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

Abstract

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.

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

“…Metastatic MCT represents a major health problem in the canine population, but the introduction of a novel class of targeted antineoplastic agents directed against KIT, TKI, has significantly changed the therapeutic options available for these dogs 7, 8. Indeed, the important role of targeted therapy against molecules contributing to tumor development, progression, and metastasis has attracted considerable attention 31…”

“…Although TKI‐based therapy is used in dogs with MCT to also treat metastatic disease in the lymph nodes,7 c‐kit status is generally evaluated in the primary lesions because metastatic sites are rarely removed or biopsied before treatment. However, it is still unknown whether c‐kit status differs in metastases compared with primary tumors.…”

“…Moreover, the treatment with TKIs is associated with potential toxicity and high costs; additionally, resistance to certain TKIs is often caused by secondary mutations of c‐kit 7, 16; therefore, it is important to critically review all aspects of the mutational testing to enhance upfront patient selection.…”

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

“…47 This study supports the use of feline SCC as a model for HNSCC, an approach that could potentially benefit both felines and humans alike. During the development of a TKI against KIT (SU11654, toceranib) 48 the human field benefited greatly from the canine studies, 47 and the development of acquired resistance to single-agent TKIs in dogs with mast cell tumors is of particular interest. 47 Further studies in cats with SCCs using EGFR targeting siRNA based therapies in combination with radiotherapy would potentially advance the treatment of the disease in both species.…”

Canine Subcutaneous Mast Cell Tumors

“…The presence of these mutations is associated with higher-grade tumors. 20,29,38 Mutations result in constitutive activation of KIT, initiating signaling cascades leading to proliferation, survival, and invasion. 9,[15][16][17][18]21,22,29 One group reported that the presence of ITD mutations of c-KIT or aberrant cytoplasmic KIT protein localization was significantly associated with higher values of Ki67.…”