Preclinical/clinical trials of thrice-weekly administration of a combination of tegafur/gimeracil/oteracil (TS-1) and toceranib phosphate in dogs with intranasal tumors

• Published in: Journal of Veterinary Medical Science 2024, Vol.86(11), pp.1129-1135
• Main Authors: NISHIYAMA, Yuta, MARUO, Takuya, FUKUYAMA, Yasuhiro, ODAKA, Yuka, KAWATA, Eiyu, UENO, Hirona, KAYANUMA, Hideki, NAKAYAMA, Tomohiro, TAKAHASHI, Hiroki
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer; Cancer therapies; Clinical trials; dog; Dog Diseases - drug therapy; Dogs; Dosage; Drug Administration Schedule; Drug Combinations; Female; Indoles - administration & dosage; Indoles - therapeutic use; Internal Medicine; intranasal tumor; Male; Malignancy; Nose Neoplasms - drug therapy; Nose Neoplasms - veterinary; Oral administration; Oxonic Acid - administration & dosage; Oxonic Acid - therapeutic use; Phosphate; Pyridines - administration & dosage; Pyridines - therapeutic use; Pyrroles - administration & dosage; Pyrroles - therapeutic use; Radiation therapy; Solid tumors; Squamous cell carcinoma; Tegafur; Tegafur - administration & dosage; Tegafur - therapeutic use; toceranib phosphate; Toxicity; TS-1; Tumors
• ISSN: 0916-7250; 1347-7439; 1347-7439
• DOI: 10.1292/jvms.23-0455

Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia®) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.