296 • Clinical Genitourinary Cancer March 2006 A Phase II Study of GW786034 Using a Randomized Discontinuation Design in Patients with Locally Recurrent or Metastatic Clear-Cell Renal Cell Carcinoma Submitted: Jan 23, 2006 Accepted: Mar 28, 2006 Address for correspondence: Thomas E. Hutson, DO, PharmD Genitourinary Oncology Program Texas Oncology, PA Charles A. Sammons Cancer Center Baylor University Medical Center 3535 Worth St, Suite 240 Dallas, TX 75246 Fax: 214-370-1190 E-mail: thomas.hutson@usoncology.com Thomas E. Hutson 1 Ronald M. Bukowski 2 Current Trial Clinical Genitourinary Cancer, Vol. 4, No. 4, 296-298, 2006 Key words: Sorafenib, Sunitinib, Vascular endothelial growth factor, von Hippel–Lindau gene Rationale The incidence of renal cell carcinoma (RCC) is increasing throughout the world. 1 Although surgery is a potential cure for patients with early- stage disease, many patients will experience recurrence after surgery or have metastatic disease at the time of initial diagnosis. Previous reviews have shown that metastatic RCC is resistant to chemotherapy. 2 Based upon compelling evidence that RCC responds to immunologic manipu- lation, cytokine therapies including interleukin-2 (IL-2) and interferon (IFN)–α have been the primary systemic treatment options for patients with metastatic RCC. 3 Unfortunately, the majority of patients do not benefit from cytokine therapy, and the few responses seen are not durable, with only a small percentage of patients (approximately 10%) remaining free of progression at 3 years. Because of the limitations of currently available therapies, new strategies for treatment of advanced- stage RCC are urgently needed. Angiogenesis is known to play a critical role in the growth of tumors and could represent an important target for the development of novel anti- cancer therapies. 4 Recent work in understanding the von Hippel–Lindau (VHL) gene has demonstrated a role for angiogenesis in the pathophysiol- ogy of RCC. Subjects with VHL syndrome have a germline mutation of the VHL gene and are at increased risk for developing RCC. In this pop- ulation, RCC occurs in 40%-60% of patients. 5 In addition, sporadic clear- cell RCC is often associated with VHL gene deletion or gene silencing by DNA methylation. Loss of VHL gene function correlates with constitutive activation of hypoxia-inducible factor (HIF)–1α and resultant increased vascular endothelial growth factor (VEGF) production. Progress is being made in the use of angiogenesis inhibitors to treat RCC. Yang et al performed a phase II study of bevacizumab, a mono- clonal antibody against VEGF, to treat patients with metastatic RCC. 6 In that study, there was a significant prolongation of time to disease pro- gression in subjects receiving the higher bevacizumab dose of 10 mg/kg versus control (4.8 months vs. 2.5 months; P < 0.001). Recently, new oral multitargeted kinase inhibitors, sorafenib and sunitinib, have been stud- ied in metastatic RCC refractory to cytokine therapy with IL-2 or IFN- α. 2 Both of these agents target the tyrosine kinase of VEGF, VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), and PDGF receptor. Objective tumor responses have been seen in as many as 40% of patients, 2 with the majority of patients having some level of tumor regres- sion. 2,7,8 Based on these results, the Food and Drug Administration gave regulatory approval for sorafenib in advanced-stage RCC on December 20, 2005, and similarly, for sunitinib on January 26, 2006. GW786034 (pazopanib) is a potent small-molecule inhibitor of Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400. 1 Baylor Charles A. Sammons Cancer Center/Texas Oncology, PA, Dallas 2 Taussig Cancer Center, Cleveland Clinic Foundation, OH