PART 1 Veterinary Oncology Roundtable The Role of Prognostic Factors in Patient Selection for Canine Mast Cell Tumor Therapy with Palladia®

Mast cell tumors (MCT) are the most common cutaneous tumors in the dog Participants (London & Thamm, 2013). A majority of cutaneous canine MCTs can be treated successfully with surgery, but locally recurrent, large or infiltrative tumors, Craig Clifford, DVM, MS, DACVIM (Oncology) and those in locations not amenable to wide surgical excision can present a Hope Veterinary Specialists, Malvern, PA therapeutic challenge. Other treatment modalities include radiation therapy, Laura D. Garrett, DVM, DACVIM (Oncology) cytotoxic chemotherapy, and most recently, targeted therapy with drugs in the College of Veterinary Medicine, University of Illinois, Urbana-Champaign, IL tyrosine kinase inhibitor (TKI) class. Carolyn Henry, DVM, MS, DACVIM (Oncology) School of Veterinary Medicine, Toceranib phosphate (Palladia®, Zoetis) was approved by the FDA in 2009 University of Missouri, Columbia, MO as the first cancer drug specifically for dogs for treatment of cutaneous MCTs. Ann E. Hohenhaus, DVM, DACVIM (SAIM, Oncology) Palladia is a tyrosine kinase inhibitor with both antitumor and antiangiogenic The Animal Medical Center, New York, NY activity through the inhibition of Kit, vascular endothelial growth factor 2 Chad Johannes, DVM, DACVIM (SAIM, Oncology) (VEGF2), and platelet-derived growth factor receptor beta (PDGFRß). College of Veterinary Medicine, Iowa State University, Virtually all canine MCTs express the KIT receptor tyrosine Ames, IA kinase (RTK), and 20% to 40% have a mutation in Pamela D. Jones, DVM, DACVIM (Oncology) and the c-kit gene that activates the Kit protein (London DACVR (Radiation Oncology) Consultant, Houston, TX & Thamm, 2013; Downing et al, 2002; London et M.K. Klein, DVM, MS, DACVIM (Oncology) and al, 1999; Zemke et al, 2002). In a clinical field trial DACVR (Radiation Oncology) Clinical Lecturer, University of Arizona Cancer Center; and of 145 dogs with Grade II (80%) or Grade III Veterinary Oncologist, Southwest Veterinary Oncology, (20%), Palladia was shown to provide an Tucson, AZ overall response rate of 37.2% (London et Cheryl A. London, DVM, PhD, DACVIM (Oncology) al, 2009). The response rate in tumors College of Veterinary Medicine, The Ohio State positive for the c-kit mutation, however, University, Columbus, OH was 60.0%, compared with 31.3% for Kathy Mitchener, DVM, CVMA tumors nega-tive for the c-kit mutation Angel Care Cancer Clinic for Animals, Memphis, TN (London et al, 2009). Administered as an Douglas H. Thamm, VMD, DACVIM (Oncology) oral tablet, Palladia can be given in com- Flint Animal Cancer Center, Colorado State University, bination with radiation therapy and/or Fort Collins, CO chemotherapy (Carlsten et al, 2012; Pellin David M. Vail, DVM, DACVIM (Oncology) School of Veterinary Medicine, University of Wisconsin, et al, 2016; Burton et al, 2015; Pan et al, Madison, WI 2016, Mitchell et al, 2012), and presents Katherine S. Gloyd, DVM (Moderator) an attractive option for treatment of Elevate DVM, Wilmington, DE cutaneous canine MCTs that cannot be treated successfully with surgery.

IMPORTANT SAFETY INFORMATION: During clinical studies, the most common adverse events associated with PALLADIA included: diarrhea, anorexia (including decreased appetite), lethargy, neutropenia, emesis, lameness, weight loss, muscu- loskeletal disorder, and blood in stool/GI bleed/hemorrhagic diarrhea. PALLADIA may cause vascular dysfunction, which can lead to edema and thromboembolism, including pulmonary thromboembolism. Serious and sometime fatal GI com- plications, including GI perforation, have occurred rarely in dogs treated with PALLADIA. If GI ulceration is suspected stop drug administration and treat appropriately. Children should not come in contact with PALLADIA. In addition, all individuals, including children and pregnant women, should avoid direct contact with broken or partially dissolved PALLADIA tablets or biological waste from dogs treated with PALLADIA. To report a suspected adverse reaction call Zoetis at 1-888-963-8471. See full Prescribing Information.

PALLADIA ROUNDTABLE | PART 1 1 PART 1

The goals of this roundtable About the Participants are twofold:

1 All participants in this discussion are residency To provide veterinary oncologists with the most current trained in oncology and/or information on best practices. Diplomates of the Ameri- can College of Veterinary Internal Medicine (ACVIM) certified in the Specialty 2 of Oncology and members of the PACE Oncology To provide an overview on Palladia and increase the Advisory Board.Many of knowledge base for internists and veterinarians in the participants were also involved in the original general practice who will be diagnosing and referring clinical trials of Palladia cancer patients to specialists, and in many cases, will leading to its approval (London et al, 2009) also be providing follow-up care for their patients. as well as current studies in progress.

PART 1 Veterinary Oncology Roundtable The Role of Prognostic Factors in Patient Selection for Canine Mast Cell Tumor Therapy with Palladia®

Mast cell tumors (MCT) are the most common cutaneous tumors in the dog Participants (London & Thamm, 2013). A majority of cutaneous canine MCTs can be treated successfully with surgery, but locally recurrent, large or infiltrative tumors, Craig Clifford, DVM, MS, DACVIM (Oncology) and those in locations not amenable to wide surgical excision can present a Hope Veterinary Specialists, Malvern, PA therapeutic challenge. Other treatment modalities include radiation therapy, Laura D. Garrett, DVM, DACVIM (Oncology) cytotoxic chemotherapy, and most recently, targeted therapy with drugs in the College of Veterinary Medicine, University of Illinois, Urbana-Champaign, IL tyrosine kinase inhibitor (TKI) class. Carolyn Henry, DVM, MS, DACVIM (Oncology) School of Veterinary Medicine, Toceranib phosphate (Palladia®, Zoetis) was approved by the FDA in 2009 University of Missouri, Columbia, MO as the first cancer drug specifically for dogs for treatment of cutaneous MCTs. of this two-part article covers prognostic Ann E. Hohenhaus, DVM, DACVIM (SAIM, Oncology) Palladia is a tyrosine kinase inhibitor with both antitumor and antiangiogenic Part I The Animal Medical Center, New York, NY activity through the inhibition of Kit, vascular endothelial growth factor 2 Chad Johannes, DVM, DACVIM (SAIM, Oncology) (VEGF2), and platelet-derived growth factor receptor beta (PDGFRß). College of Veterinary Medicine, Iowa State University, Virtually all canine MCTs express the KIT receptor tyrosine Ames, IA kinase (RTK), and 20% to 40% have a mutation in Pamela D. Jones, DVM, DACVIM (Oncology) and the c-kit gene that activates the Kit protein (London DACVR (Radiation Oncology) Consultant, Houston, TX & Thamm, 2013; Downing et al, 2002; London et M.K. Klein, DVM, MS, DACVIM (Oncology) and al, 1999; Zemke et al, 2002). In a clinical field trial DACVR (Radiation Oncology) Clinical Lecturer, University of Arizona Cancer Center; and of 145 dogs with Grade II (80%) or Grade III Veterinary Oncologist, Southwest Veterinary Oncology, (20%), Palladia was shown to provide an Tucson, AZ overall response rate of 37.2% (London et factors, diagnostics, and criteria for selection of Cheryl A. London, DVM, PhD, DACVIM (Oncology) al, 2009). The response rate in tumors College of Veterinary Medicine, The Ohio State positive for the c-kit mutation, however, University, Columbus, OH was 60.0%, compared with 31.3% for Kathy Mitchener, DVM, CVMA tumors nega-tive for the c-kit mutation Angel Care Cancer Clinic for Animals, Memphis, TN (London et al, 2009). Administered as an Douglas H. Thamm, VMD, DACVIM (Oncology) oral tablet, Palladia can be given in com- Flint Animal Cancer Center, Colorado State University, bination with radiation therapy and/or Fort Collins, CO chemotherapy (Carlsten et al, 2012; Pellin David M. Vail, DVM, DACVIM (Oncology) School of Veterinary Medicine, University of Wisconsin, et al, 2016; Burton et al, 2015; Pan et al, Madison, WI 2016, Mitchell et al, 2012), and presents canine MCT patients for treatment with Palladia. Katherine S. Gloyd, DVM (Moderator) an attractive option for treatment of Elevate DVM, Wilmington, DE cutaneous canine MCTs that cannot be treated successfully with surgery.

IMPORTANT SAFETY INFORMATION: During clinical studies, the most common adverse events associated with PALLADIA included: diarrhea, anorexia (including decreased appetite), lethargy, neutropenia, emesis, lameness, weight loss, muscu- loskeletal disorder, and blood in stool/GI bleed/hemorrhagic diarrhea. PALLADIA may cause vascular dysfunction, which can lead to edema and thromboembolism, including pulmonary thromboembolism. Serious and sometime fatal GI com- plications, including GI perforation, have occurred rarely in dogs treated with PALLADIA. If GI ulceration is suspected stop drug administration and treat appropriately. Children should not come in contact with PALLADIA. In addition, all individuals, including children and pregnant women, should avoid direct contact with broken or partially dissolved PALLADIA tablets or biological waste from dogs treated with PALLADIA. To report a suspected adverse reaction call Zoetis at 1-888-963-8471. See full Prescribing Information.

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PART 2

Veterinary Oncology Roundtable Palladia® Treatment Protocols and Consensus on Current Best Practices

While the majority of cutaneous canine mast cell tumors (MCTs) can be Participants In Part 2, treatment protocols in combination treated successfully with surgery, locally recurrent, large or infiltrative tumors and those in locations not amenable to wide surgical excision can Craig Clifford, DVM, MS, DACVIM (Oncology) present a therapeutic challenge. Part I of this two-part article covered prog- Hope Veterinary Specialists, Malvern, PA nostic factors, diagnostics, and criteria for selection of canine MCT patients Laura D. Garrett, DVM, DACVIM (Oncology) College of Veterinary Medicine, University of Illinois, for treatment with toceranib phosphate (Palladia®). Treatment protocols in Urbana-Champaign, IL combination with other modalities, adverse Carolyn Henry, DVM, MS, DACVIM (Oncology) events and quality of life issues, and School of Veterinary Medicine, the roles of the oncologist and University of Missouri, Columbia, MO referring veterinarian in moni- Ann E. Hohenhaus, DVM, DACVIM (SAIM, Oncology) toring patients treated with with other modalities, adverse events and quality The Animal Medical Center, New York, NY Palladia are covered here Chad Johannes, DVM, DACVIM (SAIM, Oncology) College of Veterinary Medicine, Iowa State University, in Part 2. Ames, IA Pamela D. Jones, DVM, DACVIM (Oncology) and DACVR (Radiation Oncology) Consultant, Houston, TX Treatment Protocols M.K. Klein, DVM, MS, DACVIM (Oncology) and DACVR (Radiation Oncology) Clinical Lecturer, University of Arizona Cancer Center; and A complete review of the Veterinary Oncologist, Southwest Veterinary Oncology, treatment of MCTs is beyond Tucson, AZ the scope of this discussion, of life issues, and the roles of the oncologist and Cheryl A. London, DVM, PhD, DACVIM (Oncology) which focuses on the use of College of Veterinary Medicine, The Ohio State University, Columbus, OH Palladia in treatment protocols for dogs with Grade III MCTs and Kathy Mitchener, DVM, CVMA (Oncology) Angel Care Cancer Clinic for Animals, Memphis, TN any Grade II MCTs with negative Douglas H. Thamm, VMD, DACVIM (Oncology) prognostic indicators. In these Flint Animal Cancer Center, Colorado State University, cases, Palladia preferably is not Fort Collins, CO used as a single agent but rather David M. Vail, DVM, DACVIM (Oncology) as part of a protocol that can School of Veterinary Medicine, University of Wisconsin, Madison, WI include surgery, radiation therapy, chemotherapy, and ancillary referring veterinarian in monitoring patients Katherine S. Gloyd, DVM (Moderator) Elevate DVM, Wilmington, DE medications (see sidebar for summary of treatment options).

IMPORTANT SAFETY INFORMATION: During clinical studies, the most common adverse events associated with PALLADIA included: diarrhea, anorexia (including decreased appetite), lethargy, neutropenia, emesis, lameness, weight loss, musculoskeletal disorder, and blood in stool/GI bleed/hemorrhagic diarrhea. PALLADIA may cause vascular dysfunction, which can lead to edema and thromboembolism, including pulmonary thromboembolism. Serious and sometime fatal GI complications, including GI perforation, have occurred rarely in dogs treated with PALLADIA. If GI ulceration is suspected stop drug administration and treat appropriately. Children should not come in contact with treated with Palladia will be covered. PALLADIA. In addition, all individuals, including children and pregnant women, should avoid direct contact with broken or partially dissolved PALLADIA tablets or biological waste from dogs treated with PALLADIA. To report a suspected adverse reaction call Zoetis at 1-888-963-8471. See full Prescribing Information.

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Patient selection for treatment with Palladia — prognostic factors and diagnostics

Canine cutaneous MCTs are not uniform in their response to the various treatment mo- dalities available. It is important to base treatment decisions on the presence or absence of certain prognostic factors to ensure the best clinical outcome. Palladia provides an excellent option for those cases in which complete surgical excision of the tumor is not possible (eg, due to location) or for treatment or prevention of systemic disease in dogs with negative prognostic factors.

Prognostic factors for canine cutaneous MCTs are listed in Table 1 From the Label: Palladia is indicated for the (London & Thamm, 2013). Histologic treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with grade remains the gold standard for or without regional lymph node involvement in dogs. predicting the biologic behavior of canine cutaneous MCTs (Table 2) (Patnaik et al, 1984). A two-tier system of histologic grading (high grade vs low grade) is currently proposed and may be more accurate in the histologic assessment and biological behavior of these tumors (Kiupel et al, 2011; Stefanello et al, 2015; Sabatini et al, 2015). While clinical stage is also predictive of prognosis (Table 3) (Ayl et al, 1992; Turrel et al, 1988; Krick et al, 2009), there is controversy regarding the impact of multiple tumors and the effect of lymph node metastasis on clinical staging and outcome (London & Thamm, 2013). This staging system may also be flawed in that stage II carries a worse prognosis than stage III (multiple tumors) (Murphy et al, 2004; Mullins et al, 2006; O’Connell & Thomson, 2013).

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TABLE 1 | Prognostic Factors for Canine MCTs*

Factor Comment

Strongly predictive of outcome. Dogs with undifferentiated tumors typically die of their Histologic grade disease following local therapy alone, whereas those with well-differentiated tumors are usually cured with appropriate local therapy.

Stages 0 and I, confined to the skin without local lymph node or distant metastasis, Clinical stage have a better prognosis than higher-stage disease

Subungual, oral, and other mucous membrane sites are associated with more high- grade tumors and worse prognosis. Preputial and scrotal tumors are also associated Location with a worse prognosis. Subcutaneous tumors may have a better prognosis. Visceral or bone marrow disease usually carries a grave prognosis.

MI, relative frequency of AgNORs, percentage of PCNA, or Ki67 immunopositivity are Cell proliferation rate predictive of postsurgical outcome.

MCTs that remain localized and are present for prolonged periods of time (months or Growth rate years) without significant change usually behave less aggressively.

There is a trend toward shorter survival times and higher-stage disease in dogs with DNA ploidy aneuploid tumors.

Increased microvessel density is associated with higher grade, a higher degree of Microvessel density invasiveness, and a worse prognosis.

Recurrence Local recurrence following surgical excision may carry a more guarded prognosis.

The presence of systemic illness (eg, anorexia, vomiting, melena, GI ulceration) may be Systematic signs associated with higher-stage disease.

Age Older dogs may have shorter median DFIs when treated with RT than younger dogs.

MCTs in Boxers (and potentially other brachycephalic breeds) tend to be low or Breed intermediate grade and are thus associated with a better prognosis.

Male dogs may have a shorter survival time than female dogs when treated with Sex chemotherapy in some studies.

Large tumors may be associated with a worse prognosis following surgical removal Tumor size and/or RT.

The presence of an activating mutation in the c-kit gene is associated with a worse c-kit mutation prognosis.

Adapted from London C, Thamm DH. Mast cell tumors. In Withrow SJ, Vail DM, Page RL (eds). Withrow and MacEwen’s Small Animal Clinical Oncology. 5th ed. St Louis: Elsevier, 2013, Chapter 20, page 337. Abbreviations: MI, Mitotic index; AgNORs, argyrophilic nucleolar organizer regions; PCNA, proliferating cell nuclear antigen; MCTs, mast cell tumors; GI, gastrointestinal; DFIs, disease-free intervals; RT, radiation therapy

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TABLE 2 | Histologic Classification of Cutaneous MCTs from Surgical Biopsy Samples*, †

Patnaik Microscopic Description Grade Grading

Clearly defined cytoplasmic boundaries with regular, spheric, Low grade I or ovoid nuclei; mitoses rare or absent; cytoplasmic granules (well-differentiated) large, deep staining, and abundant

Cells closely packed with indistinct cytoplasmic boundaries, nucleus-to-cytoplasmic ratio lower than anaplastic, infrequent Intermediate grade II mitoses, more granules than anaplastic

Highly cellular, undifferentiated cytoplasmic boundaries, High grade III irregular size and shape of nuclei, frequent mitoses, sparse (anaplastic, undifferentiated) cytoplasmic granules

* From Patnaik AK, Ehler WJ, MacEwen EG: Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol. 1984;21:469-474. † A two-tier system of histologic grading is currently proposed and may be more accurate in the histologic assessment and biological behavior of these tumors (Kiupel et al, 2011).

TABLE 3 | World Health Organization Clinical Staging System for MCTs

Stage Description

One tumor completely excised from the dermis, identified histologically, without regional lymph 0 node involvement 1. Without systemic signs 2. With systemic signs

One tumor, confined to the dermis, without regional lymph node involvement I 1. Without systemic signs 2. With systemic signs

One tumor confined to the dermis, with regional lymph node involvement II 1. Without systemic signs 2. With systemic signs

Multiple dermal tumors; large infiltrating tumors with or without regional lymph node involvement III 1. Without systemic signs 2. With systemic signs

IV Any tumor with distant metastases, including blood or bone marrow involvement

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Discussion

Dr. Gloyd: In this discussion we’ll dogs go directly to surgery and Two recent studies showed, focus on those dogs that are do not get staged with abdominal however, that the sonographic determined to have MCTs that are ultrasound. As far as abdominal appearance of the spleen does not amenable to wide surgical evaluation for cases with negative not correlate with whether there excision. What are the lessons prognostic factors, in the past, we is mast cell infiltration (Book et al, learned since Palladia has been would just do ultrasounds, and 2011; Stefanello et al, 2009). The available in terms of diagnostics, only if the scans were suspicious danger of splenic aspiration is workup, and patient selection for would we aspirate the spleen. that mast cells are in the spleen treatment?

