A Multi-center, Randomized, Double Blind, Placebo Controlled Clinical Trial to Evaluate the Efficacy of Intratumoral Injection TD-B10 in Dogs with Perianal Gland Tumors

近年來許多研究專注於研發新穎的癌症治療方式，此研究中使用的藥物TD-B10為一種小分子藥物的複合型藥劑，其成分包括每福敏、阿斯匹靈及血清素。主要成分每福敏為一種二甲雙胍類降血糖藥物，目前在人類醫學上被廣泛使用於第二型糖尿病的治療，其被證實可以活化AMPK路徑並抑制mTOR，可抑制肝臟的糖質新生作用，並且有控制蛋白質生成和細胞增生的效果，另外，由腫瘤壞死因子引起的壞死也是TD-B10重要的抗癌機制。 本雙盲試驗之目標為確認腫瘤內注射TD-B10於犬隻圍肛腺瘤之治療效果、安全性及適用性。經由組織病理切片確診為圍肛腺瘤之犬隻根據良惡性、腫瘤分級分層，並隨機分配至藥物組和安慰劑組，於連續兩週的週一至週五，每日一次，共進行十劑注射，治療後連續四週進行追蹤。主要試驗終點為治療後四週的治療反應率及腫瘤消退率。 共26隻犬隻完成試驗，包含藥物組14隻和安慰劑組12隻。藥物組的平均腫瘤消退率（45.16 ± 42.87%）優於安慰劑組（-6.15 ± 45.64%），達統計上顯著差異（P=0.0168），另外，藥物組的平均治療反應率為57.14%（8/14; 2 CR, 6 PR），顯著優於安慰劑組8.33%（1/12; 1 PR）（P=0.0145）。在考量多種因素下，包含病畜之品種、腫瘤體積、臨床分級等，藥物組的治療效果仍顯著優於安慰劑組。依據獸醫癌症協會，多數副作用為一至二級，常見的副作用包含注射區域反應、疼痛及消化道症狀，少數藥物組病畜出現三級注射區域反應，認為和藥物造成之腫瘤壞死及脫落有關。 本研究結果顯示，TD-B10腫瘤內注射對於犬隻圍肛腺瘤有顯著的抗腫瘤效果，並能有效地造成腫瘤消退。TD-B10 is a formula composite of which the principal component is metformin, a biguanide hypoglycemic agents for type 2 diabetes treatment. Metformin is known to have antineoplastic activity by activating the AMPK/mTOR pathway. Necrosis induced by tumor necrosis factor (TNF) is also considered an important part in the TD-B10 antitumor activity. The aim of this study is to determine the treatment efficacy in canine perianal gland tumors also the safety and feasibility of TD-B10 intratumoral injection in small animal cancer patients. Dogs with histopathologically confirmed perianal gland tumors are stratified and randomly divided into two groups. The tumors will receive either TD-B10 injection or placebo control once daily on weekdays for two consecutive weeks for total of 10 injections. The primary end point is the response rate and the tumor regression rate at the end of the 4-weeks follow-up period. A total of 26 dogs were recruited. The tumor regression rate in treatment group (n=14) was 45.16 ± 42.87% compared with -6.15 ± 45.64% for placebo group (n=12) (P=0.0168). The objective response rate in treatment group was 57.14% (8/14; 2 CR, 6 PR) compared with 8.33% (1/12; 1 PR) for placebo group (P=0.0145). The tumor regression rate of TD-B10 group was higher than the placebo group despite the patients’ breed, tumor volume, clinical stage and multiple factors. The toxicities were mostly limited to grade I to II where injection site reactions, pain and gastrointestinal toxicities were most commonly observed. The result of this study demonstrated that TD-B10 has significant anti-tumor activity and can evoke tumor regression in canine perianal tumors