The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects

Because of their locally invasive growth and high recurrence rate despite of aggressive local therapy, treatment of feline sarcomas is challenging. The tyrosine kinase inhibitor (TKI) toceranib is currently licensed for the treatment of canine mast cell tumours. There are only few reports about TKI usage in cats. Previous studies indicated promising potential of TKI for the treatment of feline injection site sarcoma (FISS). In this prospective clinical trial, 18 cats with unresectable FISS were treated at a target dosage of 3.25 mg kg^?1 every other day to evaluate the clinical efficacy and toxicity of toceranib. There was no clinical response measurable. Adverse events were generally mild and temporary. Grade 3 or 4 adverse events developed infrequently and all resolved with drug holidays and dose reductions.     

Retrospective evaluation of canine heart base tumours treated with toceranib phosphate (Palladia): 2011‐2018

Heart base tumours (HBT) occur commonly in older, brachycephalic dogs. A presumptive diagnosis is made based on location and appearance of the tumour via echocardiogram. Effective treatment options are limited to surgery (when feasible) or radiation therapy. Benefit of medical management is presently unknown. The goal of this retrospective study was to assess the efficacy and tolerability of toceranib phosphate for dogs with HBT. Twenty‐eight dogs with histologically, cytologically confirmed or presumed HBT were evaluated retrospectively. Twenty‐seven dogs were treated with single agent toceranib. One dog received combination therapy with concurrent metronomic chemotherapy. This dog was not included in response or survival analysis. Factors assessed included clinical signs, hematologic/biochemical parameters and response to treatment. For the 27 dogs receiving single agent toceranib, an overall response rate of 10% was found. Overall median survival time was 823 days (range, 68‐1190 days). The overall response rate for the dogs presenting with metastasis was 28.5%, with a median survival time of 532 days (range, 77‐679 days). This was not significantly different than the median survival time of 796 days for dogs who did not present with metastasis. Of the dogs displaying clinical signs at the time of diagnosis, 90% had improvement and 81% had complete resolution of signs after starting toceranib. Toxicity was seen in 54% of dogs with gastrointestinal distress as the most common toxicity but dose reductions were infrequent required. Results demonstrate that toceranib phosphate is a well‐tolerated and effective treatment for inoperable canine heart base tumours including dogs with advanced or metastatic disease.     

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single‐agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose‐finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg^?1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose‐limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m^?2 of DOX q 21 days given concurrently with toceranib 2.75 mg kg^?1 PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti‐tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long‐term AE profiles.     

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour‐bearing dogs: A phase I dose finding study

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low‐dose metronomic and/or anti‐angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose‐finding clinical trial assumed an open‐label 3 + 3 cohort design. Client‐owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg^?1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m^?2. A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m^?2. AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG‐CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose‐limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m^?2 IV every 21 days and approximately 2.75 mg kg^?1 PO EOD, respectively. The dose‐limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well‐tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials.     

Distribution,metabolism, and excretion of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor,in dogs

Yancey, M. F., Merritt, D. A., White, J. A., Marsh, S. A., Locuson, C. W. Distribution, metabolism, and excretion of toceranib phosphate (Palladia?, SU11654), a novel tyrosine kinase inhibitor, in dogs. J. vet. Pharmacol. Therap. 33 , 154–161. Toceranib phosphate (Palladia?, SU11654), a multireceptor tyrosine kinase inhibitor with anti‐tumor and anti‐angiogenic activity, has been developed for the treatment of mast cell tumors in dogs. An overview of the distribution, metabolism, and excretion of toceranib phosphate in dogs is presented. When [¹⁴C]‐toceranib was orally administered to dogs, the majority of the radioactivity (92%) was excreted in feces and only a small portion (7%) was excreted in urine. Seven days after a single 3.25 mg/kg oral dose, radioactivity was the highest in bile and liver, with measurable concentrations in lymph nodes, colon, adrenals, bone marrow, kidneys, lungs, spleen, pancreas, and skin. Plasma protein binding of toceranib in fresh plasma ranged from 90.8% to 92.8% at concentrations between 20 ng/mL and 500 ng/mL and was independent of concentration. Microsomal and hepatocyte incubations resulted in the formation of a single metabolite. Spectrometric analysis of the metabolite was consistent with the formation of an alicyclic N‐oxide of toceranib. The combination of the high rate of fecal excretion and the long elimination half‐life of toceranib indicate enterohepatic recirculation of the parent compound and/or the N‐oxide metabolite.     