Dr. Thamm: Many of the changes over the past seven years have Diagnosis of Cutaneous Canine MCTs involved what we do before The initial diagnosis is based on fine-needle aspiration (FNA) of the mass surgery — how much or how little and regional lymph nodes, surgery with wide (3 cm) margins), and biopsy we do. Eighty percent of dogs with histopathologic testing. with MCT do not need medical If the tumor is in a location amenable to surgery and no negative therapy — they are cured with prognostic indicators (Table 1) are present, no further tests are necessary prior to wide surgical excision other than: surgery with adequate margins. • Minimum database (complete blood count, serum We’re talking about the very biochemistry profile) rarified population of dogs that • FNA cytology of the mass and (if possible) the regional either need further treatment after (draining) lymph node surgery or can’t have surgery. Those • Histopathologic assessment of the biopsy sample of the mass are the cases in which we are po- to determine tumor grade and mitotic index (MI) tentially going to be reaching for If the tumor location is not amenable to surgery, or if negative prog- some type of drug, whether it’s a nostic factors are noted on physical examination or in the history, or if surgery is attempted but clean margins are not attained, further tests cytotoxic or a kinase inhibitor. are indicated to assess prognosis and guide treatment decisions.

Some tests that historically have been included in complete staging of MCTs are now considered by many veterinary oncologists to be Abdominal Ultrasound and unnecessary in dogs with MCTs that do not have negative prognostic Aspiration Biopsy of the factors (see Discussion). Spleen and Draining Node Abdominal ultrasound with cytologic assessment of the spleen or liver if warranted Dr. Garrett: For staging, we Bone marrow aspiration cytology Buffy coat smear always attempt to aspirate the Thoracic radiographs locoregional lymph node for cyto- logic assessment. A large number Tissue samples also can be submitted to a veterinary diagnostic labo- of dogs do not have any negative ratory, such as the Molecular Pathology Laboratory at Colorado State prognostic factors in their history University or the Diagnostic Center for Population and Animal Health at or physical appearance; these Michigan State University for a panel of prognostic tests.

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normally, which can be over-inter- aspirating a lymph node, we don’t Dr. London: First, at the most preted as metastasis. These recent do much until we have the histol- basic level, they need to perform studies developed cytologic cri- ogy in hand. a fine needle aspiration before teria to classify whether mast cell to confirm that it is a MCT before involvement represented metas- Dr. Jones: I perform abdominal they take it off. I think that’s the tasis or merely a normal resident ultrasound on a case by case biggest barrier for us — getting population. The patients that were basis. If a tumor is histologically practitioners to get a diagnosis classified as positive for malignant high grade, has a poor prognostic before they take a lump off so that mast cell involvement did signifi- factor, positive lymph node on the surgery is done correctly the cantly worse on follow-up in both cytology, or if I am going to per- first time. Second, I am always try- of those studies. So, as a result, we form a large invasive surgery with ing to get them to at least ink the now routinely aspirate spleens if radiation therapy, then I follow deep margin because the whole we are going to do an abdominal with abdominal ultrasound and cy- anatomy often falls apart once ultrasound when staging these tology of liver and spleen because they place the mass in formalin. dogs. I think if you are going to positive liver or spleen has been That way, when the pathologist bother to ultrasound, you should shown to carry a poor prognosis cuts in the sample, it is done bother to do cytology. with short survival time. correctly.

Dr. Gloyd: You don’t get an Dr. Hohenhaus: We want general abdominal ultrasound on all dogs CONSENSUS practitioners to send the entire that present with MCTs? mass — everything they cut off — P INT to the lab. Unfortunately, veteri- Dr. Garrett: No. If the tumor is nary reference labs provide them located somewhere where we can It is not necessary to with a small jar and they often aspirate an external lymph node, can’t fit the entire mass in it, which we will just do that. Otherwise, routinely perform is a huge barrier for general prac- unless there is something in the abdominal titioners. I would also want the mi- history or physical exam or lymph ultrasonography on croscopic description, not just the node cytology that carries neg- histology or pathologic diagnosis. ative prognostic information, we every dog with a MCT. Furthermore, if you know it’s a perform wide surgical excision, MCT and it’s in an anatomically wait on histologic and surgical bad location, don’t attempt the margin assessment, and then eval- surgery yourself. Refer the patient uate further if warranted. to a board-certified surgeon to Dr. Gloyd: What advice do you ensure that adequate margins Dr. Vail: I agree. If the tumors are have for general practitioners are attained. in a location that can be cut easily when they aspirate a lump or get and we don’t have negative prog- a biopsy for histopathology? How nostic indices, other than do you want that sample to be handled so that you get the maxi- mum amount of information?

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Dr. London: Yes, plan to resect Dr. Garrett: If the draining node is and the tumor and lymph node is it appropriately the first time so a sub-lumbar node, for example, still excised. that you don’t end up having to then we will do abdominal ultra- recut it or have recurrent disease. sound, and while we’re doing it, Dr. Vail: I am unconvinced of I think that the challenge is that we will aspirate the spleen be- the need to aspirate the normal- often these are after-the-fact di- cause we are there. anatomy spleen and liver in agnoses and that makes it harder these cases, especially if the to manage. Dr. London: In human medicine node is clean. the paradigm for any disease that has the potential to be metastatic Dr. London: I agree; if the node is CONSENSUS is to always examine the draining clean I usually would not aspirate node. I don’t think we have been the spleen. But sometimes you P INT appropriately aggressive enough can’t find the node, and in those in veterinary medicine in following cases, if the patient has a negative A suspected MCT that dogma. I think it has made prognostic indicator (eg, the mass should always be a difference in human cancer has exhibited recent rapid growth, therapy, so it’s something that we or the mass is really ulcerated, aspirated to confirm always encourage our referring or the dog is sick), then I will the diagnosis before veterinarians and our clients to perform a fine needle aspiration of consider pursuing. the spleen. surgery. Dr. Vail: There is a large dataset Dr. Henry: We are moving more coming out of the UK showing towards using PET scans, too. We that if a draining node is negative are finding that what we thought you will not find spread to distant was the draining node is not Dr. Gloyd: What’s the next step? sites (eg, spleen and other abdom- necessarily the draining node, and inal viscera) (Warland et al, 2014). what we thought we should be Dr. London: We have become If I have what I feel quite certain aspirating probably wasn’t getting much more aggressive about find- is the draining node, and it isn’t us anywhere. ing the draining lymph node, and positive, I don’t spend the client’s if necessary, we will use ultrasound money on an abdominal exam and Dr. Clifford: The problem we to find it and aspirate it. If there is aspiration of the spleen. have in regards to staging is the any potential metastatic disease financial limitations of our clients. there, we usually try to remove the Dr. Clifford: If the draining node For a potential “garden variety” lymph node at the time of surgery is positive then we will certainly mast cell case, an ultrasound costs to confirm metastasis because it pursue further staging prior to ~$400, an aspirate is ~$90, cytol- may change how we proceed. surgery, including abdominal ultra- ogy is $160, and that adds up. sound, to evaluate for any involve- ment of the spleen or liver. If it is not, the patient will go to surgery

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So it would be a challenge for us Dr. Clifford: If it is a positive node, Tumor Location Not to be able to stage every MCT yes, then without question. But Amenable to Surgery that way. I offer it to owners but for the garden variety MCT, I don’t do not require. perform an ultrasound before Dr. Henry: Tumors in some loca- surgical removal. tions are not necessarily going to Dr. Garrett: Even if they have be resectable — an eyelid for ex- negative prognostic factors? ample — which is going to change the approach. Many tumors that are in unresectable locations also CONSENSUS P INT are not going to be great can- didates for radiation therapy. In these cases, the question is do I The draining node should always be aspirated for perform a minimal debulking cytology whether there are negative prognostic (cytoreductive) surgery and follow 1 up with chemotherapy? Or do I factors or not because results determine whether not touch it at all with surgery or systemic therapy is indicated. with radiation therapy? The dog we had on Palladia the longest was one that had an eyelid MCT to start with and it was just way too huge to consider surgery. Abdominal ultrasound is indicated for MCT cases 22 with negative prognostic factors, especially if the Dr. Garrett: If you are going to treat systemically anyway then draining node is positive. looking for metastasis becomes less relevant; and it is expensive.

Dr. Vail: Even in resectable cases, if it is going to be a difficult resec- LACK OF CONSENSUS tion, if it’s going to be aggressive, or if your margins are not clean, the likelihood increases that you The benefit of fine-needle aspiration and cytology may want to follow up with some of ultrasonographically normal-appearing liver other treatment. In those cases where the owner is going to and spleen is a topic of ongoing debate; however, spend a lot of money dealing it is recommended in MCT cases with a positive with the primary tumor, we will offer staging because it’s kind of draining node or negative prognostic indices.

