Individualized chemotherapy drug dose escalation in dogs with multicentric lymphoma.

BACKGROUND: This study was performed to determine the ability to escalate drug doses in a 15-week CHOP protocol in dogs with multicentric lymphoma. HYPOTHESIS: We hypothesized that at least 50% of dogs could successfully be escalated in at least 1 drug. Secondary aims were to establish objective response rate (ORR), progression-free interval (PFI), and overall survival time (OST). ANIMALS: Thirty dogs with newly diagnosed multicentric lymphoma were prospectively treated with a 15-week CHOP protocol. METHODS: This was a prospective cohort study. Drug doses that did not cause dose-limiting adverse effects (AEs) were increased using a standardized escalation protocol. AEs and response were assessed using VCOG criteria. Serial blood samples were collected after the first dose of each drug for pharmacokinetic analysis. RESULTS: Of the 23 dogs with the opportunity to dose escalate, at least 1 drug was successfully escalated in 18 (78%). Vincristine was successfully escalated to 0.8 mg/m2 or higher in 11 dogs, cyclophosphamide to 300 mg/m2 or higher in 16 dogs, and doxorubicin to 35 mg/m2 or 1.4 mg/kg or higher in 9 dogs. Three of the 23 dogs (13%) were hospitalized at least once because of drug-induced AEs. Neutropenia was the most common dose-limiting toxicosis for all drugs. Peak doxorubicin concentrations were significantly lower in dogs where doxorubicin was successfully escalated. The objective response rate was 100%. The median progression free interval was 171 days. The median overall survival time was 254 days. CONCLUSIONS: Drugs in the CHOP protocol can often be escalated safely with manageable AEs.

Oclacitinib and Myxoma Virus Therapy in Dogs with High-Grade Soft Tissue Sarcoma.

Human rhabdomyosarcomas are rarely cured by surgical resection alone. This is also true for high-grade soft tissue sarcomas in dogs. Dogs with spontaneous sarcoma are good models for clinical responses to new cancer therapies. Strategic combinations of immunotherapy and oncolytic virotherapy (OV) could improve treatment responses in canine and human cancer patients. To develop an appropriate combination of immunotherapy and OV for dogs with soft tissue sarcoma (STS), canine cancer cells were inoculated with myxoma viruses (MYXVs) and gene transcripts were quantified. Next, the cytokine concentrations in the canine cancer cells were altered to evaluate their effect on MYXV replication. These studies indicated that, as in murine and human cells, type I interferons (IFN) play an important role in limiting MYXV replication in canine cancer cells. To reduce type I IFN production during OV, oclacitinib (a JAK1 inhibitor) was administered twice daily to dogs for 14 days starting ~7 days prior to surgery. STS tumors were excised, and MYXV deleted for serp2 (MYXV∆SERP2) was administered at the surgical site at two time points post-operatively to treat any remaining microscopic tumor cells. Tumor regrowth in dogs treated with OV was decreased relative to historical controls. However, regrowth was not further inhibited in patients given combination therapy.

Increased incidence of gastrointestinal toxicity in canine cancer patients treated with concurrent abdominal radiation therapy and toceranib phosphate.

Receptor tyrosine kinase inhibitors (TKIs) are used to treat human and canine cancers and may be combined with radiation therapy (RT) to enhance tumor control due their anticancer and antiangiogenic effects; however, recent case reports have emerged describing incidences of gastrointestinal toxicity when antiangiogenic therapies are combined with hypofractionated radiotherapy in human cancer patients. We evaluated the incidence of gastrointestinal (GI) toxicity in dogs receiving concurrent hypofractionated abdominal RT and the TKI toceranib (TOC) compared to those receiving abdominal RT alone, TOC alone, or concurrent non-abdominal RT and TOC. Medical records of canine cancer patients were retrospectively reviewed and identified dogs were included in the following treatment categories: dogs which received RT to a portion of the abdomen and concurrent TOC (n = 19), abdominal RT alone (n-29), TOC alone (n = 20), or non-abdominal RT plus TOC (n = 9). Toxicities were graded using the Veterinary Cooperative Oncology Group - Common Terminology Criteria for Adverse Events criteria and compared to published data on TOC-associated GI toxicity. Patients receiving TOC while undergoing abdominal RT had significantly increased rates of any grade of diarrhea (p = 0.002), hyporexia (p = 0.0045), and vomiting (p = 0.003), as well as severe hyporexia (p = 0.003) when compared across the treatment groups. This retrospective study reveals significantly increased incidences of GI toxicity when abdominal RT is combined with TOC in canine patients. These findings are in-line with the clinical concerns reported for increased normal tissue toxicity in human patients when antiangiogenics are combined with RT.

