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
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
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DOI：
10.1158/1078-0432.ccr-08-1860
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发表时间：
2009-06-01
影响因子：
11.5
通讯作者：
Michels, Gina M.
中科院分区：
文献类型：
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作者：
London, Cheryl A.;Malpas, Phyllis B.;Michels, Gina M.
目的：本研究的目的是确定用磷酸托ceranib （Palladia, SU11654）治疗犬肥大细胞瘤（MCT）后的客观缓解率（ORR），磷酸托ceranib是一种激酶抑制剂，通过抑制KIT、血管内皮生长因子受体2和PDGFR β具有抗肿瘤和抗血管生成活性。次要目的是确定生物反应率、肿瘤进展时间、客观反应持续时间、健康相关生活质量和Palladia的安全性。实验设计：在盲法期，狗随机接受每隔一天口服Palladia 3.25 mg/kg或安慰剂，持续6周。之后，符合条件的狗接受了开放标签的帕拉迪亚。结果：palladia治疗犬（n = 86）的盲法期ORR为37.2%（7例完全缓解，25例部分缓解），而安慰剂治疗犬（n = 63; P = 0.0004）的盲法期ORR为7.9%（5例部分缓解）。在安慰剂逃逸后接受Palladia治疗的58只狗中，41.4%（8只完全缓解，16只部分缓解）出现客观反应。145只接受Palladia治疗的狗的ORR为42.8%（21只完全缓解，41只部分缓解）；在62名应答者中，客观缓解和肿瘤进展的中位持续时间分别为12.0周和18.1周。接受帕拉地治疗的应答者在健康相关生活质量方面得分高于接受帕拉地治疗的无应答者（P = 0.030）。出现3/4级不良事件的犬只数量差异无统计学意义；通过剂量调整和/或支持性治疗，不良事件通常是可控的。结论：Palladia具有抗犬mct的生物活性，可以连续给药，无需常规计划治疗中断。本临床试验进一步表明，犬自发性肿瘤是临床评价靶向治疗指标的良好模型。
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 PDGFR beta. 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.