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like an insurance policy. But if we find something, we may not get as CONSENSUS P INT aggressive on the primary tumor. In dogs with bulky MCTs, it is always preferable Dr. Clifford: Yes, especially in a to downstage the tumor with cytoreductive case that we are going to irradiate, we will always more fully stage surgery prior to starting treatment with Palladia. the patient. If the tumor is unresectable, chemotherapy or

Dr. Vail: We now know that unre- radiation are options for cytoreduction before sectable MCTs can also be treated Palladia treatment. with a combination of hypofrac- tionated (once weekly) radiation therapy in combination with Palladia (Carlsten et al, 2012). Grading and Mast Cell biggest challenge with grade II Tumor Panels MCTs, which the vast majority of Dr. Thamm: Back to the challeng- these cases are, is to try to pick ing issue about doing minimal Dr. Clifford: The tumor grade is out the small percentage that debulking versus not, I think we another important factor that is really needs the drugs before you are all probably in agreement that going to play a role in which treat- treat them. if there’s an opportunity to at least ment we select in an individual get the case down to microscopic case. We are going to approach a Dr. Gloyd: What information do and achieve primary closure, that tumor that is incompletely excised you want from the referring veteri- is always preferable to trying to and has a 2.0 mitotic index (MI) narian (rDVM)? treat a bulky MCT with chemother- differently than a grade III tumor apy or Palladia up front. with a MI of 18. Dr. Jones: The first thing I would want is the description of any Dr. Garrett: It depends, however, Dr. Klein: The problem is every- pathology. The problem is that on the aggressiveness of the thing in between. No matter which rDVMs typically do two things: surgery required — for example, a grading system you use, 10% to First, they get only the mini histo- mandibulectomy, which is the case 15% of those grade II MCTs are pathologic report that gives only I saw recently. going to behave badly and the the diagnosis, so they don’t get rest are going to respond. How the mitotic index or a description Dr. Thamm: Yes, or if you have to do I identify that small minority of of the pathology from the patholo- do a hemipelvectomy to get dirty patients that need the drugs? That gist. Second, they will get the MCT margins, then that would be a is always going to be a challenge panel that the labs recommend. different case. until we get better biomarkers, The panel can run $600, and when whether PCR or mutations in c-kit. Whatever the marker, there is not 100% certainty that the patient will or will not respond. I think the

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I can’t interpret it because they many people are routinely doing Dr. Thamm: Colorado State didn’t get the full report, I can’t MCT prognostic panels on every University is one of the sites that tell the rDVM that it was worth the dog with a resected MCT that offers the MCT panel and they get money their client spent. walks in the door? about 30 or 40 cases a week sent in from elsewhere. At the CSU Dr. Hohenhaus: I think we’d all Dr. London: I only set up for the Cancer Center, however, we rarely agree that we would tell rDVMs c-kit exon 8 and exon 11 mutation use the MCT panel. not to get the mini biopsy — get status. I think the c-kit mutation the full biopsy report. Get all the testing has helped when I am try- Dr. Klein: Michigan State Universi- work that the pathologist wants ing to decide which therapy may ty’s Diagnostic Lab website has a to run. be most appropriate. This pref- flow chart for making therapeutic erence is not based on anything decisions based on prognostic we’ve published yet, but on the parameters. human experience. CONSENSUS Dr. Garrett: Veterinarians call me P INT Dr. Klein: I agree; if I struggle with MCT panel results and want trying to decide, that’s when I’ll me to interpret them. I tell them Histologic grading do the PCRs and see if the c-kit that I don’t actually run these pan- mutations are present. With that els. Just tell me the mitotic index should be performed information, I know whether I (along with the grade). on all surgical biopsy have a decent chance of the samples. Veterinar- tumor responding if I’m going to Dr. Clifford: I will usually tell the choose Palladia. rDVM when we get the panels they ians should order ordered that I don’t necessarily the full biopsy Dr. Clifford: We looked at a large find them all that useful so they subset of dogs with grade II MCTs won’t make the mistake of order- report with mitotic and followed them with the com- ing these expensive panels for all index, grade, plete MCT panel (unpublished). cases in the future. The times I It was challenging to be able to discuss the use of a panel include and microscopic draw any conclusions because an incomplete resection of a low or description of individual case might have a high moderate grade tumor (Smith et the pathology. PCNA but a low AgNOR, and how al, 2015) in which low Ki67 index & do you interpret that? As a result, AgNOR x Ki67 (Ag67) values were for the most part, if the tumor is unlikely to recur; if the biologic a grade III or has a high mitotic behavior does not fit histopa- index, I now will send off for a PCR thology; the tumor is located at a Dr. Thamm: That brings up one of on it for mutation status in order “hot” anatomic sites (eg, muzzle, the questions that will probably be to tailor the use of Palladia. On a a subject of some debate. How very, very basic level, it represents personalized medicine.

PALLADIA ROUNDTABLE | PART 1 11 PART 1

mucocutaneous), or the owner has a low risk tolerance. Prognostic Factors in Tumor Profile Panels for Canine MCTs Dr. Garrett: I don’t order mutation analysis very often. The majority Ki-67 of MCT cases do not get mutation Determines the number of proliferating cells analysis because you are going to AgNORs (argyrophilic nucleolar organizer regions) cure the large majority of cases with Correlates with speed of cell proliferation surgery alone. If you decide later PCNA (proliferating cell nuclear antigen) that you want to find out about the Not as reliable of MCT proliferative behavior as other markers mutation status, then you can send Mitotic index (MI) a sample from the biopsy. Number of mitoses/10 HPF in hematoxylin and eosin (H&E) stained sections Dr. Gloyd: Is the consensus that c- kit PCR (polymerase chain reaction) you don’t run the MCT prognostic Detects internal tandem duplication (ITD) mutations in exon 11 and exon panels? 8. ITD mutations in exon 11 of c-kit have been detected in about 20% to 30% of canine cutaneous MCTs. MCTs with such mutations are highly aggressive, but respond well to TKI therapies. ITD mutations in exon 8 Yes! There have Dr. Garrett: of c-kit are less common and have been detected in 2% to 5% of canine been no published studies cutaneous MCTs. These tumors are also expected to respond to TKIs. showing how these panels may Kit immunohistochemistry provide additional benefit over Analyzes expression of the Kit tyrosine kinase receptor the MI and grade for prediction of tumor behavior.

Dr. Thamm: There are some it anymore. The cost increased CONSENSUS exceptional circumstances. One quite a bit so we stopped doing P INT example is a grade 2 tumor with a them as often, and I don’t think my mitotic index that is borderline, say cases are doing any better or any Veterinary oncolo- between 4 and 6, and I don’t know worse for lack of that information. what that really means. Sometimes Sometimes these MCT cases do gists do not rou- I think doing some of these more very poorly and sometimes they tinely use the full sensitive proliferation markers can do much better than you thought help be a tie-breaker. But those are and you’re still not sure why that MCT prognostic only about 1% of cases. happened. panels and, in general, do not Dr. Hohenhaus: We used to do Dr. Clifford: All this information MCT panels in-house at The Animal probably led to us over-treating want veterinarians Medical Center, but we have since cases for a while. In addition, it’s to ask for them. changed labs and don’t do very rare that all the results in the panel point the same way. You may have to pick from three or

PALLADIA ROUNDTABLE | PART 1 12 PART 1

four results. Which one is the most had to pick a relatively short-term is having an effect on longevity important? endpoint, response at 5 weeks in and quality of life. In at least some gross disease. That doesn’t answer of the investigational studies we Dr. Hohenhaus: If there are two or the question about whether what have done with Palladia, response three indicators in agreement, I’ll we see in 5 weeks translates into a to therapy definitely correlated treat. But then it’s totally empirical. long-term survival advantage and with survival. So, if the drug works it also doesn’t say anything about you live longer, which implies that — Dr. Henry: I think there are a lot how this might influence the choice depending on your definition — it of misconceptions about what of adjuvant therapy. is more than a Band-Aid. Does it Kit staining means — when are mean that we are curing them? No. you looking at a mutation and Dr. London: Dr. Thamm brings up when you are not. I don’t do Kit an important point that we haven’t staining because I personally find addressed yet — in human as well CONSENSUS it uninterpretable. It’s the same as in veterinary medicine — and P INT thing when you get a panel and that is the use of these drugs in you have a bad AgNOR plus Ki-67 the adjuvant setting, which ideally number and it has Kit stain pattern is where you want to use them. In gross disease, one; I don’t know what any of this We haven’t done those studies a response to means, so I tend not to do them. but there’s such a big difference Palladia will be seen, But Dr. Thamm is in the middle of a in what you are looking at with clinical trial that will hopefully help respect to endpoint in the gross but the durability clear up some of these questions. disease study versus the micro- of response is I think that if there’s something scopic disease study — that is, that comes out of that study that to using Palladia in the adjuvant generally low, about shows there is a subset of staining setting after a gross macroscopic 6 months. that seems to be correlated with tumor has been down-staged to response to Palladia, especially microscopic disease. durable response, that would be important to know. Dr. Vail: I think we all agree that Dr. Thamm: The question if you in gross disease, you will see look at the statistics is: does over- Dr. Thamm: We are conducting a response to Palladia but dura- all survival increase if the patient randomized study comparing cyto- bility is generally low. There are is a responder versus if they are toxic chemotherapy with vinblas- exceptions to every rule, but that not, and I think the answer is yes. tine or therapy with Palladia, and just tells us that we are using the the randomization is based on the drug as a Band-Aid method right Dr. London: There was no change, results of both Kit staining at exons now without data on whether we however, in overall survival with 8 and 11 and c-kit mutation testing. should be moving beyond that. c-kit mutation status in the pivotal Because of the study design we study (London et al, 2009). Dogs Dr. Thamm: Clinical response with tumor mutations in the c-kit equated with living longer, and gene were more than twice that’s an indicator that the therapy

