Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies.
OBJECTIVE
The purpose of the following study was to investigate the safety and efficacy of the novel multitargeted indolinone receptor tyrosine kinase (RTK) inhibitor, SU11654, using a canine model of spontaneous tumors. This p.o. bioavailable compound exhibits potent inhibitory activity against members of the split kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Kit, and Flt-3, resulting in both direct antitumor and antiangiogenic activity.


METHODS
This was a Phase I trial in which successive cohorts of dogs with spontaneous tumors that had failed standard treatment regimens received escalating doses of SU11654 as oral therapy. Pharmacokinetics, toxicity, and tumor response were assessed.


RESULTS
Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors (n = 11), mixed mammary carcinomas (n = 2), soft tissue sarcomas (n = 2), and multiple myeloma (n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57).


CONCLUSIONS
This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.
London
Cheryl A
CA
School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA.
Hannah
Alison L
AL
Zadovoskaya
Regina
R
Chien
May B
MB
Kollias-Baker
Cynthia
C
Rosenberg
Mona
M
Downing
Sue
S
Post
Gerald
G
Boucher
Joseph
J
Shenoy
Narmada
N
Mendel
Dirk B
DB
McMahon
Gerald
G
Cherrington
Julie M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008297:Male; D008956:Models, Chemical; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000662:veterinary*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C464577:toceranib phosphate; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor