Palladia (Toceranib phosphate)

by Cheryl Harris, DVM, DACVIM (Oncology and Small Animal Internal Medicine)

Palladia (toceranib phosphate) was the first FDA-approved antiangiogenic and antiproliferative cancer treatment specifically for dogs. It is manufactured by Pfizer and was released for use by veterinary oncologists in 2009 for the treatment of Patnaik grade II or III, recurrent cutaneous mast cell tumors with or without regional lymph node involvement in dogs. It has been a remarkable adjunct for the treatment of canine mast cell tumors (MCT) and is now being used for a variety of canine and even feline tumors. It is now available for widespread use by all licensed veterinarians.

Palladia is a receptor tyrosine kinase (RTK) inhibitor. Inhibition of RTKs on endothelial cells, pericytes, and tumor cells disrupts multiple processes necessary for tumor growth. Palladia inhibits the activity of VEGFR-2, an RFK expressed on endothelial cells. It inhibits the activity of PDGFR-B, an RTK expressed on pericytes and inhibits the RTK KIT on tumor cells. KIT is commonly dysregulated in canine MCT.

The original clinical field study using toceranib phosphate was a multi-center, double-blind, placebo-controlled trial conducted at 10 oncology referral centers and included 151 dogs with MCT. In dogs treated with Palladia, approximately 60% of MCT disappeared, regressed, or stabilized.

Most oncologists are no longer using the label dose of 3.25 mg/kg, but instead use dose ranges between 2.5 to 2.75 mg/kg, EOD or on a MWF basis. This appears to be associated with better tolerability while maintaining efficacy. Prednisone or NSAIDs can be used on alternate days. Many dogs are receiving Cytoxan in addition to Palladia as part of a metronomic therapy. Dogs are started on Cytoxan 10-12 mg/m2 (EOD or T/Th/Sat/Sun) and famotidine for 2 weeks prior to initiation of Palladia. Palladia should be given with food.

All dogs should have a baseline CBC, chemistry profile, urinalysis and fecal occult blood prior to starting Palladia. Owners must observe carefully for loose stools, anorexia or lethargy. For dogs that develop diarrhea, loperamide is used SID/BID and continued during therapy. For dogs with decreased appetite, add canned food to the diet and use metoclopramide, ondansetron or Cerenia.

Dogs are rechecked weekly with CBC and hemoccults for the first 2-4 weeks and body weight should be monitored very closely. It is then recommended to monitor at least monthly with hemoccult, CBC and chemistry panels. Neutropenia can occur but is tolerable as long as neutrophils stay above 1500. If they are lower than 1500, a drug holiday is recommended until the neutrophil count is normal, then the dose is modified. The same holds true for muscle cramping and lameness, an occasionally reported side effect of the drug. Newly reported side effects are elevations in ALT and ALP, protein-losing nephropathy, hypertension and pancreatitis.

The following guidelines on treatment of MCT are based on the Ohio State University treatment experience and that of Dr. Cheryl London who has participated in much of the original research using Palladia.

Palladia is usually incorporated into treatment protocols for Grade III MCT and any Grade II MCT with negative prognostic indicators (mitotic index >5, recent rapid growth, recurrence following surgery, positive lymph nodes.) In general, Palladia is part of a treatment protocol that includes surgery +/- radiation therapy and chemotherapy. It is usually not used as a single agent unless the dog has failed these modalities or it is the only treatment available. For dogs with gross disease, every attempt is made to downstage the cancer prior to initiation of Palladia therapy. If surgery is not possible, dogs can receive vinblastine/prednisone chemotherapy for 2-6 weekly treatments prior to Palladia or receive radiation therapy or a combination of chemotherapy and radiation therapy.

All MCT patients are started on famotidine and Benadryl in addition to prednisone. Any dog with positive hemoccult tests at the start of treatment is pretreated with omeprazole and sucralfate for 1-2 weeks prior to Palladia. Dogs with significant mast cell tumor burden are at high risk for developing side effects from Palladia, particularly if they are already sick. H1 and H2 blockers should always be used in dogs with gross MCT.

It is usually recommended to give Palladia for 30 days to see the full response but some responses are dramatic and seen in the first 7 days. It is unknown how long to treat dogs who are having a good response but many will have their disease recur if Palladia is discontinued. If they are tolerating the drug well, it is currently recommended to keep them on the drug on a M/W/F basis indefinitely.