PALLADIA ROUNDTABLE | PART 1 13 PART 1

as likely to respond to Palladia Dr. Thamm: In the radiation study 2015), c-kit mutation status had no as those without the mutation (Carlsten et al, 2012) a large effect on outcome. (60.0% vs 31.3%). In the phase I majority of the tumors were tested study response was close to 90%. for mutations. Of 14 dogs tested, 8 Dr. Thamm: However, the effect At that time we weren’t testing dogs had no mutation identified, 1 of mutation status on outcome for the exon 8 mutation, so it’s had an exon 8 mutation, and 5 had is context-dependent and may entirely possible that some of the exon 11 mutations. The presence of be different when Palladia responders actually had exon 8 the c-kit mutation was a negative is used in combination with mutations. If you look at the data prognostic factor for long-term other treatments. on single-agent drugs, Palladia is outcome. At 1 year, 66.7% of dogs the most effective single agent with c-kit mutant MCT and 100% Dr. London: One of the huge other than prednisone. of dogs with c-kit wild-type MCT challenges in our profession is were alive. In the pulse-Palladia that we are taking a spectrum of Dr. Jones: There are studies that plus lomustine study (Burton et al, disease and trying to lump it into have concluded the presence of one thing, and it’s not. It is clear c-kit mutations is associated with that in humans, breast cancer is high histologic grade and are CONSENSUS not just breast cancer; there are associated with a shorter pro- P INT several different subtypes. So, gression-free survival and overall we’re talking about mast cell dis- survival (Zemke D et al, 2002; ease in the same manner, and this Takeuchi et al, 2013). At this time, c-kit mutation underrepresents that complexity c-kit hasn’t been firmly estab- status, if known, of the cancer. It is very hard to lished as an independent prognos- apply a single paradigm with re- tic factor although I use it to help can be a factor in spect to prognosis onto a disease guide treatment decisions. making treatment that exhibits a range of biologic decisions. Dogs behaviors. Dr. Klein: I will use mutation status sometimes if a client is with tumor really struggling with making a mutations in the decision. If we decide that Palladia is indicated but the tumor muta- c-kit gene were tion status is negative, then I will more than twice tell them that their dog has a third rather than a two thirds chance of as likely to respond responding. That can make a dif- to Palladia as ference as to whether they decide those without the to go with Palladia because it is a big financial commitment. mutation (60.0% vs. 31.3%).

PALLADIA ROUNDTABLE | PART 1 14 PART 1

References

Ayl RD, Couto GC, Hammer AS, et al. Correlation of DNA ploidy to tumor histologic grade, clinical variables, and survival in dogs with mast cell tumors. Vet Pathol. 1992;29:386-390.

Book AP, Fidel J, Willis T, et al. Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors. Vet Radiol Ultrasound. 2011;52(5):548-554.

Burton JH, Venable RO, Vail DM, et al. Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs. J Vet Intern Med. 2015 Jul-Aug;29(4):1098-104.

Carlsten KS, London CA, Haney S, et al. Multicenter prospective trial of hypofraction- ated radiation treatment, toceranib, and prednisone for measurable canine mast cell tumors. J Vet Intern Med. 2012;26:135–141.

Downing S, Chien MB, Kass PH, et al. Prevalence and importance of internal tandem duplications in exons 11 and 12 of c-kit in mast cell tumors of dogs. Am J Vet Res. 2002;63(12):1718-1723.

Finora K, Leibman NF, Fettman MJ, et al. Cytological comparison of fine-needle aspi- rates of liver and spleen of normal dogs and of dogs with cutaneous mast cell tumors and an ultrasonographically normal appearing liver and spleen. Vet Comp Oncol. 2006;4(3):178–183.

Kiupel, M, Webster JD, et al. Proposal of a 2-tier grading system for canine cutaneous mast cell tumors to more accurately predict biologic behavior. Vet Pathol. 2011;48:147.

Krick EL, Billings AP, Shofer PS, et al. Cytological lymph node evaluation in dogs with mast cell tumors: association with grade and survival. Vet Comp Oncol. 2009;7:130-138.

London C, Thamm DH. Mast cell tumors. In Withrow SJ, Vail DM, Page RL (eds). Withrow and MacEwen’s Small Animal Clinical Oncology. 5th ed. St Louis: Elsevier, 2013, Chapter 20, pages 335-355.

London CA, Galli SJ, Yuuki T, et al. Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. Exp Hematol. 1999;27(4)689-697.

London CA, Malpas PB, Wood-Follis SL, et al. Multi-center placebo-controlled, dou- ble-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res. 2009;15(11):3856-3865.

Mitchell L, Thamm DH, Biller BJ. Clinical and immunomodulatory effects of toceranib combined with low-dose cyclophosphamide in dogs with cancer. J Vet Intern Med. 2012 Mar-Apr;26(2):355-362.

Mullins MN, Dernell WS, Withrow SJ, et al. Evaluation of prognostic factors associated with outcome in dogs with multiple cutaneous mast cell tumors treated with surgery with and without adjuvant treatment: 54 cases (1998-2004). J Am Vet Med Assoc. 2006;228(1):91-95.

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Murphy S, Sparkes AH, Smith KC, et al. Relationships between the histological grade of cutaneous mast cell tumours in dogs, their survival and the efficacy of surgical resection. Vet Rec. 2004;154:743–746.

O’Connell K, Thomson M. Evaluation of prognostic indicators in dogs with multiple, simultaneously occurring cutaneous mast cell tumours: 63 cases. Vet Comp Oncol. 2013; 11(1):51-62.

Pan X, Tsimbas K, Kurzman ID, Vail DM. Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia(®)in tumour-bearing dogs: a phase I dose-finding study. Vet Comp Oncol. 2016 Jun;14(2):202-209.

Patnaik AL. Ehler WJ, MacEwen EG. Canine cutaneous mast cell tumor: Morphologic grading and survival time in 83 dogs. Vet Pathol. 1984;21:469-464

Pellin MA, Wouda RM, Robinson K, et al. Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose-finding study. Vet Comp Oncol. 2016 May 5. doi: 10.1111/vco.12232. [Epub ahead of print]

Sabattini et al. Histologic grading of canine mast cell tumor: Is 2 Better Than 3? Vet Pathol. 2015.

Smith J, Kiupel M, et al. Recurrence rates and clinical outcome for dogs with grade II mast cell tumours with a low AgNOR count and Ki67 index treated with surgery alone. Vet Comp. Oncol. 2015;15(1): 36-45.

Stefanello D, Buracco P, et al. Comparison of 2- and 3-category histologic grading systems for predicting the presence of metastasis at the time of initial evaluation in dogs with cutaneous mast cell tumors: 386 cases (2009–2014). J Am Vet Med Assoc. 2015;246:765-769.

Stefanello D, Valenti P, Faverzani S, et al. Ultrasound-guided cytology of spleen and liver: a prognostic tool in canine cutaneous mast cell tumor. J Vet Intern Med. 2009;23(5):1051–1057.

Takeuchi et al. Validation of the prognostic value of histopathological grading or c-kit mutation in canine cutaneous mast cell tumours: A retrospective cohort study. Vet J. 2013.

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Warland J, Amores-Fuster I, Newbury W, et al. The utility of staging in canine mast cell tumors. Vet Comp Oncol. 2014;12:287-298.

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PALLADIA ROUNDTABLE | PART 1 16 ® (toceranib phosphate) Tablets