Multicenter, randomized, double-blinded, placebo-controlled study of rabacfosadine in dogs with lymphoma.

BACKGROUND: Rabacfosadine (RAB, Tanovea-CA1) is a novel chemotherapy agent conditionally approved for the treatment of lymphoma in dogs. HYPOTHESIS/OBJECTIVES: To determine the efficacy and safety of RAB in dogs with lymphoma. ANIMALS: One hundred and fifty-eight client-owned dogs with naïve or relapsed multicentric lymphoma were prospectively enrolled from January to October 2019. METHODS: Dogs were randomized to receive RAB or placebo at a 3 : 1 ratio. Treatment was given every 21 days for up to 5 treatments. Study endpoints included progression-free survival (PFS), overall response rate (ORR) at a given visit, best overall response rate (BORR), and percent progression free 1 month after treatment completion. Safety data were also collected. RESULTS: The median PFS was significantly longer in the RAB group compared to placebo (82 vs 21 days; P < .0001, HR 6.265 [95% CI 3.947-9.945]). The BORR for RAB-treated dogs was 73.2% (50.9% complete response [CR], 22.3% partial response [PR]) and 5.6% (0% CR, 5.6% PR) for placebo-treated dogs (P < .0001). One month after the last treatment, 37 RAB-treated dogs (33%) were progression free compared with no placebo-treated dogs (P < .0001). The most common adverse events observed in the RAB group were diarrhea (87.5%), decreased appetite (68.3%), and vomiting (68.3%) and were generally low grade and reversible. Serious adverse events were reported in 24 RAB-treated (20%) and 5 placebo-treated dogs (13%). CONCLUSIONS AND CLINICAL IMPORTANCE: Rabacfosadine demonstrated statistically significant antitumor efficacy in dogs with lymphoma when administered every 21 days for up to 5 treatments as compared to placebo.

Prospective clinical trial testing COXEN-based gene expression models of chemosensitivity in dogs with spontaneous osteosarcoma.

BACKGROUND: This study is a prospective clinical trial in dogs with osteosarcoma testing a gene expression model (GEM) predicting the chemosensitivity of tumors to carboplatin (CARBO) or doxorubicin (DOX) developed using the COXEN method. PATIENTS AND METHODS: Sixty dogs with appendicular osteosarcoma were enrolled in this trial. RNA isolation and gene expression profiling were conducted with 2 biopsies for 54/63 screened tumors, and with a single biopsy for 9 tumors. Resulting gene expression data were used for calculation of a COXEN score for CARBO and DOX based on a previous study showing the significance of this predictor on patient outcome utilizing retrospective data (BMC Bioinformatics 17:93). Dogs were assigned adjuvant CARBO, DOX or the combination based on the results of the COXEN score following surgical removal of the tumor via amputation and were monitored for disease progression by chest radiograph every 2 months. RESULTS: The COXEN predictor of chemosensitivity to CARBO or DOX was not a significant predictor of progression-free interval or overall survival for the trial participants. The calculation of DOX COXEN score using gene expression data from two independent biopsies of the same tumor were highly correlated (P < 0.0001), whereas the calculated CARBO COXEN score was not (P = 0.3039). CONCLUSION: The COXEN predictor of chemosensitivity to CARBO or DOX is not a significant predictor of outcome when utilized in this prospective study. This trial represents the first prospective trial of a GEM predictor of chemosensitivity and establishes pet dogs with cancer as viable surrogates for prospective trials of prognostic indicators.

Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats.

The updated VCOG-CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG-CTCAE v1.0 and v1.1 were consulted for input, and additional co-authors sought for expansion and refinement of the adverse event (AE) categories. VCOG-CTCAE v2 includes expanded neurology, cardiac and immunologic AE sections, and the addition of procedural-specific AEs. It is our intent that, through inclusion of additional authors from ACVIM subspecialties and the American College of Veterinary Surgery, that we can more comprehensively capture AEs that are observed during clinical studies conducted across a variety of disease states, clinical scenarios, and body systems. It is also our intent that these updated veterinary CTCAE guidelines will offer improved application and ease of use within veterinary practice in general, as well as within clinical trials that assess new therapeutic strategies for animals with a variety of diseases. Throughout the revision process, we strived to ensure the grading structure for each AE category was reflective of the decision-making process applied to determination of dose-limiting events. As phase I trial decisions are based on these criteria and ultimately determine the maximally tolerated dose, there is impact on standard dosing recommendations for any new drug registration or application. This document should be updated regularly to reflect ongoing application to clinical studies carried out in veterinary patients.