Chronic lymphocytic leukaemia in the cat: 18 cases (2000–2010)

There is little information regarding the presentation, biologic behaviour, treatment and prognosis in cats with chronic lymphocytic leukaemia (CLL), and further investigation is needed to characterize this disease in cats. The goal of this study was to describe the clinical presentation, response to treatment and prognosis of feline CLL. A multi‐institutional retrospective study of 18 cats diagnosed with CLL between 2000 and 2010 was performed. CLL was defined as the presence of a mature lymphocytosis (> 9000 lymphocytes µL^?1) and confirmation of an immunophenotypically monomorphic or clonal lymphoid population. Each patient was required to also have at least one of the two following criteria: (1) concurrent cytopenia of at least one cell line and/or (2) >15% mature lymphocytes in the bone marrow. Data on signalment, history, clinical signs, clinicopathologic features and response to treatment were reviewed. Median age of the cats at initial presentation was 12.5 years (range: 5–20 years). The most common presenting complaint was chronic weight loss, which was present in 8/18 (44%) cats. Sixteen of 18 (89%) cats were treated with chlorambucil and prednisolone; four of these cats also received vincristine. Two (11%) cats were treated with multi‐agent injectable chemotherapy (L‐CHOP, l ‐asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisolone). Eighty‐eight percent of cats evaluable for response achieved a complete (nine cats) or partial (six cats) remission. Median overall remission was 15.7 months (range: 1.3–22.8 months). The median overall survival in the 17 cats with follow‐up data was 14.4 months (range: 0.9–25.3 months). Results of this study suggest that CLL affects older‐aged cats and responds favourably to treatment with oral chlorambucil and prednisolone.     

Investigation of thyroid function in dogs treated with the tyrosine kinase inhibitor toceranib

Tyrosine kinase inhibitors are widely utilized in veterinary oncology for the treatment of mast cell and solid tumours. In man, these drugs are associated with thyroid dysfunction: however, to date only one study has investigated this in dogs. The aim of this study was to prospectively assess thyroid function in a group of dogs with cancer receiving toceranib. Thirty‐four dogs were prospectively enrolled at two referral hospitals into two groups; those receiving toceranib with prednisolone and those receiving toceranib alone. Total thyroxine (TT4) and thyroid stimulating hormone (TSH) was monitored at regular time points during treatment. Follow‐up data was available for 19 dogs. Overall, 12 incidences of elevated TSH occurred but none of these dogs had concurrent low TT4 concentrations. There was a significant difference in median TSH at week six compared with baseline. Hypothyroidism was not diagnosed in any patient during the study period. Patient drop‐out was higher than anticipated which prevented the assessment of longer term toceranib administration on thyroid function. Toceranib therapy was not associated with hypothyroidism in this study but did result in elevations in TSH which confirms what has been previously reported. Toceranib should be considered to cause thyroid dysfunction in dogs and monitoring is advised.     

Genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib in a canine mast cell tumor cell line

One of the potential mechanisms underlying acquired resistance to toceranib in canine mast cell tumor (MCT) is the emergence of a secondary mutation in the KIT gene. Here, genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib were investigated in the toceranib‐susceptible canine MCT cell line VI‐MC, which carries a KIT‐activating mutation resulting in a predicted p.(Asn508Ile) amino acid change in the receptor tyrosine kinase protein KIT. Two sublines were cloned from VI‐MC and toceranib‐resistant sublines then were established by continuous exposure to toceranib. The mutation status of KIT in parental VI‐MC and its sublines was investigated using next‐generation sequencing (NGS). Additionally, effects of secondary mutations on toceranib sensitivity in p.(Asn508Ile)‐mutant KIT were examined. KIT secondary mutations, including those encoding p.(Asn679Lys)‐, p.(Asp819Val)‐, and p.(Asp819Gly)‐mutant KIT, that confer toceranib insensitivity to p.(Asn508Ile)‐mutant KIT emerged only in toceranib‐resistant VI‐MCs. These mutations were not detected by NGS in the parental VI‐MC line or in the toceranib‐naive cloned VI‐MCs, although the parental line and sublines exhibited genetic heterogeneity in KIT that may have been caused by genetic evolution during clonal expansion. VI‐MC clones with these secondary mutations in KIT appear to have arisen from subclones during treatment with toceranib rather than being pre‐existing. However, further study using a higher resolution technique will be needed to confirm the developmental mechanism of KIT secondary mutation in canine MCT cells with acquired resistance to toceranib.     

Febrile neutropenia in cats treated with chemotherapy

The purpose of this study was to describe the clinical presentation, potential causative agents, treatment and outcome of febrile neutropenia (FN) in chemotherapy‐treated cats. Medical records from eight institutions were retrospectively reviewed. A total of 22 FN events in 20 cats were evaluated. Lymphoma was the most common cancer diagnosis; lomustine and vinca alkaloids were the most frequently implicated causative agents. Presenting clinical signs included decreased appetite, lethargy, vomiting and diarrhoea. Median body temperature and absolute neutrophil count at presentation were 104.1 °F; 40 °C (range: 103.1–105.1 °F; 39.5–40.6 °C) and 246 mL^‐1 (range: 0–1600 mL^‐1), respectively. Median number of days between chemotherapy administration and FN onset was 5 (range: 4–25 days). All but one cat were treated with intravenous fluids and broad spectrum antibiotics. Fevers resolved in all cases and absolute neutrophil counts returned to normal in 19 cats. Clinical presentation of cats with FN appears similar to that of dogs.     

INITIAL EVALUATION OF SAFETY OF WIDE‐FIELD IRRADIATION IN THE TREATMENT OF HEMATOPOIETIC NEOPLASIA IN THE CAT

Localized radiation therapy is well tolerated in cats with confined tumors; however, the use of wide‐field radiation therapy to treat disseminated neoplasia has not been evaluated systematically in this species. Wide‐field external beam radiation therapy, which we define as irradiation of cranial or caudal halves of the body either individually or sequentially, was undertaken as an experimental option to treat cats with either chemotherapy‐refractory or naïve hematopoietic neoplasia considered to have a poor prognosis. Fifteen cats with hematopoietic malignancies received wide‐field external beam radiation therapy between 2003 and 2006. Cats received 8 Gy delivered in 4 Gy fractions with ⁶⁰Co photons. Treatment‐related toxicity was scored according to criteria established by the Veterinary Cooperative Oncology Group. Animals without preexisting abnormalities on hemograms exhibited no or mild (Grade 1 or 2) hematopoietic toxicity. Although most cats (14 of 15) had preexisting gastrointestinal (GI) signs, these signs were stable (29%) or improved (42%) following irradiation. Worsening GI signs following irradiation occurred transiently in two cats and in association with progressive disease in two others. No pulmonary, renal, hepatic, or dermatologic toxicities were detected. In summary, wide‐field external beam radiation therapy can be administered safely to, and may provide therapeutic benefit for, cats with disseminated hematopoietic neoplasia.     

Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia®) in tumour‐bearing dogs: a phase I dose‐finding study

While maintaining a standard toceranib dosage [2.75 mg kg^?1, PO, every other day (EOD)], three dose‐escalating CCNU cohorts up to and including 60 mg m^?2, PO, q3wk, were completed. The dose‐limiting toxicities (DLT) for the combination were neutropenia and the maximum tolerated dose (MTD) for CCNU when given with continuous toceranib was determined to be 50 mg m^?2, q3wk. While activity is not a primary objective of phase I trials, we observed one complete (lymphoma) and four partial responses (lymphoma, sarcoma, undifferentiated carcinoma and prostatic carcinoma) and two dogs experienced stable disease for >6 weeks [gastric adenocarcinoma and metastatic multilobulated osteochondrosarcoma (MLO)] for an objective response rate of 38.4% and a biological response rate of 53.8%. Concurrent continuous toceranib (2.75 mg kg^?1, EOD) and pulse dose CCNU (50 mg m^?2, q3wk) was well tolerated. Phase II effectiveness and phase III prospective randomized trials should further interrogate the potential activity of this combination.     

Use of imiquimod 5% cream (Aldara™) in cats with multicentric squamous cell carcinoma in situ: 12 cases (2002–2005)*

Multicentric squamous cell carcinoma in situ (MSCCIS) is a variant of squamous cell carcinoma in cats, commonly referred to as Bowen’s‐like disease. Imiquimod 5% cream (Aldara?) is a novel immune response modifier (IRM) that has been reported as a successful treatment for Bowen’s disease in humans. The purpose of this study was to describe clinical findings, treatment protocols and survival in cats with MSCCIS treated with imiquimod 5% cream and to examine the effects of imiquimod 5% cream in cats with MSCCIS. The expression of papillomavirus group‐specific antigen in the study population was also determined. From review of medical records, 12 cats were identified with a histologic diagnosis of MSCCIS and treatment with imiquimod 5% cream. Initial lesions responded to imiquimod 5% cream in all cats. Most cats (75%) developed new lesions. New lesions also responded to imiquimod 5% cream in all cats treated. Five cats (41%) had side effects suspected to be associated with the use of imiquimod 5% cream, including local erythema (25%), increased liver enzymes and neutropenia (8%), and partial anorexia and vomiting (8%). Kaplan–Meier median treatment duration and median survival time probabilities for cats in this study were 1189 days, respectively. A time to failure model was generated as many cats were censored from analysis well before the aforementioned projected median. This model resulted in a shorter median survival time of 243 days. No patient‐related, tumour‐related or treatment‐related prognostic variables were identified. No expression for papilloma group‐specific antigen was found. Imiquimod 5% cream appears to be well tolerated in the majority of cats, and further studies are warranted to further examine its usefulness in cats with this disease.     

EFFICACY AND TOXICITY OF AN ACCELERATED HYPOFRACTIONATED RADIATION THERAPY PROTOCOL IN CATS WITH ORAL SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma (SCC) is the most common feline oral tumor. Standard radiation protocols have been reported to achieve tumor control durations of 1.5–5.5 months (45–165 days). The purpose of this study was to describe the efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral SCC. Twenty‐one cats with histologically confirmed oral SCC and T1‐3N0M0 were treated with 10 once‐daily fractions (Monday–Friday) of 4.8 Gy. Seventeen cats had macroscopic disease and four were microscopic after incomplete excision. Acute toxicity consisted of grade 2 mucositis in all cats and this was effectively managed using esophageal or gastric tube feeding, pain medication, and antibiotics. Late toxicity effects for cats with available follow‐up data included alopecia (4 cats), leukotricia (6), tongue ulceration (1), and oronasal fistula (1). Response could be assessed in 17 cats (seven complete response and five partial response). Four cats (19%) developed metastatic disease without evidence of local progression. The median progression‐free survival (PFS) was 105 days (1 year PFS of 23%), median local progression‐free survival (LPFS) was 219 days (1 year LPFS of 41%), and median overall survival (OS) was 174 days (1 year OS of 29%). Only tumor stage was prognostic, with T1 having a median PFS of 590 days. Findings indicated that this accelerated hypofractionated radiation therapy protocol was well tolerated in cats with oral SCC, with manageable adverse events. Tumor response was observed in most cats and long tumor control durations were achieved in some cats.     

