PALLADIA is an oral receptor tyrosine kinase (RTK) inhibitor that blocks the activity of multiple receptors on cancer cells and blood vessels. The active ingredient in PALLADIA is toceranib. It is approved for use in dogs with recurrent, cutaneous mast cell tumors (Patnaik grade II or III) with or without regional lymph node involvement.

PALLADIA is a antineoplastic agent belonging to the receptor tyrosine kinase (RTK) inhibitor class of drugs.

Kinases are enzymes that catalyze the transfer of phosphate groups from ATP. Receptor tyrosine kinases (RTKs) are tyrosine kinases on the cell surface that are activated through binding of growth factors. Receptor tyrosine kinsases play a role in signaling pathways that govern normal cellular processes such as proliferation, migration, metabolism, and differentiation. Examples of RTKs include: platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), stem cell factor receptor (Kit). In normal cells, RTK activity is tightly controlled. In some cancerous conditions, abnormalities such as mutations can lead to abnormal activation of RTKs resulting in increased cellular proliferation and growth, prevention of apoptosis (cellular death) as well as increased angiogenesis and metastasis. The result of RTK dysfunction is phosphorylation of the kinase in the absence of an appropriate signal and constitutive signaling and abnormal promotion of cell growth and survival. These conditions promote tumor development, growth and progression.^{14, 15}

Toceranib phosphate is a small molecule that has both direct antitumor and antiangiogenic activity. In non-clinical pharmacology studies, toceranib selectively inhibited the tyrosine kinase activity of several members of the split kinase receptor tyrosine kinase (RTK) family, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Toceranib inhibited the activity of Flk-1/KDR tyrosine kinase (vascular endothelial growth factor receptor, VEGFR2), platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (Kit) in both biochemical and cellular assays. Toceranib has been shown to exert an antiproliferative effect on endothelial cells in vitro. Toceranib treatment can induce cell cycle arrest and subsequent apoptosis in tumor cell lines expressing activating mutations in the split kinase RTK, c-Kit. Canine mast cell tumor growth is frequently driven by activating mutations in c-Kit. ^{2, 13}

PALLADIA is indicated for the treatment of Patnaik Grade II or III, recurrent, cutaneous mast cell tumors (MCT) with or without regional lymph node involvement in dogs.

Always provide Client Information Sheet with prescription. Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day. Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg (1.0 mg/lb) every other day) and dose interruptions (cessation of PALLADIA for up to two weeks) may be utilized, if needed, to manage adverse reactions. Adjust dose based on approximately weekly veterinary assessments for the first 6 weeks and approximately every 6 weeks, thereafter. PALLADIA may be administered with or without food. Do not split tablets.

A radiolabel study was performed with laboratory beagle dogs. The dogs were administered radiolabeled PALLADIA as a single oral gavage at a dose of 3.25 mg/kg. Plasma, urine and feces were collected out to 168 hours post dosing. Tissue and fluid samples were collected at necropsy on day 7. The majority of radioactivity was excreted in the feces accounting for approximately 89-94% of the dose.
Urinary excretion accounted for approximately 6.3 - 8.1%.¹⁶
Using an in vitro hepatocyte and liver microsome test system, the Z isomer was found to be metabolized to the N-oxide derivative of toceranib in dogs, humans, cats, and rats. Although a small gender difference was observed in the in vitro study (81% conversion in male dogs, 56% conversion in female dogs) no differences in toceranib pharmacokinetics was observed in vivo. The effects of renal impairment, hepatic impairment or breed on the pharmacokinetics of toceranib have not been investigated.

The IC50 is a parameter measuring the inhibition of phosphorylation of the receptor once stimulated. The cellular inhibitory activity (IC50) of PALLADIA² is:
c-Kit (wild-type): 0.01-0.1 μM
c-Kit (JM mutation): 0.01-0.1 μM
PDGFR-β: 0.01-0.1 μM
Flk-1/KDR (VEGFR2): 0.005-0.05 μM

During the blinded phase, regardless of treatment group (PALLADIA or placebo), dogs with tumors positive for c-Kit ITD were more likely to have an objective response compared to those negative for c-Kit ITD (44.8%, 13/29 vs. 20.3%, 24/118, P=0.009). Within the PALLADIA treated group, dogs with c-Kit positive tumors were more likely to respond than those with c-Kit negative tumors (60.0% (12/20) vs. 31.3% (20/64) P= 0.0099).⁶ It has been demonstrated in vitro that PALLADIA has inhibitory effects on RTKs other than c- KIT, such as VEGF and PDGFR, which is one of the possible mechanisms of response in clinical cases with tumors that are not c-KIT positive.