Clinical outcome in 23 dogs with exocrine pancreatic carcinoma.

Exocrine pancreatic carcinoma is uncommon in the dog and the veterinary literature surrounding the disease is minimal. Twenty-three cases of canine exocrine pancreatic carcinoma were reviewed in a retrospective manner to obtain information on clinical presentation, behaviour and survival associated with the disease. Presenting clinical signs were nonspecific and included anorexia, lethargy, vomiting and abdominal pain. The overall median survival time was only 1 day but was confounded by the large number of dogs that were euthanized shortly after diagnosis. Metastatic disease was detected in 78% of cases at the time of diagnosis, attesting to the aggressive nature of the disease. Neither lymph node metastasis, tumour size nor tumour location had an impact on overall survival. Only one patient was a previous diabetic who is contrary to reports of the disease in people and felines. This retrospective study reaffirms the need for early detection measures to optimize disease control. However, the benefits of therapy with surgery or radiation and adjuvant chemotherapy remain to be elucidated in dogs with exocrine pancreatic carcinoma.

Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma.

BACKGROUND: Lymphoma is a common cancer in dogs. While most dogs receiving chemotherapy experience remission, very few are cured, and median survival times are generally in the 12-month range. Novel approaches to treatment are unquestionably needed. The Inhibitor of Apoptosis Protein (IAP) family member survivin, which is one of the most commonly overexpressed proteins in human cancer, plays a key role in apoptosis resistance, a major cause of drug-resistant treatment failure. Survivin targeting therapies have shown promise preclinically; however, none have been evaluated in dogs to date. The goal of the current study was to determine the safety and pharmacodynamic effects of systemic administration of the anti-survivin locked nucleic acid antisense oligonucleotide EZN-3042 in dogs with lymphoma. RESULTS: We performed a prospective phase-I clinical trial in dogs with biopsy-accessible peripheral nodal lymphoma. Eighteen dogs were treated with EZN-3042 as a 2-h IV infusion at 5 dose levels, from 3.25 to 8.25 mg/kg twice weekly for 3 treatments. No dose-limiting toxicities were encountered. Reduction in tumor survivin mRNA and protein were observed in 3 of 5 evaluable dogs at the 8.25 mg/kg dose cohort. CONCLUSIONS: In conclusion, reduced survivin expression was demonstrated in lymphoma tissues in the majority of dogs treated with EZN-3042 at 8.25 mg/kg twice weekly, which was associated with minimal adverse effects. This dose may be used in future studies of EZN-3042/chemotherapy combinations in dogs with spontaneous lymphoma and other cancers.

Phosphorylated KIT as a predictor of outcome in canine mast cell tumours treated with toceranib phosphate or vinblastine.

Canine cutaneous mast cell tumour (MCT) is the most common malignant skin tumour in dogs and can exhibit variable biologic behaviour. Dysregulated signalling through the receptor tyrosine kinase (RTK) KIT can promote cell proliferation and survival, and assessment of its dysregulation via detection of activating c-kit gene mutations or assessment of KIT protein localization is associated with multiple features of malignancy. The aim of the current study was to use a previously validated immunohistochemical (IHC) assay to directly measure phosphorylated KIT (pKIT) in order to investigate its association with other established prognostic markers, response to therapy, progression free interval (PFI) and overall survival time (OST) in dogs treated medically for measurable MCT. Tumour tissue from 74 dogs enrolled in a prospective study comparing toceranib and vinblastine for MCT treatment were evaluated for pKIT immunoreactivity. pKIT was variably expressed, with some degree of positivity observed in 49/74 cases (66%). pKIT immunoreactivity was significantly associated with aberrant KIT localization, high mitotic index and high histologic grade. On univariate analysis, pKIT immunoreactivity predicted shorter PFI and OST in the entire patient population as well as shorter PFI in the toceranib treated group, and was the sole predictive factor for OST upon multivariate analysis, while mitotic index was the sole independent predictive factor for PFI. These results demonstrate that IHC detection of pKIT correlates with several features of aggressive behaviour, and may confer information that is complementary to other prognostic factors. However, the role of pKIT in predicting outcome needs to be studied further before recommendations can be made for its routine use.

Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma.

Many oncolytic viruses that are efficacious in murine cancer models are ineffective in humans. The outcomes of oncolytic virus treatment in dogs with spontaneous tumors may better predict human cancer response and improve treatment options for dogs with cancer. The objectives of this study were to evaluate the safety of treatment with myxoma virus lacking the serp2 gene (MYXVΔserp2) and determine its immunogenicity in dogs. To achieve these objectives, dogs with spontaneous soft tissue sarcomas were treated with MYXVΔserp2 intratumorally (n = 5) or post-operatively (n = 5). In dogs treated intratumorally, clinical scores were recorded and tumor biopsies and swabs (from the mouth and virus injection site) were analyzed for viral DNA at multiple time-points. In all dogs, blood, urine, and feces were frequently collected to evaluate organ function, virus distribution, and immune response. No detrimental effects of MYXVΔserp2 treatment were observed in any canine cancer patients. No clinically significant changes in complete blood profiles, serum chemistry analyses, or urinalyses were measured. Viral DNA was isolated from one tumor swab, but viral dissemination was not observed. Anti-MYXV antibodies were occasionally detected. These findings provide needed safety information to advance clinical trials using MYXVΔserp2 to treat patients with cancer.

Malignant mesenchymoma with widespread metastasis including bone marrow involvement in a dog.

A male castrated Golden Retriever was presented for evaluation of a large mass over the left shoulder extending to the lower part of the neck that had been present for an extended period of time, but had a recent history of rapid growth. Previous aspirates of the mass were consistent with a lipoma. The mass was surgically excised and was diagnosed as an extraskeletal osteosarcoma based on histopathology. After surgery, the dog was initiated on a chemotherapy protocol with carboplatin and metronomic cyclophosphamide. He became neutropenic, anemic, and thrombocytopenic 14 days after the carboplatin treatment was administered. The neutropenia resolved, but the anemia and thrombocytopenia progressed. A bone marrow aspirate revealed erythroid hypoplasia, myeloid hyperplasia with a predominance of early precursors, and a subset of cells that made up 20% of the total population that were reported as bizarre and unclassifiable. These cells were discrete in nature and were thought to be hematopoietic in origin. The dog was euthanized due to deterioration of the clinical condition. On postmortem examination, widespread metastasis involving the lungs, liver, kidney, heart, and bone marrow was found. Histopathology of the tumor lesions determined 2 distinct malignant populations of liposarcoma and osteosarcoma, consistent with malignant mesenchymoma. However, the possibility of 2 separate neoplastic processes cannot be definitively excluded. This is the first report of bone marrow metastasis of a malignant mesenchymoma in a dog.

Endobronchial metastasis in a dog with sarcoma.

A 3-year-old neutered male Australian Shepherd mix dog presented with metastatic soft tissue sarcoma arising from a primary tumor in the left lumbar fascia. Two separate metastases to the lungs were characterized by neoplasia within bronchiolar walls, which caused obstruction of the bronchiolar lumina and atelectasis of adjacent alveoli, a characteristic feature of endobronchial metastasis. Neoplastic cells of the primary lumbar neoplasm, metastatic pulmonary lesions, and additional widespread metastatic masses identified postmortem were similarly immunoreactive for vimentin, but non-immunoreactive for cytokeratin, cluster of differentiation 18, synaptophysin, chromogranin, and desmin. The present report describes a naturally occurring case of endobronchial metastasis in a dog.

Full recovery after cardiac arrest secondary to accidental iatrogenic venous air embolism in a cat.

OBJECTIVE: To describe the successful management of cardiac arrest following accidental venous air embolism (VAE) in a cat. CASE SUMMARY: A 3-year-old spayed female domestic shorthair cat, weighing 4 kg, was presented for continuation of its chemotherapy protocol. The cat was inadvertently administered approximately 5.5 mL of air IV during initiation of fluid therapy. Immediate cardiac arrest resulted and CPR successfully achieved return of spontaneous circulation. The cat was discharged 5 days later and is reportedly clinically normal 7 months post-discharge. NEW OR UNIQUE INFORMATION PROVIDED: VAE has been rarely reported in the veterinary literature. This is the first report of a cat surviving cardiac arrest secondary to VAE.