Preliminary evaluation of serial (18) FDG-PET/CT to assess response to toceranib phosphate therapy in canine cancer

Palladia(TM) (toceranib phosphate-Pfizer Animal Health) is a novel orally administered receptor tyrosine kinase inhibitor (TKI) approved for treatment of canine mast cell tumors. Receptor tyrosine kinase dysregulation leads to tumor growth, progression, and metastasis. Toceranib's targets include vascular endothelial growth factor receptor (VEGFR-2/Flk-1/KDR), platelet-derived growth factor receptor, and kit. Positron Emission Tomography/Computed Tomography (PET/CT) is used commonly to diagnose, prognosticate, and monitor response to antineoplastic therapy in human patients. In this study, serial PET/CT imaging with (18) F-fluorodeoxyglucose ((18) FDG) was used to assess response to toceranib therapy in dogs with measurable solid malignancies. Six tumor-bearing dogs underwent tumor assessment using both standard RECIST criteria and PET/CT prior to and at a median of 5 weeks postinitiation of toceranib treatment. Toceranib was prescribed initially at a target dose 3.25 mg/kg PO q48 h, with subsequent modifications based on observed toxicity. Treatment was continued in patients achieving stable disease with acceptable drug tolerance. One dog was maintained on drug despite dose modification due to toxicity; measurable clinical and image-based responses were seen after 10 weeks of therapy. All others had stable or progressive disease based on clinical restaging and PET/CT at first recheck. . Due to discordance with anatomic and metabolic imaging, further studies are needed to investigate the role of molecular imaging in assessment of drug response and identify other potential molecular targets of toceranib.     

THYROID SCINTIGRAPHY FINDINGS IN 2096 CATS WITH HYPERTHYROIDISM

Thyroid scintigraphy is currently the reference standard for diagnosing and staging cats with hyperthyroidism, but few studies describing the scintigraphic characteristics in a large number of cats have been reported. The objective of this study was to better characterize thyroid scintigraphy findings by evaluating 2096 consecutive cats with hyperthyroidism that were referred over a 3.5‐year period. Of these cats, 2068 (98.7%) had a high thyroid‐to‐salivary ratio (>1.5), whereas 2014 (96.1%) were found to have a high thyroid‐to‐background ratio (>6.1). When the patterns of the cats’ thyroid disease were recorded, 665 (31.7%) had unilateral disease, 1060 (50.6%) had bilateral‐asymmetric disease (two thyroid lobes unequal in size), 257 (12.3%) had bilateral‐symmetric disease (both lobes similar in size), and 81 (3.9%) had multifocal disease (≥3 areas of increased radionuclide uptake). The number of areas of ^99mTcO^?₄ uptake in the 2096 cats ranged from 1 to 6 (median, 2), located in the cervical area in 2057 (98.1%), thoracic inlet in 282 (13.5%), and in the thoracic cavity in 115 (5.5%). Ectopic thyroid tissue (e.g. lingual or mediastinal) was diagnosed in 81 (3.9%) cats, whereas thyroid carcinoma was suspected in 35 (1.7%) of the cats. The results of this study support conclusions that most hyperthyroid cats have unilateral or bilateral thyroid nodules, but that multifocal disease will develop in a few cats that have ectopic thyroid disease or thyroid carcinoma. Both ectopic thyroid disease and thyroid carcinoma are relatively uncommon in hyperthyroid cats, with a respective prevalence of ～4% and ～2% in this study.     

