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.     

Diagnosis, treatment and outcome of orbital neoplasia in dogs: a retrospective study of 44 cases

Forty-four dogs with confirmed orbital neoplasia were studied. Eighteen tumour types were represented and 95 per cent of the neoplasms were classified as malignant. The tumour types most commonly diagnosed were osteosarcoma, fibrosarcoma and nasal adenocarcinoma. Thirty-six per cent of the dogs had at least one clinical sign that was compatible with a diagnosis of orbital abscessation or cellulitis. Fifty-six per cent of the dogs, where follow-up information was available, were euthanased or had died within six months of diagnosis, while 19 per cent of the total were still alive after one year post-diagnosis. Cytological examination was diagnostic for orbital neoplasia in 49 per cent of the fine needle aspirates of the retrobulbar space. In contrast, 56 per cent of the non-surgical biopsies were diagnostic for orbital neoplasia. Of those dogs that had died or been euthanased within six months of diagnosis, only 22 per cent had undergone some form of therapy for orbital neoplasia. In comparison, 86 per cent of dogs surviving longer than six months post-diagnosis had undergone such therapy.     

A dose‐finding study with a novel water‐soluble formulation of paclitaxel for the treatment of malignant high‐grade solid tumours in dogs

A new formulation of water‐soluble paclitaxel (Paccal® Vet) has been developed for canine cancer patients, without the need for pre‐medication (traditionally required in non‐water‐soluble paclitaxel formulations). The objective of the study was to determine a clinically safe and efficacious dose of Paccal Vet and to estimate progression‐free and overall survival and to evaluate single‐dose pharmacokinetics in tumour‐bearing dogs. A positive risk:benefit ratio was established for Paccal Vet administered at 150 mg m^–2 intravenous (IV) for three or more treatment cycles. Preliminary efficacy was demonstrated by best objective response rate (86%), median time to response (14 days) and median progression‐free survival (131 days). Paccal Vet was associated with expected adverse events (AE) (e.g. myelosuppression), however the majority were transient, clinically silent and manageable. This is the first clinical report of a water‐soluble formulation of paclitaxel suggesting successful administration and being safely used without pre‐medication in dogs.     

Efficacy and safety of cefovecin (Convenia) for the treatment of urinary tract infections in dogs

OBJECTIVES: To determine the efficacy and safety of cefovecin (Convenia); Pfizer Animal Health) in the treatment of urinary tract infections in dogs. METHODS: A multi-centre, blinded, randomised study was conducted in 129 dogs with urinary tract infections. Cephalexin (Rilexine) administered twice daily at 15 mg/kg bodyweight orally for 14 days was compared with a single, subcutaneous injection of cefovecin (Convenia) in dogs. The primary efficacy parameter assessed was bacterial elimination of the pretreatment uropathogen. RESULTS: One hundred and twenty-nine dogs were included in efficacy assessments. Escherichia coli was eliminated in 90.5 per cent of cefovecin-treated dogs compared with 52.9 per cent of cephalexin-treated dogs (P=0.0004). Overall cure rates for dogs with Escherichia coli infections were 79.1 per cent for cefovecin and 36.4 per cent for cephalexin-treated dogs (P=0.0003). There were no suspected adverse drug reactions attributed to treatment with cefovecin or cephalexin. CLINICAL SIGNIFICANCE: Cefovecin was shown to be an effective and safe treatment for urinary tract infections.     

MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000)

The purpose of this retrospective study was to evaluate the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. One hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Before treatment with MOPP, all dogs received a median of 6 chemotherapy drugs for a median duration of 213 days. Thirty-one percent (36 of 117) had a complete response (CR) to MOPP for a median of 63 days, and 34% (40 of 117) had a partial response (PR) for a median of 47 days. Sixteen percent (19 of 117) had stable disease (SD) for a median of 33 days. Predictors for response to MOPP were not identified. Gastrointestinal (GI) toxicity occurred in 28% (33 of 117) of the dogs, and 13% (15 dogs) required hospitalization. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma and was well tolerated by the majority of affected dogs.     

A randomized trial investigating the efficacy and safety of water soluble micellar paclitaxel (Paccal Vet) for treatment of nonresectable grade 2 or 3 mast cell tumors in dogs

Background

Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early‐phase studies.

Hypothesis/Objectives

The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was μ_p = μ_L (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively).

Animals

Two hundred and fifty‐two dogs with advanced stage nonresectable grade 2 or 3 MCT.

Methods

Prospective multicenter randomized double‐blind positive‐controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE).

Results

Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)‐treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty‐seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7).

Conclusions and Clinical Importance

Paclitaxel (micellar)'s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols.     

Clinical features of epistaxis in dogs: a retrospective study of 35 cases (1999-2002)

Epistaxis was retrospectively evaluated in 35 dogs. Systemic disease was diagnosed in seven dogs and intranasal disease in 29. Nineteen dogs with intranasal disease had neoplasia. Dogs with neoplasia were older (mean 10.0 years) than dogs with nonneoplastic intranasal disease (mean 5.6 years). Signs persisting for >1 month occurred more often in dogs with intranasal than systemic disease. Unilateral epistaxis did not distinguish intranasal from systemic disease. Only dogs with intranasal disease had facial deformity, decreased airflow, or regional sub-mandibular lymphadenopathy. Dogs with systemic disease had a lower packed cell volume (mean 31.8%) than dogs with intranasal disease (mean 42.7%).     

Clinical management of flail chest in dogs and cats: a retrospective study of 24 cases (1989-1999)

Cases of flail chest injury for 24 client-owned companion animals following various traumas were evaluated. Concurrently sustained injuries, initial emergency treatments, and definitive treatment and outcome for regimens that utilize stabilization of the flail segment were compared with cases treated with no stabilization. Flail chest was confirmed in 24 animals: 21 dogs and three cats. There was an even division (12 each) of right and left flail segments. The median number of ribs involved was three (range, two to seven). Flail segment stabilization was performed in nine, and 15 were treated with no stabilization. Statistical analysis using multiple data permutations evaluating all combinations failed to reveal a significant difference in outcome between stabilized and unstabilized cases.     

Single‐ and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT‐116 (a TRPV1 antagonist) in dogs

Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT‐116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT‐116. Results showed a half‐life of 6.9 h, k_el of 0.1/h, AUC of 56.5 μg·h/mL, T_max of 3.7 h, and C_max of 3.8 μg/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT‐116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 μg/mL previously determined for rodents) for analgesia during the 24‐h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT‐116 following oral delivery in dogs.     

A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high‐dose vinblastine and prednisone (CVP) for treatment of dogs with high‐grade,metastatic or nonresectable mast cell tumours

Safety and efficacy of a protocol of alternating 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU; 70 mg m^?2) and vinblastine (3.5 mg m^?2), and prednisone (1–2 mg kg^?1; CVP) in dogs with mast cell tumours (MCT) were evaluated. A total of 17 dogs had nonresectable MCTs and 35 received CVP as adjunctive treatment to locoregional control of metastatic MCTs or grade III MCTs. Neutropenia with fever occurred in 8% of dogs after treatment with vinblastine and in 2% after treatment with CCNU. Persistent elevation of serum alanine transaminase, suggestive of hepatotoxicity, occurred in 9% of the dogs. Response rate in dogs with nonresectable MCTs was 65%; five achieved a complete response (median, 141 days) and six achieved a partial response (median, 66 days). Overall median progression‐free survival (PFS) time in dogs treated in the adjuvant setting was 489 days. Dogs with grade III MCTs had shorter PFS compared with dogs with metastatic grade II MCTs (190 days versus 954 days; P < 0.001). Phase III studies are needed to provide reliable information about the comparative efficacy of this protocol.     

Multi-centre assessment of mycotic rhinosinusitis in dogs: a retrospective study of initial treatment success (1998 to 2008)

Objectives : To retrospectively review the first treatment response of dogs with mycotic rhinosinusitis to commonly utilised treatment techniques. Methods : Medical records of dogs treated for mycotic rhinosinusitis were obtained retrospectively via a manual review of the clinical databases of six veterinary referral centres for the period of January 1998 to June 2008, and first treatment outcome was evaluated. Historical and clinicopathological findings were also reviewed to evaluate their impact on treatment success or failure. Results : There was no significant difference in first treatment outcome between treatment groups (P=0·21). When all topical treatments were considered together (n=85), 39 dogs (45·8%) had a successful first treatment. Initial treatment success was associated with a younger age (56·3 versus 75·8 months; P=0·02) and was 2·7 times more likely in dogs with unilateral disease, although this was not significant (P=0·07). Adjunctive therapy with systemic antifungal agents was associated with treatment failure (PÄ0·01). Fifty-nine dogs (69·4%) responded successfully following multiple treatments. Clinical Significance : Treatment of mycotic rhinosinusitis remains challenging, and multiple treatments are frequently required for adequate treatment. Reasons for first treatment failure are likely multifactorial in origin, making it difficult to predict those dogs that are likely to have a superior prognosis, regardless of the treatment type used.     

Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose

The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2 mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51 ± 0.22 L and total plasma clearance (Cl) of 0.109 ± 0.023 L/h kg. The permanence of this drug was long in vultures (T_1/2λ = 12.51 ± 2.52 h; MRT_∞ = 13.54 ± 2.29 h). The optimal dose of marbofloxacin estimated is 2.73 mg/kg per day for the treatment of infections in vultures with MIC₉₀ = 0.2 μg/mL.     

Clinical signs, diagnosis, and treatment of alkalemia in dogs: 20 cases (1982-1984)

Alkalemia (pH greater than 7.50) was measured in 20 dogs admitted over a 3-year period for various clinical disorders. Alkalemia was detected in only 2.08% of all dogs in which blood pH and blood-gas estimations were made. Thirteen dogs had metabolic alkalosis (HCO3- greater than 24 mEq/L, PCO2 greater than 30 mm of Hg), of which 8 had uncompensated metabolic alkalosis, and of which 5 had partially compensated metabolic alkalosis. Seven dogs had respiratory alkalosis (PCO2 less than 30 mm of Hg, HCO3- less than 24 mEq/L); 4 of these had uncompensated respiratory alkalosis and 3 had partially compensated respiratory alkalosis. Ten dogs had double or triple acid-base abnormalities. Dogs with metabolic alkalosis had a preponderance of clinical signs associated with gastrointestinal disorders (10 dogs). Overzealous administration of sodium bicarbonate or diuretics, in addition to anorexia, polyuria, or hyperbilirubinemia may have contributed to metabolic alkalosis in 8 of the dogs. Most of the dogs in this group had low serum K+ and Cl- values. Two dogs with metabolic alkalosis had PCO2 values greater than 60 mm of Hg, and 1 of these had arterial hypoxemia (PaO2 less than 80 mm of Hg). Treatments included replacement of fluid and electrolytes (Na+, K+, and Cl-), and surgery as indicated (8 dogs). Six dogs with respiratory alkalosis had a variety of airway, pulmonary, or cardiac disorders, and 3 of these had arterial hypoxemia. Two other dogs were excessively ventilated during surgery, and 1 dog had apparent postoperative pain that may have contributed to the respiratory alkalosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

A prospective,randomized, double-blind,placebo-controlled multisite,parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab,a canine anti-nerve growth factor monoclonal antibody

ObjectiveBedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to support registration in the USA.Study designRandomized, double-blind, placebo-controlled, multicenter, parallel-group study.AnimalsGeneral practice client-owned dogs with osteoarthritis (n = 272).MethodsDogs were block randomized 1:1 to placebo (saline, n = 137) or bedinvetmab (n = 135; 0.5–1.0 mg kg^–1) administered subcutaneously, once monthly. The primary end point, day 28 Canine Brief Pain Inventory (CBPI) treatment success (TS), required pain severity score (PSS; 0–10) decrease ≥1 and pain interference score (PIS; 0–10) decrease ≥ 2. CBPI TS rates [and number needed to treat (NNT)], change in scores [and standardized effect size (ES)], change in quality of life (QoL) and bedinvetmab half-life were calculated.ResultsSignificant (p < 0.05) improvement with bedinvetmab over placebo occurred (days 28, 42, 56, 84) for CBPI TS. Of cases evaluable for day 28 CBPI TS (placebo, n = 131; bedinvetmab, n = 128), success rates were 36.6% and 47.4%, respectively (p = 0.0410) (NNT, 9.3; PSS and PIS ES, 0.3). CBPI TS increased after the second dose in both groups, plateaued for bedinvetmab at day 42 and decreased for placebo beginning day 84. Day 84 NNT (4.3), PSS (0.4) and PIS (0.5) showed continued improvement with monthly dosing. After the first dose, mean (± standard deviation) bedinvetmab half-life was 19.1 (8.3) days. Adverse events were similar between groups and not considered treatment-related. There was a significant effect of bedinvetmab versus placebo on all CBPI components (PIS, PSS, QoL).Conclusions and clinical relevanceThese results corroborated those previously reported and provide further support of safety and effectiveness of bedinvetmab (0.5–1.0 mg kg^–1) administered subcutaneously at monthly intervals to dogs for control of osteoarthritis-related pain.