Other types of tumors which have demonstrated response to Palladia include anal sac adenocarcinomas, metastatic osteosarcomas, thyroid carcinomas, nasal carcinomas, melanomas, squamous cell carcinomas, multiple myeloma and transitional cell carcinomas.

Palladia is very well tolerated in cats. The recommended starting dosage is 2.8 mg/kg EOD. Compounding is recommended to get accurate dosing. Responses have been seen in mast cell tumors, squamous cell carcinomas and vaccine-associated sarcomas. GI toxicity and myelosuppression should be monitored.

Palladia is supplied in 10, 15 and 50 mg tablets and are packaged in 30 count bottles. The tablets should not be split or crushed and should be handled with gloves. A chemical hood such as is used for administration of chemotherapy is not required. The tablets should not be handled by pregnant women.

For more information on the use of Palladia in treating tumors in dogs and cats, please feel free to call the oncologists at Veterinary Answers.

Case Report - 5 Year Old FS Boxer with Severe Mast Cell Disease

Zachary M. Wright DVM, DACVIM (oncology)

History:

Maddi originally presented to my oncology service with a 6 month history of a mass on the right flank. The mass was eventually completely excised by the referring veterinarian and diagnosed as a grade II mast cell tumor. Maddi did very well post-operatively. 1 month prior to the oncology referral, the owner noticed multiple skin growths on her forehead and inner thighs. Every day had resulted in more noticeable masses and progression of the original tumors. At the time of presentation, Maddi was on routine hydroxyzine and Tramadol for discomfort.

Assessment:

T- 102.6 HR- 110 RR-panting Wt- 57.8lbs.

Maddi was bright and alert. Her heart and lungs ausculted within normal limits. Her abdomen was soft and non painful. All of her peripheral lymph nodes palpated within normal limits. She had approximately 300 dermal masses throughout her entire body (see photos). The lesions were red, raised, and of varying sizes. The remainder of her physical exam was unremarkable.

Cytology of multiple, randomly picked masses were all consistent with well granulated mast cell tumors.

Recommendations:

The treatment of choice for all mast cell disease is surgical removal with wide (2cm) surgical margins. However, in Maddi’s presentation, the number of masses was so extensive that surgical removal was unrealistic. Thus, Maddi’s disease should be treated as a systemic illness since the entirety of her skin is involved.

The standard chemotherapy options for stage III or IV mast cell disease is a combination of vinblastine, lomustine and prednisone. However, the recent advancement of tyrosine kinase inhibitors (TKI) as a treatment for mast cell tumors has just recently landed on the veterinary market. C-kit (CD117) is a tyrosine kinase receptor (TKR) that is both mutated and over-expressed in many canine mast cell tumors. Some laboratories (Michigan State University) can evaluate histopathologic samples for these mutations and over expressions. These changes in c-kit will lead to increase cell cycle replication and more aggressive mast cell tumors.

Palladia (Pfizer) is the first veterinary approved tyrosine kinase inhibitor for the treatment of canine cancers. While it blocks a variety of different TKR, it is specifically created to block c-kit and thus has its greatest efficacy against canine mast cell disease.

Due to financial restraints, additional diagnostics (including c-kit evaluation and routine mast cell tumor staging) could not be performed and the owner elected to try the more experimental Palladia therapy instead of conventional chemotherapy.

Maddi was started on 3.0mg/kg of Palladia every other day. She was also started on standard dosages of Benadryl and Pepcid AC. Due to significant gastrointestinal toxicity associated with Palladia, it is recommended to put all naïve patients on daily sucralfate as well.

Follow-Up:

Maddi presented for a recheck exam 7 days after initiation of therapy. No Palladia toxicity was reported by the owner. Her physical exam noted dramatic reduction in most of her masses (see photos). The remainder of her physical exam was unremarkable.

She had a mild neutropenia (2000) on a CBC

which is anticipated with Palladia therapy. Treatment was continued at the previously prescribed frequencies and dosages.

Maddi again presented for a recheck exam 3 weeks later. There was still no clinical signs associated Palladia toxicity. On physical exam, her masses had almost completely resolved. However, in areas where masses were no longer palpated, Maddi had developed depigmentation in the areas of previous mast cell tumors. Her neutropenia remained but was stable.

Maddi continued to do well on the Palladia treatment protocol for another 3 months. At that time, her masses developed a resistance to the treatment and progressed rapidly causing significant pruritus and a general decline in overall quality of life. At that time, the owners elected for humane euthanasia.