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

被引：311

作者：

London, Cheryl A. ^{[2
]}

Malpas, Phyllis B. ^{[1
]}

Wood-Follis, Stacey L. ^{[1
]}

Boucher, Joseph F. ^{[1
]}

Rusk, Anthony W. ^{[3
]}

Rosenberg, Mona P. ^{[4
]}

Henry, Carolyn J. ^{[5
]}

Mitchener, Kathy L. ^{[6
]}

Klein, Mary K. ^{[7
]}

Hintermeister, John G. ^{[8
]}

Bergman, Philip J. ^{[9
]}

Couto, Guillermo C. ^{[10
]}

Mauldin, Guy N. ^{[11
]}

Michels, Gina M. ^{[1
]}

机构：

[1] Pfizer Anim Hlth, Kalamazoo, MI 49001 USA

[2] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA

[3] Anim Clin Invest Friendship Hosp Anim, Washington, DC USA

[4] Vet Canc Referral Grp, Tustin, CA USA

[5] Univ Missouri, Dept Vet Med & Surg, Columbia, MO USA

[6] Angel Care Canc Clin Anim, Memphis, TN USA

[7] SW Vet Oncol, Tucson, AZ USA

[8] Vet Specialty Ctr, Buffalo Grove, IL USA

[9] Anim Med Ctr, New York, NY USA

[10] Ohio State Univ, Coll Vet Med, Columbus, OH 43210 USA

[11] Louisiana State Univ, Sch Vet Med, Baton Rouge, LA 70803 USA

来源：

CLINICAL CANCER RESEARCH | 2009年 / 15卷 / 11期

关键词：

GASTROINTESTINAL-STROMAL-TUMORS; LIGAND-INDEPENDENT ACTIVATION; ACUTE MYELOID-LEUKEMIA; PROTOONCOGENE C-KIT; TANDEM DUPLICATIONS; MASTOCYTOMA-CELLS; PLASMA HISTAMINE; MUTATIONS; PREDNISONE; LINE;

D O I：

10.1158/1078-0432.CCR-08-1860

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：3856 / 3865

页数：10

共 51 条

[1] Establishment of a novel high-affinity IgE receptor-positive canine mast cell line with wild type c-kit receptors [J].