Did you know? Our Board-Certified Specialists. Inactive RTK System. Activated RTK System

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1 Did you know? ASH is the only hospital in Southwest Florida to have 7 boardcertified specialists under one roof ASH is the only hospital on the Gulf coast to have both MRI and CT on site V O L U M E 1, I S S U E 2 N O V E M B E R Palladia A Novel Receptor Tyrosine Kinase Inhibitor with Antiangiogenic and Antiproliferative Properties and Its Use in Small Animal Oncology Lisa DiBernardi, DVM, Diplomate ACVIM (Oncology), Diplomate ACVR (Radiation Oncology) Referrals are accepted and specialists are oncall 24/7/365 Our Board-Certified Specialists Ashley Ayoob, DVM, DACVIM (Medicine), DACVECC Michelle Carnes, MS, DVM, DACVIM (Neurology) Lisa DiBernardi, DVM, DACVIM (Oncology), DACVR (Radiation Oncology) Brandy Dugas, DVM, DACVIM (Medicine) Marc Havig, DVM, DACVS, CCRP Introduction Palladia (toceranib phosphate) is the first FDA approved antiangiogenic and antiproliferative cancer treatment specifically for dogs. This drug is a member of a class of drugs called small molecule inhibitors and shares this class with human approved drugs such as Avastin, Torisel, Gleevec and Sutent. Palladia is an orally administered receptor tyrosine kinase (RTK) inhibitor, blocking the function of various receptors leading to its antiangiogenic and antiproliferative activity. To permit the formation of a clinically relevant tumor, the work of Dr. Folkman demonstrated the necessity for the cells to establish a vascular supply. Therefore, the principles of tumor angiogenesis are fundamental for an understanding of tumor biology. This offers the potential to offer novel avenues for tumor control. Angiogenesis and vasculogenesis are two processes resulting in the formation of vascular structures in normal and pathological conditions. Vasculogenesis versus angiogenesis: Vasculogenesis is new vessel formation from in situ bone marrow derived progenitor cells. Angiogenesis is the in growth of blood vessels sprouting off of preexisting arteries. Protein tyrosine kinases (TK) are located on the surface of cells, within the cytoplasm and nucleus. They are enzymes responsible for the activation of proteins (tyrosine residues). This action plays an integral role in the regulation of signal transduction and consequently the regulation of gene expression. Receptor tyrosine kinases (RTK) are a class of cell membrane receptors with high affinity for many growth factors, cytokines and hormones. RTK have been shown not only to be key regulators of normal cellular processes but also have a critical role in the development and progression of many types of cancer through signaling pathways involved in angiogenesis. Their role is thought to be through the stimulation of biochemical reactions such as cell survival, migration, proliferation and gene activation. (Continued on next page) Nick Schroeder, DVM, DACVIM (Cardiology) Christi Warren, DVM, DACVO Schleesinger J. Cell. 2000;103: Inactive RTK System Activated RTK System

2 P A G E 2 Palladia A Novel Receptor Tyrosine Kinase Inhibitor with Antiangiogenic and Antiproliferative Properties and Its Use in Small Animal Oncology Palladia is indicated for use in recurrent Grade II or III cutaneous mast cell tumors. (continued from last page) As seen in the figures on the previous page, cell surface RTKs are activated once bound to growth factors. Once activated, RTK downstream signaling molecules carry out cellular responses such as abnormal cell growth and signaling. Dysregulation of RTKs can result in a cellular response (activation) despite the lack of growth factor binding. This dysregulation enhances inappropriate cell signaling and may cause volatility in the regulation of cell growth and cell survival. The cell membrane receptor important for the growth, adhesion, migration and survival of mast cells is Kit (CD 117). KIT is often dysregulated in mast cell tumors of both dogs and cats and Palladia not only inhibits mutated Kit but also non mutated Kit. There are other receptor tyrosine kinases inhibited by Palladia. These are vascular endothelial growth factor receptor 2 (VEGFR-2) located on endothelial cells, and platelet derived growth factor receptor-b (PDGFR-b) found on pericytes (connective tissue cell found around small blood vessels). Studies utilizing mouse models have recognized through combined inhibition of both VEGFR-2 and PDGFR-b tumor regression takes place. to be the driving force for the initiation and progression of angiogenesis. The presence of hypoxia initiates the release of vascular endothelial growth factor (VEGF) and platelet derived growth factor. When these substances bind to their receptor tyrosine kinases (PDGFR-b and VEGFR-2, respectively) they become key building blocks for tumor angiogenesis. Bergers et al., showed evidence of tumor vascular disruption through the blockade of PDGFR-b. With the addition of blockade of both PDGFR-b and VEGFR, Potapova et al., witnessed enhanced regression of tumor vasculature in addition to blocking either receptor alone. Mast Cell Tumors When the KIT RTK binds to its growth factor, stem cell factor (SCF), this incites a series of downstream events essential for mast cells to develop and grow. In cultured cells, blockade of these events caused the cells to undergo apoptosis. Inhibition of KIT occurs in a clinically achievable Palladia serum concentration. Palladia is indicated for use in recurrent Patnaik Grade II or Grade III cutaneous mast cell tumors having or lacking regional lymph node involvement. Therefore the standard of care in localized mast cell tumors is still surgical excision. Incompletely resected grade II tumors with microscopic disease have a 2 year control rate of 85-95% after treatment with external beam radiation. In areas where radiation is not available a second surgery or chemotherapy may be viable treatment alternatives. First line of therapy in regional or distant mast cell disease is chemotherapy and in some cases adjunctive radiation therapy. Frequently utilized first line treatments are often a combination or as single agent chemotherapeutics such as vinblastine, CCNU ( l o m u s t i n e ), L e u k e r a n (chlorambucil), cyclophosphamide, vinorelbine and prednisone. (Continued on next page.) Regulation of Angiogenesis Hypoxia is believed

