact of toceranib administration on progression free survival in dogs with stage I or II HSA following splenectomy and single agent DOX chemotherapy. We hypothesized that dogs with splenic HSA treated with adjuvant DOX followed by toceranib would have prolonged disease-free interval (DFI) and overall survival time (OS) when compared to historical dogs treated with DOX-based chemotherapy alone. RESULTS: Dogs with stage I or II splenic HSA were administered 5 cycles of single-agent DOX every 2 weeks beginning within 14 days of splenectomy. Dogs were restaged 2 weeks after completing DOX, and those without evidence of metastatic disease began toceranib therapy at 3.25 mg/kg every other day. Forty-three dogs were enrolled in this clinical trial. Seven dogs had evidence of metastatic disease either before or at re-staging, and an additional 3 dogs were found to have metastatic disease within 1 week of toceranib administration. Therefore 31 dogs went on to receive toceranib following completion of doxorubicin treatment. Twenty-five dogs that received toceranib developed metastatic disease. The median disease free interval for all dogs enrolled in this study (n = 43) was 138 days, and the median disease free interval for those dogs that went on to receive toceranib (n = 31) was 161 days. The median survival time for all dogs enrolled in this study was 169 days, and the median survival time for those dogs that went on to receive toceranib was 172 days. CONCLUSIONS: The use of toceranib following DOX chemotherapy does not improve either disease free interval or overall survival in dogs with stage I or II HSA.

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.

Elite suppressor-derived HIV-1 envelope glycoproteins exhibit reduced entry efficiency and kinetics.

Elite suppressors (ES) are a rare subset of HIV-1-infected individuals who are able to maintain HIV-1 viral loads below the limit of detection by ultra-sensitive clinical assays in the absence of antiretroviral therapy. Mechanism(s) responsible for this elite control are poorly understood but likely involve both host and viral factors. This study assesses ES plasma-derived envelope glycoprotein (env) fitness as a function of entry efficiency as a possible contributor to viral suppression. Fitness of virus entry was first evaluated using a novel inducible cell line with controlled surface expression levels of CD4 (receptor) and CCR5 (co-receptor). In the context of physiologic CCR5 and CD4 surface densities, ES envs exhibited significantly decreased entry efficiency relative to chronically infected viremic progressors. ES envs also demonstrated slow entry kinetics indicating the presence of virus with reduced entry fitness. Overall, ES env clones were less efficient at mediating entry than chronic progressor envs. Interestingly, acute infection envs exhibited an intermediate phenotypic pattern not distinctly different from ES or chronic progressor envs. These results imply that lower env fitness may be established early and may directly contribute to viral suppression in ES individuals.