Antineoplastic Table 2. Dose Modification Based on Toxicity Observed For oral use in dogs only Toxicity Dose Adjustment Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed Neutropenia veterinarian. >1000/μL Maintain dose level Description: PALLADIA, a multi-kinase inhibitor targeting several receptor tyrosine kinases ≤1000/μL or neutropenic fever or Stop drug until >1000/μL and clinical (RTK), is the phosphate salt of toceranib. The empirical formula is C22H25FN4O2H3O4P and the molecular weight is 494.46. The chemical name is (Z)-5-[(5-Fluoro-2-oxo-1,2-dihydro- infection signs normal; then decrease dose by 3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1Hpyrrole-3-carbox- 0.5 mg/kg amide phosphate. Toceranib phosphate is a small molecule with an indolinone chemical Renal Toxicities (Creatinine) structure. <2.0 mg/dL Maintain dose level The chemical structure of toceranib phosphate is ≥2.0 mg/dL Stop drug until <2.0 mg/dL then decrease dose by 0.5 mg/kg O H3C Albumin F N N H <1.5 g/dL Stop drug until >2.5 g/dL then N decrease dose by 0.5 mg/kg H CH3 .H3PO4 O N Hematocrit H <26% Stop drug until >30% then decrease dose by 0.5 mg/kg Indications: PALLADIA tablets are indicated for the treatment of Patnaik grade II or III, Diarrhea recurrent, cutaneous mast cell tumors with or without regional lymph node involvement <4 watery stools/day for less than 2 days Maintain dose level and institute in dogs. supportive care Dosage and Administration: Always provide Client Information Sheet with prescription. ≥4 watery stools/day or ≥ 2 days Stop drug until formed stools and Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day institute supportive care. When dosing (see Table 1). Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg (1.0 mg/lb) is resumed, decrease dose by 0.5 mg/kg every other day) and dose interruptions (cessation of PALLADIA for up to two weeks) may be utilized, if needed, to manage adverse reactions (see Table 2 as well as Warnings and GI Bleeding Precautions). Adjust dose based on approximately weekly veterinary assessments for the Fresh blood in stool or black tarry stool Stop drug and institute supportive care first 6 weeks and approximately every 6 weeks, thereafter. PALLADIA may be administered for > 2 days or frank hemorrhage or until resolution of all clinical signs of with or without food. Do not split tablets. blood clots in stool. blood in stool, then decrease dose by Table 1. 3.25 mg/kg Dose Chart 0.5 mg/kg. Dog Body Weight Number of Tablets Contraindications: Pounds Kilograms Dose 10 mg 15 mg 50 mg Do not use in dogs used for breeding, or for pregnant or lactating bitches (see Clinical Pharmacology). 11.0 – 11.8 5.0 - 5.3 15 mg 1 11.9 – 15.2 5.4 - 6.9 20 mg 2 Warnings: PALLADIA may cause vascular dysfunction which can lead to edema and thromboembolism, 15.3 – 18.5 7.0 - 8.4 25 mg 1 1 including pulmonary thromboembolism. Discontinue drug until clinical signs and clinical 18.6 – 22.0 8.5 - 10.0 30 mg 2 pathology have normalized. To assure vasculature homeostasis, wait at least 3 days after 22.1 – 25.4 10.1 - 11.5 35 mg 2 1 stopping drug before performing surgery (see Adverse Reactions). 25.5 – 28.7 11.6 - 13.0 40 mg 1 2 Serious and sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred rarely in dogs treated with PALLADIA (see Adverse Reactions). 28.8 – 32.2 13.1 - 14.6 45 mg 3 If gastrointestinal ulceration is suspected, stop drug administration and treat appropriately. 32.3 – 35.5 14.7 - 16.1 50 mg 1 Human Warnings: 35.6 – 38.8 16.2 - 17.6 55 mg 1 3 NOT FOR USE IN HUMANS. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF 38.9 – 42.3 17.7 - 19.2 60 mg 1 1 CHILDREN. Children should not come in contact with PALLADIA. Keep children away from feces, urine, or vomit of treated dogs. 42.4 – 45.6 19.3 - 20.7 65 mg 1 1 To avoid exposure to drug, wash hands with soap and water after administering PALLADIA 45.7 – 50.7 20.8 - 23.0 70 mg 2 1 and wear protective gloves to prevent direct contact with feces, urine, vomit, and broken 50.8 – 59.3 23.1 - 26.9 80 mg 2 1 or moistened PALLADIA tablets. Place all waste materials in a plastic bag and seal before 59.4 – 65.9 27.0 - 29.9 95 mg 3 1 general disposal. If eyes are accidentally exposed to the drug, rinse eyes with water imme- diately. In case of accidental ingestion by a person, seek medical advice immediately, show 66.0 – 71.2 30.0 - 32.3 100 mg 2 the package insert or label to the physician. Gastrointestinal discomfort such as vomiting 71.3 – 76.3 32.4 - 34.6 110 mg 1 2 or diarrhea may occur if this drug is accidentally ingested. 76.4 – 79.6 34.7 - 36.1 115 mg 1 2 Pregnant women, women who may become pregnant, or nursing mothers should pay 79.7 – 84.7 36.2 - 38.4 120 mg 2 2 special attention to these handling precautions. (See handling instructions above.) PALLADIA, like other drugs in its class, prevents the formation of new blood vessels in 84.8 – 94.8 38.5 - 43.0 130 mg 2 2 tumors. In a similar manner, PALLADIA may affect blood vessel formation in the 94.9 – 105.0 43.1 - 47.6 150 mg 3 developing fetus and may harm an unborn baby (cause birth defects). For pregnant women, 105.1 – 110.0 47.7 - 49.9 160 mg 1 3 accidental ingestion of PALLADIA may have adverse effects on pregnancy. 110.1 – 113.5 50.0 - 51.5 165 mg 1 3 Precautions: 113.6 – 118.6 51.6 - 53.8 170 mg 2 3 Temporarily discontinue the use of PALLADIA if anemia, azotemia, hypoalbuminemia, and hyperphosphatemia occur simultaneously. Resume treatment at a dose reduction of 118.7 – 128.8 53.9 - 58.4 180 mg 2 3 0.5 mg/kg after 1 to 2 weeks when values have improved and albumin is >2.5 g/dL. 128.9 – 138.9 58.5 - 63.0 200 mg 4 Temporary treatment interruptions may be needed if any one of these occurs alone: 139.0 – 144.0 63.1 - 65.3 210 mg 1 4 hematocrit <26%, creatinine ≥2.0 mg/dL or albumin <1.5 g/dL. Then resume treatment at 144.1 – 157.6 65.4 - 71.5 215 mg 1 4 a dose reduction of 0.5 mg/kg once the hematocrit is >30%, the creatinine is <2.0 mg/dL, and the albumin is >2.5 g/dL. 157.7 – 173.1 71.6 - 78.5 250 mg 5 Temporarily discontinue the use of PALLADIA if neutrophil count is ≤1000/μL. Resume 173.2 – 177.9 78.6 - 80.7 260 mg 1 5 treatment after 1 to 2 weeks at a dose reduction of 0.5 mg/kg, when neutrophil count 178.0 – 191.6 80.8 - 86.9 265 mg 1 5 has returned to >1000/μL. Further dose reductions may be needed if severe neutropenia 191.7 – 220.5 87.0 - 100.0 300 mg 6 reoccurs. The presence of systemic mast cell tumor prior to treatment may predispose a dog to Table 4. Summary of the most common adverse reactions during the study (masked clinically significant mast cell degranulation with possible severe systemic adverse phase combined with the open-label phase)a reactions when treated with PALLADIA. Attempts should be made to rule out systemic PALLADIA (n = 145) a mastocytosis prior to initiation of treatment with PALLADIA. Adverse Reactions Any Gradeb Grade 3 or 4b PALLADIA has been associated with severe diarrhea or GI bleeding that requires prompt Diarrhea 58.6% 8.3% treatment. Dose interruptions and dose reductions may be needed depending upon the severity of clinical signs. (See Table 2 in Dosage and Administration.) Anorexia 49.7% 8.3% Vomiting 47.6% 9.7% Use non-steroidal anti-inflammatory drugs with caution in conjunction with PALLADIA due to an increased risk of gastrointestinal ulceration or perforation. Lethargy 39.3% 4.1% PALLADIA is metabolized in the liver. Co-administration of PALLADIA with strong Lameness 22.8% 0.0% inhibitors of the CYP3A4 family may increase PALLADIA concentrations. The effect of Weight loss 21.4% 2.8% concomitant medications that may inhibit the metabolism of PALLADIA has not been Blood in stool/GI bleed/ evaluated. Drug compatibility should be monitored in patients requiring concomitant hemorrhagic diarrhea 18.6% 2.8% medications. Dehydration 15.2% 2.1% The safe use of PALLADIA has not been evaluated in dogs less than 24 months of age or Pruritus 12.4% 0.0% weighing less than 5 kg. Pigmentation disorder 11.7% 0.0% Adverse Reactions: Dermatitis 11.0% 0.0% A US clinical field study comprised of a 6-week masked phase, followed by an open-label Musculoskeletal disorder 11.0% 0.0% phase, evaluated the safety and effectiveness of PALLADIA in 151 client-owned dogs that had Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional General pain 8.3% 0.0% lymph node involvement. The most common adverse reactions reported during the Otitis externa 8.3% 0.0% masked phase are summarized in Table 3; those reported during the entire study (masked Tachypnea 8.3% 0.0% phase combined with the open-label phase) are summarized in Table 4. Nausea 7.6% 1.4% Table 3. Summary of the most common adverse reactions during the masked phasea Polydipsia 7.6% 0.0% Placebo (n = 64) PALLADIA (n = 87) Pyrexia 6.9% 2.8% Adverse Reaction Any Gradeb Grade 3 or 4b Any Gradeb Grade 3 or 4b Arthritis 6.2% 0.0% Diarrhea 26.6% 3.1% 46.0% 6.9% Localized edema 6.2% 0.0% Anorexia 31.3% 6.3% 39.1% 6.9% Bacterial skin infection 5.5% 0.0% Lethargy 29.7% 3.1% 35.6% 4.6% Conjunctivitis 5.5% 0.0% Vomiting 32.8% 6.3% 32.2% 9.2% Laboratory Abnormality Any Gradec Grade 3 or 4c Lameness 9.4% 0.0% 17.2% 0.0% Neutropenia 44.8% 1.4% Weight loss 3.1% 0.0% 14.9% 1.1% Hypoalbuminemia 28.3% 1.4% Blood in stool/GI bleed/ Thrombocytopenia 28.3% 2.1% hemorrhagic diarrhea 3.1% 0.0% 12.6% 2.3% Increased alanine aminotransferase 27.6% 4.1% Musculoskeletal disorder 6.3% 0.0% 11.5% 1.1% Decreased hematocrit 11.0% 2.8% Dehydration 4.7% 0.0% 9.2% 2.3% Increased creatinine 13.8% 1.4% Dermatitis 9.4% 1.6% 9.2% 0.0% Hyperbilirubinemia 6.9% 0.0% Pruritus 4.7% 0.0% 9.2% 0.0% Urinary tract infection 7.6% 0.0% Tachypnea 4.7% 0.0% 8.0% 1.1% a The duration of treatment with PALLADIA ranged from 2 to 812 days (mean, 144 days; median, Localized pain 4.7% 0.0% 8.0% 0.0% 68 days). All dogs received at least 1 dose of PALLADIA. b Investigators assigned severity grade of 1, 2, 3 or 4 (1 – least severe; 4 – most severe). Nausea 3.1% 0.0% 8.0% 1.1% c Grading of laboratory abnormalities was based on the National Cancer Institute’s Common Toxicity General pain 4.7% 1.6% 6.9% 0.0% Criteria guideline adapted for canines (1 – least severe; 4 – most severe). Polydipsia 7.8% 0.0% 6.9% 0.0% Other adverse events were reported but occurred in < 5% of dogs. Any individual dog may have had multiple adverse events. Pyrexia 3.1% 0.0% 5.7% 2.3% There were 5 deaths during this study that were possibly drug related. Pathology findings Flatulence 3.1% 0.0% 5.7% 0.0% generally revealed evidence of vascular dysfunction including pulmonary thromboembolism Pigmentation disorder 1.6% 0.0% 5.7% 0.0% (post-operative); multi-organ failure associated with vasculitis and thrombosis; vascular Laboratory Abnormality Any Gradec Grade 3 or 4c Any Gradec Grade 3 or 4c thrombosis with disseminated intravascular coagulopathy (DIC) and pancreatitis; and Neutropenia 6.3% 0.0% 46.0% 0.0% vasculitis with DIC. One dog died secondary to gastric perforation; the duration of treatment with PALLADIA was 221 days and there was no evidence of mast cell tumor at Thrombocytopenia 20.3% 0.0% 24.1% 0.0% necropsy. These deaths occurred in the presence or absence of gross-disease; treatment Increased alanine durations ranged from 18 to 221 days. aminotransferase 21.9% 4.7% 24.1% 1.1% The relationship of the following deaths to drug are unknown. One dog, first treated for Hypoalbuminemia 7.8% 0.0% 12.6% 0.0% 3 weeks with a placebo, died of unknown cause 7 days after initiation of PALLADIA Decreased hematocrit 7.8% 0.0% 5.7% 3.4% therapy. Another dog died of unknown cause 92 days after initiation of PALLADIA therapy. Hyperbilirubinemia 1.6% 1.6% 5.7% 0.0% No necropsy was conducted in either dog. Increased creatinine 4.7% 0.0% 5.7% 0.0% Twenty seven dogs developed some form of gastrointestinal bleeding with 2.8% of dogs Urinary tract infection 1.6% 0.0% 5.7% 0.0% having severe bleeding. One dog developed gastric ulceration which was possibly drug related. Three dogs died from gastric (1 dog) or duodenal (2 dogs) perforations during a The mean time on study during the masked phase was 37.0 days for PALLADIA-treated dogs (median, 42.0 days) and 27.6 days for placebo-treated dogs (median, 21.0 days); no adjustments were made in the study. One dog with a duodenal perforation received only 1 dose of study drug and, the statistical comparisons for this disparity. therefore, was not considered drug related. b Investigators assigned severity grade of 1, 2, 3 or 4 (1 - least severe; 4 - most severe). Seven dogs developed nasal depigmentation within the first few weeks of treatment. c Grading of laboratory abnormalities was based on the National Cancer Institute’s Common Toxicity Eleven dogs developed coat color or skin changes during the study. Two of these dogs had Criteria guideline adapted for canines (1 - least severe; 4 - most severe). complete coat color changes from fawn to white and from deep red to blonde. Seven dogs experienced alopecia. There is a drug related effect on body weight: 20.0% of dogs had >13% weight loss in the masked plus