3 V O L U M E 1, I S S U E 2 P A G E 3 (Continued from opposite page) Response rates achieving either partial or complete responses for single agent treatment of mast cell tumor ranges between 7-42% with potentially improved results with combination chemotherapy (46-64% response rate). Palladia therapy is typically instituted once a patient fails the standard mast cell tumor treatments, or if the patient presents with a non surgical localized mast cell tumor (with or without regional metast a s i s ). The cost of a 30 day supply of Palladia for a 60 lb dog ranges from $600-$1,000 depending on the distributor plus the cost of diagnostics etc. 22 dogs with Mast cell tumor were evaluated by London et al.; 50% of dogs had either a complete or partial response with 59% of dogs having a biological response (stable disease for 10 weeks or a partial or complete response). Palladia Dosing, Response and Side Effects In Phase I Clinical Trials the maximum tolerated dose of Palladia was determined to be 3.25mg/kg orally EOD. However, doses as low as 2.7mg/kg dosed on a Monday-Wednesday-Friday schedule have been shown to be effective. Tablet strengths are 10mg, 15mg and 50mg. These tablets are coated and should not be divided. Palladia is primarily metabolized by the liver and concurrent use of drugs known to inhibit cytochrome P450 enzyme CYP3A4 (cimetidine, omeprazole) may elevate serum concentrations and predispose the patient to side effects. Most Palladia induced side effects are mild to moderate however some can be serious. The most commonly experienced side effects are: diarrhea (46%), anorexia (39%), lethargy (35%), emesis (32%), neutropenia (46%), and lameness (17%). Instituting a 2 week rest from Palladia administration is warranted if severe diarrhea, gastrointestinal ulceration, neutropenia (<1000), anemia, azotemia, hypoalbuminemia, or hyperphosphatemia occur. Concurrent use of NSAID s increases the risk of gastrointestinal ulceration. Therefore other methods of pain or arthritis control such as opioids should be considered. Dogs with advanced diseased states or concurrent illnesses have a g r e a t e r l i k e l i - hood of undesirable side effects. A patient with systemic mast cell disease is predisposed to mast cell degranulation and potential life threatening side effects if treated with Palladia. Often prevention of gastrointestinal side effects with antihistamine, antacids and antiemetic agents is instituted prior to or at the start of Palladia. Dose reductions or schedule change are implemented after an adverse event(s). Patients should have a complete blood count, biochemistry profile, urinalysis, urine protein creatinine ratio and blood pressure prior to initiating Palladia and every 4-6 weeks there after. Response rates of 50% have been reported - Biological response is a newer and more appropriate evaluator of response with targeted therapies. The goal in veterinary oncology is to permit a good quality of life. While there is no standardized measurement for quality of life, the majority of owners report good quality of life with Palladia administration. Palladia Use in Cats and in Dogs With Non Mast Cell Tumor Cancer (Compassionate Use) Currently there is an ongoing clinical trial evaluating the use Palladia in feline oral squamous cell carcinoma; anecdotal administration in cats has yielded minimal results in the area of oral squamous cell carcinoma and injection site sarcomas. However to date we are lacking controlled prospective evaluation of Palladia for the use in feline mast cell disease. In the dog, reports of responses have been identified with metastatic tumors. These have included: gastrointestinal stromal cell tumors, osteosarcoma, thyroid carcinoma and anal sac apocrine gland adenocarcinomas, to name a few. The majority of these patients had long term stable disease. The majority of patients under Palladia treatment for non mast cell tumor disease fortunately subjectively have a lower side effect rate than the mast cell tumor patients. Summary The standard of care for localized low to intermediate grade mast cell tumors is surgery. There is a clear need to supplement the standard mast cell tumor treatments in patients that are poor surgical candidates or have limited surgical options. Palladia offers a good opportunity for disease control. Side effects should be anticipated and addressed early and aggressively.