In the PALLADIA efficacy study dogs could be included in the study if there was one regional group of lymph nodes involved. Dogs were excluded if there was evidence of systemic MCT disease, and/or involvement of more than one lymph node region. During the blinded phase, the objective response rate (ORR) in dogs with lymph node involvement was 29.4% (10/34) for PALLADIA-treated dogs compared to 4% (1/25) for placebo treated dogs. For dogs without lymph node involvement the ORR was 42.3% (22/52) for PALLADIA treated dogs and 10.5% (4/38) for placebo treated dogs. Lymph node metastasis was not associated with objective responses (P=0.349 and P=0.109). In the blinded + open phase, dogs without regional lymph node metastasis had a longer time to tumor progression than those with lymph node involvement but this was not significant (P=0.056). Regional lymph node metastasis was not significantly associated with duration of response (P=0.090).³

No concurrent steroid use was allowed during the clinical trial as it might confound the efficacy evaluation. Dogs that were previously treated with corticosteroids were required to be off corticosteroid treatment for 14 days in order to enroll in the clinical trial.³

The most common adverse effects are gastrointestinal (diarrhea, decrease appetite (anorexia), weight loss, blood in stool, lethargy, vomiting). Most GI AE are mild and moderate and can be managed with supportive therapy recommended by the veterinarian. Serious, and sometimes fatal, GI complications, including GI perforations, have occurred rarely in dogs treated with PALLADIA. Some adverse events may require a dose adjustment, stopping treatment, and/or supportive therapy. When PALLADIA is prescribed, pet owners should be provided the Client Information Sheet available with every package insert. The Client Information Sheet provides instructions on when to stop PALLADIA and contact their veterinarian if their dog experiences clinical signs while on the drug.

During the clinical efficacy study, PALLADIA was administered concomitantly with other medications such as antimicrobials, H-2 receptor blockers, antihistamines, anti-emetics, non-steroidal anti-inflammatory drugs, locally-acting anti-ulcer medications, opiate gastro-intestinal motility modifiers, opioids, vaccines, anthelmintics, antiparasitics, and topical/ophthalmic/otic corticosteroid preparations. During the open-label phase only, 5 dogs received a brief course of short-acting corticosteroids. Specifically the most common concomitant treatments in the blinded and open label phase: Metronidazole, diphenhydramine, famotidine, metoclopramide, fluids, amoxicillin-clavulanic acid, cephalexin, ampicillin, enrofloxacin, sucralfate, omeprazole, carprofen, cimetidine, dolasetron mesylate, loperamide, ranitidine. A statistically higher number of PALLADIA treated dogs received metronidazole.

PALLADIA was investigated as a single agent therapy compared to placebo during the clinical field study. PALLADIA use in combination with other chemotherapy agents used in MCT has not been evaluated.

PALLADIA is for use ONLY in dogs. PALLADIA is not for use in humans.Children should not come in contact with PALLADIA. Store out of reach of children.Keep children away from feces, urine, or vomit of treated dogs. To avoid exposure to drug, wash hands with soap and water after administering PALLADIA and wear protective gloves to prevent direct contact with feces, urine, vomit, and broken or moistened PALLADIA tablets. Place all waste materials in a plastic bag and seal before general disposal. If eyes are accidentally exposed to the drug, rinse eyes with water immediately. In case of accidental ingestion by a person, seek medical advice immediately, show the package insert or label to the physician.Gastrointestinal discomfort such as vomiting or diarrhea may occur if this drug is accidentally ingested. Pregnant women, women who may become pregnant, or nursing mothers should pay 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 tumors. In a similar manner, PALLADIA may affect blood vessel formation in the developing fetus and may harm an unborn baby (cause birth defects). For pregnant women, accidental ingestion of PALLADIA may have adverse effects on pregnancy. Handling instructions are available on the Prescribing Information and Client Information Sheet.