open-label phase attributable to drug. Of these, 5 dogs had >25% weight loss. Three dogs had seizure-like activity while on study drug. It can not be determined if these were drug related. Two dogs developed epistaxis that was not associated with thrombocytopenia. Another dog developed epistaxis with concurrent disseminated intravascular coagulopathy. For a copy of the Safety Data Sheet (SDS) or to report adverse events call Zoetis at 1-888-963-8471. Information for Dog Owners: Mast Cell Tumor – Primary Effectiveness Endpoint Results Always provide Client Information Sheet with prescription and review with owners. Owners Effectiveness Parameter Placebo (n = 63) PALLADIA (n = 86) P-value should be advised on possible adverse reactions and when to stop drug and call the veterinarian. Owners should be advised of the handling instructions. Objective Response Clinical Pharmacology: Rate * 7.9% 37.2% < 0.001 Mechanism of Action: Toceranib phosphate is a small molecule that has both direct * The difference in objective response rate between groups was not significantly associated with tumor antitumor and antiangiogenic activity. In non-clinical pharmacology studies, toceranib burden (presence vs. absence of regional lymph node involvement) or tumor grade (P > 0.05). selectively inhibited the tyrosine kinase activity of several members of the split kinase During the study, PALLADIA was administered concomitantly with other medications such receptor tyrosine kinase (RTK) family, some of which are implicated in tumor growth, as antimicrobials, H-2 receptor blockers, antihistamines, anti-emetics, non-steroidal anti- pathologic angiogenesis, and metastatic progression of cancer. Toceranib inhibited the inflammatory drugs, locally-acting anti-ulcer medications, opiate gastrointestinal motility activity of Flk-1/KDR tyrosine kinase (vascular endothelial growth factor receptor, modifiers, opioids, vaccines, anthelmintics, antiparasitics, and topical/ophthalmic/otic VEGFR2), platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor corticosteroid preparations. During the open-label phase only, 5 dogs received a brief (Kit) in both biochemical and cellular assays. Toceranib has been shown to exert an anti- course of short-acting corticosteroids. proliferative effect on endothelial cells in vitro. Toceranib treatment can induce cell cycle Animal Safety: arrest and subsequent apoptosis in tumor cell lines expressing activating mutations in the In the target animal safety study presented below, PALLADIA was demonstrated to have split kinase RTK, c-kit. Canine mast cell tumor growth is frequently driven by activating 1, 2 a narrow margin of safety; dogs being treated with PALLADIA should be monitored for mutations in c-kit. adverse reactions which may indicate a dose adjustment is required. Two dogs in the Other compounds in the antiangiogenesis class of antineoplastic agents are known to 6 mg/kg group were euthanized for clinical toxicities on Days 23 and 27 of the study, increase embryolethality and fetal abnormalities. As angiogenesis is a critical component respectively. of embryonic and fetal development, inhibition of angiogenesis following administration of Toceranib was administered orally to 20 male and 20 female adult Beagle dogs (approx- PALLADIA should be expected to result in adverse effects on the pregnancy in the bitch. imately 2 years of age) at doses of 0 mg/kg (placebo, 12 dogs), 2 mg/kg (0.5X, 8 dogs), Pharmacokinetics 4 mg/kg (1X, 12 dogs), or 6 mg/kg (1.5X, 8 dogs) once every other day for 13 consecutive Following intravenous administration, the pharmacokinetics of toceranib is characterized weeks without dose interruption. Toceranib caused weight loss, decreased feed consump- by a very large volume of distribution (>20 L/kg, indicating partitioning into tissues), a tion, pancreatic, gonadal, adrenal, muscle, and hematopoietic changes. terminal elimination half-life of about 16 hrs, and a clearance of >1 L/hr/kg. With a regimen Feed consumption was decreased in the 6 mg/kg group compared to placebo, with the of 3.25 mg free base equivalent (fbe)/kg doses of toceranib administered by tablet orally largest difference in means occurring at Day 35. Decrease in body weights in the 4 mg/kg every other day for 2 weeks (7 doses), the pharmacokinetic parameters of toceranib in group were seen at Day 31 and in the 6 mg/kg group at Day 15 compared with placebo plasma in healthy Beagle dogs (between 7.2 – 12.5 kg) are shown in the table below. and continued through the study. Dose related lameness, observed almost exclusively in Table 5. Pharmacokinetic Parameters the hind limbs, and limb pain was greater in all treatment groups as compared to placebo, with the 6 mg/kg group demonstrating the highest incidence. Stiffness and weakness were Pharmacokinetic Parameters Total (n=11; 6M, 5F) Total (n=10; 5M, 5F) noted to occur almost exclusively in the 6 mg/kg group. Redness of oral mucosa was (Mean + 1SD) Dose 1 Dose 7 observed in all treatment groups. One dog in the 4 mg/kg group had oral ulcerations and Elimination half-life, t1/2 (h) 16.4 ± 3.6 17.2 ± 3.9 one dog in the 6 mg/kg group had skin ulcerations, both with bacterial infections present. Time to maximum plasma Diarrhea or soft stool were seen in all four groups. concentration, Tmax (h) 5.3 ± 1.6 6.2 ± 2.6 Hematology analyses showed decreases in hematocrit, hemoglobin, and erythrocyte count Maximum plasma concentration, and a decrease in reticulocyte count in the 4 and 6 mg/kg groups that tended to recover Cmax (ng/mL) 86 ± 22 109 ± 41 sufficiently to limit further erythrocyte count decreases. White blood cell counts were sig- a, b Cmin (ng/mL) 12.7 ± 6.0 18.7 ± 8.3 nificantly lower across the study in all treated groups compared to placebo, primarily due Area under the plasma concentration to a decrease in neutrophils. Lymphocytes decreased to a lesser degree, especially at the time-curve, AUC (ng·h/mL) a 1833 ± 508 2635 ± 939 low dose. Eosinophils and basophils showed marked, persistent decreases. Monocytes 0-48 were not affected. a Dose-normalized value (adjusted to 3.25 mg/kg dose) b Platelet counts increased slightly in 4 and 6 mg/kg groups. Increases were observed in Cmin is the concentration at 48 h post-dose, which corresponds to the dose interval. fibrinogen in the 4 and 6 mg/kg group. Oral bioavailability of toceranib is 77%. PALLADIA is highly protein bound at 91% to 93%. Increases were observed in aspartate aminotransferase, creatine kinase, and serum phos- It should be noted that despite the homogeneity of subjects included in this study, large phorus concentrations in the 4 and 6 mg/kg groups. Increases in alkaline phosphatase between-subject variability was observed. Regardless of the route of administration, linear were seen in the 6 mg/kg group. An increase in amylase was seen in one dog in each of pharmacokinetics has been observed at doses up to 5 mg/kg twice daily. Using an in vitro the treatment groups. An increase in serum potassium was seen in one dog in the 6 mg/kg hepatocyte and liver microsome test system, the Z isomer was found to be metabolized to group. Increases in lactate dehydrogenase and globulins were observed in the 6 mg/kg the N-oxide derivative of toceranib in dogs, humans, cats, and rats. Although a small gender group. difference was observed in the in vitro study (81% conversion in male dogs, 56% conver- sion in female dogs) no differences in toceranib pharmacokinetics was observed in vivo. Treatment-related microscopic changes included slight to marked reduction in cellularity The effects of renal impairment, hepatic impairment or breed on the pharmacokinetics of of sternal and femoral bone marrow. There was a corresponding mild extramedullary toceranib have not been investigated. hematopoiesis, mainly erythropoiesis, in the spleen. In the pancreas, dose-related slight to moderate acinar degranulation, characterized by diffuse loss of zymogen granules, Effectiveness: occurred. In the adrenal glands, minimal cortical congestion/hemorrhage occurred at all The effectiveness and safety of PALLADIA oral tablets for the treatment of mast cell doses, with suggestive dose-relationship. Adrenal cortical vacuolation was noted with low tumors was evaluated in a randomized, placebo-controlled, double-masked, multicenter frequency in all groups. Dose related changes were noted in reproductive organs of both clinical field study. The purpose of this study was to evaluate the effectiveness and safety sexes. Males showed a dose-related germ cell depletion, tubular vacuolation, and reduc- of PALLADIA in the treatment of mast cell tumors in dogs that had recurrent measurable tions in numbers of mature spermatozoa. In females, ovaries showed a reduced incidence disease after surgery and to evaluate objective response (complete or partial response). of mature/regressing corpora lutea and an increased incidence of small follicles. PALLADIA treatment was compared to placebo treatment using response rates at the end of the 6-week masked phase. Response rates were determined using the National Cancer Two dogs (one male, one female) in the 6 mg/kg group were euthanized for treatment- Institute’s Response Evaluation Criteria in Solid Tumors Guideline3 which was modified related clinical toxicities on Days 23 and 27 of the study, respectively. Onset of the terminal specifically for the evaluation of canine mast cell tumors. syndrome was seen as markedly reduced feed intake and melena. Over the following 9 One-hundred-fifty-three dogs were randomly assigned to treatment with either 3.25 mg/kg days, the decreased feed intake progressed to near-complete anorexia and hematochezia PALLADIA (n = 88) or placebo (n = 65) orally, every other day for 6 weeks, or until disease appeared. Weight loss, lethargy, hindlimb lameness and weakness were observed. The progression or withdrawal from the study for another cause. Treatment was unmasked at following clinical pathology results are consistent with changes seen in the other dogs in the time of disease progression: dogs receiving placebo were then offered crossover to the 6 mg/kg group as well as changes due to the dogs’ debilitated conditions just prior to open-label PALLADIA; dogs receiving PALLADIA were discontinued from the study. Dogs euthanasia. Both dogs had increases in total protein, globulins, phosphorus, cholesterol, were required to have Patnaik grade II or III, recurrent, cutaneous mast cell tumors with triglycerides and fibrinogen. One dog had pancytopenia, decreased hematocrit, hemoglo- or without regional lymph node involvement. At least 1 tumor had to be at least 20 mm in bin, reticulocytes, albumin, and PT and increased bands. Hematuria was also present. The diameter. Dogs had a limit of 1 completed radiation protocol and a limit of 1 prior systemic other dog also had decreased lymphocytes, eosinophils, chloride, and sodium and increases chemotherapy regimen. Dogs with evidence of systemic mast cell tumor were excluded. in RBC, hematocrit, hemoglobin, platelets, ALP, amylase, creatinine, BUN, magnesium, Treatment with systemic corticosteroids during the study or within 14 days prior to study potassium, and total bilirubin. Clotting profile showed a decreased PT and increased in initiation was not permitted. If needed to manage adverse reactions, dose interruptions PTT in both dogs. These dogs showed lymphoid depletion in lymph nodes, thymus, and (cessation of PALLADIA for up to 2 weeks) were prescribed and/or dosage was reduced gut-associated lymphatic tissues and mild to marked gastrointestinal lesions in addition to as low as 2.2 mg/kg. to the microscopic findings described in animals surviving to the end of the study. These The effectiveness analysis showed a statistically significant advantage for PALLADIA over two dogs also had lesions in the gastrointestinal tract, kidneys, pancreas, pituitary gland placebo in the primary effectiveness endpoint of objective response at the end of the six and adrenal glands. week masked phase. Objective response is complete response + partial response. Partial Storage Conditions: Store at controlled room temperature 20° to 25° C (68° to 77° F). response is ≥ 30% decrease in the sum of the longest diameter of target lesions, taking How Supplied: PALLADIA tablets contain 10 mg, 15 mg, or 50 mg of toceranib as as reference the baseline sum, non-progression of non-target lesions and appearance of toceranib phosphate per tablet. The tablets are packaged in 30 count bottles. no new lesions. References: NADA #141-295, Approved by FDA u London CA, Hannah AL, Zadovoskaya R, et al. Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Manufactured by: Pfizer Inc, Ascoli, Italy Malignancies. Clinical Cancer Research 9(7):2755-2768; 2003 Distributed by: Zoetis Inc., Kalamazoo, MI 49007 v Pryer NK, Lee LB, Zadovoskaya R, et al. Proof of Target for SU11654: Inhibition of KIT phosphorylation in Canine Mast Cell Tumors. Clinical Cancer Research 9(15): Revised: August 2015 5729-5734; 2003 w http://ctep.cancer.gov/protocolDevelopment/