4 ASH Events Calendar Enjoy time off during the Holidays ASH is open 24/7/365 to handle all of your Holiday Emergencies!! Sun Mon Tue Wed Thu Fri Sat 1 Happy New Year! January Botanical Garden Dog Day* 22 Pets On Third* Run for the Paws 5K* *Events sponsored by ASH Contact ASH for more information. Spotlight on: Dr. Lisa DiBernardi Lisa DiBernardi, DVM, DACVIM (Oncology), DACVR (Radiation Oncology) Dr. Lisa DiBernardi is now seeing appointments on both Mondays and Wednesdays. Since completion of her medical oncology and radiation oncology boardcertifications, Dr. DiBernardi has been in private practice in Texas and Florida for the past 7 years. In addition to seeing patients, Dr. DiBernardi volunteers her veterinary services at special event venues, such as Dolphin Stadium where she worked with the canine detection teams. In addition, she has treated several cancer patients of the Miami Metro Zoo and Lion Country Safari. Dr. DiBernardi s professional interests include clinical pathology and pain management. She has presented research nationally and is a member of the Veterinary Cancer Society. She participates in clinical trials with the Veterinary Radiation Therapy and Oncology Group and Animal Clinical Investigators group. Dr. DiBernardi routinely performs biopsy, fine needle aspiration and cytology, bone marrow aspirates and pathology report consultation. Treatments that may be incorporated for cancer therapy include: chemotherapy, clinical trials, immunotherapy and radiation therapy. Dr. DiBernardi is one of < 15 doubleboarded medical and radiation oncologists in the World

5 Quick Case of the Month: The Melanoma Vaccine Bailey, a 10 year old male neutered Shih Tzu mix, presented to the oncology department at ASH for evaluation of a previously excised oral melanoma with microscopic disease at the surgical site. Bailey s original mass was located on the gingiva near the right upper premolar. The mass was described as a pigmented, pedunculated soft tissue mass 2cm in size. Prior to a second surgery to remove microscopic disease, fine needle aspirate of the mandibular lymph nodes (ipsilateral and contralateral nodes due to variability in draining patterns) were submitted for review, as well as three view thoracic radiographs and abdominal ultrasound. A complete blood count and biochemistry profile and urinalysis were performed at the initial surgery. All diagnostic tests were negative for any metastasis and a second surgery was scheduled to remove the remaining microscopic disease. A right segmental maxillectomy extending from the 1st molar to the first pre-molar tooth was performed to assure complete surgical excision. Oncept canine melanoma vaccine was initiated. The vaccine (0.4ml) was administered transdermally to the medial thigh every two weeks. A total of four initial treatments are administered then one vaccine every six months thereafter. Bailey is doing well (6 months post-op); he has had no side effects from the vaccine or the administration of the vaccine and has no local or metastatic evidence of melanoma. His prognosis prior to Oncept with treatment was approximately only a 1 year survival. However, he is expected to have a greater then two year survival after vaccine administration. Canine oral melanoma is the most common malignant oral tumor of the dog. It also occurs in the nail and footpad. These tumors are aggressive and frequently metastasize to the lymph nodes, lungs, and abdominal organs. Local control may be achieved through surgery, radiation therapy or a combination of the two. However, most dogs will succumb to metastatic disease therefore a systemic treatment to delay or prevent metastasis is necessary. The Oncept vaccine was developed through a partnership between Merial and Memorial Sloan-Kettering Cancer Center and has been available to veterinary oncologists since March The vaccine is delivered via a needless system and local reactions are limited to acute wheal, hematoma formation, discomfort and or bruising at the site of administration. The American Journal of Veterinary Research December 2011 revealed the median survival time could not be determined for vaccinates because < 50% died of melanoma before the end of the observation period. No systemic reactions requiring veterinary intervention have been associated with vaccination. The cost of the initial vaccine series is approximately $2500; while this may seem expensive, we are now able to provide patients with malignant melanoma a great quality and quantity of life. If you have a patient that may be a candidate for the melanoma vaccine, please contact Dr. DiBernardi at Market St. Suite 1 Naples, FL (phone) (fax) info@ashfl.com