Toxicity and outcome in cats with oral squamous cell carcinoma after accelerated hypofractionated radiotherapy and concurrent systemic treatment

Recently, a multimodal approach to oral squamous cell carcinoma (SCC) in cats, combining medical treatment and accelerated radiation therapy, showed a substantial outcome improvement in a small pilot study. Herein we retrospectively review 51 cats with unresectable, histologically confirmed oral SCC and a complete initial staging work‐up: cats in group A (n = 24) received medical anti‐angiogenic treatment consisting of bleomycin, piroxicam and thalidomide, cats in group B (n = 27) received the anti‐angiogenic treatment and concurrent accelerated hypofractionated radiation therapy with 48Gy delivered in 10 fractions. Overall median progression‐free interval (PFI) was poor with 70 days (95% CI: 48;93). In the irradiated cats (group B), however, PFI was significantly longer with 179 days (95% CI: 58;301) days, vs 30 days (95% CI: 23;38) in medically only treated cats (P < .001). Overall median overall survival (OS) was 89 days (95% CI: 55;124), again significantly longer in the irradiated cats (group B) with 136 (95% CI: 40;233) vs 38 days (95% CI: 23;54) (P < .001). In 8 of the 27 (29.6%) cats in group B, however, severe toxicity (grade 3) occurred. Neither onset nor severity of toxicity could be associated with any of the tested variables, including anatomic site, tumour size, clinical stage and duration of neoadjuvant medical treatment. Given the potential severe acute effects and the impact on quality of life after chemo‐radiotherapy, owners must be clearly informed about the risks of treatment. With the overall poor outcome and high occurrence of acute toxicity, we cannot recommend the use of this accelerated radiation protocol combined with anti‐angiogenic therapy for oral SCC in cats.     

Single agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997)

Medical records of 21 cats with confirmed lymphoma treated with single-agent doxorubicin were reviewed. Nineteen cats met the inclusion criteria for this retrospective study. Doxorubicin was given at a dosage of 25 mg/m2 (n = 8) or 1 mg/kg (n = 11) IV, every 3 weeks for a total of 5 treatments. Four of 16 tested cats were positive for feline leukemia virus (FeLV) and all 16 cats tested negative for feline immunodeficiency virus. Eight of the 19 cats (42%) responded to doxorubicin for a median duration of 64 days (range, 35-575 days). Five cats (26%) achieved a complete response (CR) to doxorubicin for a median duration of 92 days (range, 54-575 days). Partial response was observed in 3 cats. Institution was the only significant prognostic indicator for response, with cats treated at Colorado State University being more likely to achieve CR than cats treated at Tufts University. Cats that achieved CR to doxorubicin and FeLV-negative cats had significantly longer survival times. Loss of appetite was the most common toxicity, observed in 9 cats (47%), and was severe in 5 cats (26%). Other toxicoses were less frequent and included vomiting, diarrhea, and myelosuppression. Doxorubicin was not very effective at inducing and maintaining remission in the cats in this study. Therefore, if doxorubicin is used for the treatment of feline lymphoma, it should be combined with other effective chemotherapeutic drugs in a combination protocol.     

Phase I clinical trial evaluating STI571 in tumor bearing cats

Introduction: STI571 (Gleevec, imatinib mesylate) is a receptor tyrosine kinase inhibitor with selectivity for Bcr‐Abl, platelet‐derived growth factor (PDGF), stem cell factor (SCF), and c‐Kit. Side effects with use in humans include vomiting, diarrhea, nausea, myalgia, edema, and cutaneous reactions. Renal and hepatic toxicity have also been reported. In dogs, there is significant hepatic toxicity at sub‐clinical doses. The purpose of this prospective study was to determine the toxicity level and potential treatment protocol in tumor bearing cats. Methods: A phase I clinical trial was performed in client owned cats using an escalating dose of STI571 in tumor bearing cats. Cats included in the study had a histologic diagnosis of fibrosarcoma or other tumors and were staged with CBC, biochemical profile, thoracic radiographs, and abdominal ultrasound. None of the cats received concurrent chemotherapy, but those previously treated with surgery, radiation therapy, or chemotherapy, were not excluded. The initial starting dose was 5 mg/cat PO SID and was gradually increased to 10 and 20 mg/cat PO SID at a 2–6 week interval depending on laboratory work and disease progression. A repeat physical examination, CBC, and biochemical profile, were performed every 2 weeks for 2 rechecks, then every 4 weeks. Results: Six cats were enrolled in the study. Four cats had oral squamous cell carcinoma, and two cats had cutaneous fibrosarcoma. One cat demonstrated leukocytosis, increased liver enzymes, and signs of acute renal failure two weeks after initiating therapy (5 mg PO SID). No dose escalation was made in this cat. Five cats endured dose escalations of 10 mg PO SID in two cats and 20 mg PO SID in three cats and were treated for 2–4 months. None of these cats experienced any signs of toxicity as measured by CBC and biochemical profile. Conclusions: Only one cat experienced toxicity that may have been associated with low dose administration of STI571. As most cats tolerated the drug without an adverse effect, further evaluation of STI571 in a phase II clinical trial is warranted.     