Client Information ® Sheet (toceranib phosphate) Tablets This summary contains important information about PALLADIA. You should Handling Instructions read this information before you start giving your dog PALLADIA and review it What do I need to know to handle PALLADIA safely? each time the prescription is refilled as there may be new information. This sheet Because PALLADIA is an anti-cancer drug, extra care must be taken when handling is provided only as a summary and does not take the place of instructions from the tablets, giving the drug to your dog, and cleaning up after your dog. your veterinarian. Talk with your veterinarian if you do not understand any of this  information or if you want to know more about PALLADIA. PALLADIA is not for use in humans.  You should keep PALLADIA in a secure storage area out of the reach of What is PALLADIA? children.  PALLADIA, a tyrosine kinase inhibitor, is a drug used to treat mast cell tumors,  Children should not come in contact with PALLADIA. Keep children away a common form of cancer that affects dogs. from feces, urine, or vomit of treated dogs.  PALLADIA works in two ways:  If you are pregnant, a nursing mother, or may become pregnant and you • By killing tumor cells. choose to administer PALLADIA to your dog, you should be particularly • By cutting off the blood supply to the tumor. careful and follow the handling procedures described below.  Your veterinarian has decided to include PALLADIA as a part of your dog’s  PALLADIA prevents the formation of new blood vessels in tumors. In a treatment plan for mast cell tumor. Other types of treatment, such as surgery, similar manner, PALLADIA may affect blood vessel formation in the drug treatment and/or radiation may be included in the plan. Be sure to speak developing fetus and may harm an unborn baby (cause birth defects). For with your veterinarian about all parts of your dog’s treatment plan. pregnant women, accidental ingestion of PALLADIA may have adverse What do I need to tell my veterinarian about my dog before administering effects on pregnancy. PALLADIA?  If PALLADIA is accidentally ingested by you or a family member, seek medical advice immediately. It is important to show the treating physician a  Tell your veterinarian about all other medications your pet is taking, including: copy of the package insert or label. In cases of accidental human ingestion prescription drugs; over the counter drugs; heartworm, flea & tick medica- of PALLADIA, you may experience gastrointestinal discomfort, including tions; vitamins and supplements, including herbal medications. vomiting or diarrhea.  Tell your veterinarian if your dog is pregnant, nursing puppies, or is intended for breeding purposes. The following handling procedures will help to minimize exposure to the active ingredient in PALLADIA for you and other members of your household: How do I give PALLADIA to my dog?  Anyone who administers PALLADIA to your dog should wash their hands  PALLADIA should be given to your dog by mouth (orally). after handling tablets.  PALLADIA may be hidden inside a treat; be certain your dog swallows the entire  When you or others are handling the tablets: tablet(s). • Do not split or break the tablets to avoid disrupting the protective film  Follow your veterinarian’s instructions for how much and how often to give coating. PALLADIA. • PALLADIA tablets should be administered to your dog immediately after  See the Handling Instructions section below in order to administer PALLADIA they are removed from the bottle. safely to your dog. • Protective gloves should be worn if handling broken or moistened tablets. How will PALLADIA affect my dog? If your dog spits out the PALLADIA tablet, the tablet will be moistened and  PALLADIA may help shrink your dog’s tumor. Like other cancer treatments, should be handled with protective gloves. it can be difficult to predict whether your dog’s tumor will respond to • If the PALLADIA tablet is “hidden” in food, make sure that your dog has PALLADIA, and if it does respond, how long it will remain responsive to eaten the entire dose. This will minimize the potential for exposure to PALLADIA. Regular check ups by your veterinarian are necessary to deter- children or other household members to PALLADIA. mine whether your dog is responding as expected, and to decide whether  Cleaning up after your dog: your dog should continue to receive PALLADIA. • Because PALLADIA is present in the stool, urine and vomit of dogs under treatment, you must wear protective gloves to clean up after your treated What are some possible side effects of PALLADIA? dog.  Like all drugs, PALLADIA may cause side effects, even at the prescribed dose. • While your dog receives PALLADIA, place the stool, feces or vomit, and Serious side effects can occur, with or without warning, and may in some any disposable towels used to clean up in a plastic bag which should be situations result in death. sealed for general household disposal. This will minimize the potential for • The most common side effects which may occur with PALLADIA include exposure to people in contact with the trash. diarrhea, decreased/loss of appetite, lameness, weight loss and blood in • You should not wash any items soiled with stool, urine or vomit from your the stool. dog with other laundry.  Stop PALLADIA immediately and contact your veterinarian if you notice any of the following changes in your dog: This client information sheet gives the most important information about • Refusal to eat PALLADIA. For more information about PALLADIA, talk with your veterinarian. • Vomiting or watery stools (diarrhea), especially if more frequent than twice To report a suspected adverse reaction call Zoetis at 1-888-963-8471. in 24 hours • Black tarry stools Manufactured by: Pfizer Inc, Ascoli, Italy • Bright red blood in vomit or stools Distributed by: • Unexplained bruising or bleeding Zoetis Inc., Kalamazoo, MI 49007 • Or if your dog experiences other changes that concern you Revised: August 2015  There are other side effects which may occur. For a more complete list, ask your veterinarian. 4304302.03A&P PART 1

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