Multi-center, Placebo-controlled, Double-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

• Published in: Clinical cancer research Vol. 15; no. 11; pp. 3856 - 3865
• Main Authors: London, Cheryl A, Malpas, Phyllis B, Wood-Follis, Stacey L, Boucher, Joseph F, Rusk, Anthony W, Rosenberg, Mona P, Henry, Carolyn J, Mitchener, Kathy L, Klein, Mary K, Hintermeister, John G, Bergman, Philip J, Couto, Guillermo C, Mauldin, Guy N, Michels, Gina M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2009
• Subjects: Animals; Anorexia - chemically induced; Antineoplastic agents; Biological and medical sciences; Diarrhea - chemically induced; Disease Progression; dog; Dog Diseases - drug therapy; Dog Diseases - metabolism; Dog Diseases - pathology; Dogs; Female; Indoles - administration & dosage; Indoles - adverse effects; Indoles - therapeutic use; kinase inhibitor; Male; mast cell tumor; Mast-Cell Sarcoma - drug therapy; Mast-Cell Sarcoma - metabolism; Mast-Cell Sarcoma - pathology; Medical sciences; Neoplasm Recurrence, Local; Pharmacology. Drug treatments; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - therapeutic use; Random Allocation; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; SU11654; Treatment Outcome; Vomiting - chemically induced; Phosphates; Fissipedia; Carnivora; Relapse; Excision; Oral administration; trk receptor; Vertebrata; Randomization; Mammalia; Treatment; Animal; Surgery; Placebo; Double blind study; Mast cell; Dog; Tumor cell
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1860

Purpose: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors
(MCT) with toceranib phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through
inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary objectives were to determine biological
response rate, time to tumor progression, duration of objective response, health-related quality of life, and safety of Palladia.
Experimental Design: Dogs were randomized to receive oral Palladia 3.25 mg/kg or placebo every other day for 6 weeks in the blinded phase. Thereafter,
eligible dogs received open-label Palladia.
Results: The blinded phase ORR in Palladia-treated dogs ( n = 86) was 37.2% (7 complete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs ( n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced
objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among
the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks,
respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders
( P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events
were generally manageable with dose modification and/or supportive care.
Conclusions: Palladia has biological activity against canine MCTs and can be administered on a continuous schedule without need for routine
planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic
index of targeted therapeutics in a clinical setting.