Pharmacokinetic properties of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor,in laboratory dogs and dogs with mast cell tumors

Yancey, M. F., Merritt, D. A., Lesman, S. P., Boucher, J. F., Michels, G. M. Pharmacokinetic properties of toceranib phosphate (Palladia?, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors. J. vet. Pharmacol. Therap. 33 , 162–171. Toceranib phosphate (Palladia?, SU11654), an oral tyrosine‐kinase inhibitor, is under investigation for the treatment of mast cell tumors in dogs. The pharmacokinetics of toceranib phosphate has been characterized in dogs. Means of the following pharmacokinetic parameters were estimated following a 1.0 mg/kg i.v. dose to laboratory beagles: plasma clearance of 1.45 L/kg/h, volume of distribution of 29.7 L/kg, and terminal half‐life of 17.7 h. Following single oral doses of 3.25 mg/kg administered to laboratory beagles, mean C_max estimates ranged from 68.6 ng/mL to 112 ng/mL with t_max ranging from 5.3 h and 9.3 h postdose. Terminal half‐life was estimated at 31 h. Oral bioavailability was 76.9%. There were no statistically significant (P > 0.05) differences with any pharmacokinetic parameter due to fed/fasted state or with time during 13 weeks of every‐other‐day dosing at 3.25 mg/kg. Toceranib concentrations were proportional with dose over the range of 2.0 to 6.0 mg/kg. The pharmacokinetics of toceranib in client‐owned dogs of a variety of pure and mixed breeds with mast cell tumors was similar to that in healthy laboratory dogs. In summary, toceranib phosphate exhibited moderate clearance, a high volume of distribution, and a moderate elimination half‐life. After a single oral dose at 3.25 mg/kg, the concentration vs. time curve showed broad, sustained exposure with measurable concentrations for more than 48 h. These pharmacokinetic parameters support every‐other‐day administration of toceranib phosphate at an initial dose of 3.25 mg/kg for the treatment of mast cell tumors in dogs.     

Potpourri oil toxicity in cats: 6 cases (2000–2007)

Objective – To describe the clinical and laboratory features, treatment, and outcome of cats with a history of potpourri oil exposure. Design – Retrospective study. Setting – Veterinary teaching hospital. Animals – Six client‐owned cats. Measurements and Main Results – The medical records of animals with oral or lingual ulceration and exposure to potpourri oil from January 2000 to December 2007 were reviewed. Information obtained from the medical records included signalment, product to which the animal was exposed, clinical signs, physical examination findings, diagnostic test results, treatment, duration of hospitalization, and outcome. Six cats qualified for inclusion in the study; 3 were castrated males and 3 were spayed females. Age range was 0.3–3.6 years. All cats had severe oral and lingual ulceration. Additional clinical findings included hyperthermia, tachypnea, ptyalism, and lethargy. Treatment of these cats included IV fluids, analgesic therapy, antimicrobial therapy, and gastrointestinal protectants. Two of these cats received an esophagostomy tube for nutritional support. Duration of hospitalization was 0–5 days. All cats survived to discharge. Follow‐up for 3 cats revealed complete healing of the oral ulceration. Conclusions – Potpourri oil toxicity should be considered as a differential diagnosis in any cat with oral and lingual ulceration. Prognosis for recovery is good with supportive care.