Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr TPS239)
Author(s): A. S. Alva, N. Agarwal, A. O. Siefker-Radtke, B. J. Roth, D. C. Smith, S. Daignault, S. Srinivas, D. A. Bradley, M. Hussain; University of Michigan, Ann Arbor, MI; University of Utah Huntsman Cancer Institute, Salt Lake City, UT; University of Texas M. D. Anderson Cancer Center, Houston, TX; Vanderbilt-Ingram Cancer Center, Nashville, TN; Stanford University School of Medicine, Stanford, CA; Duke University Medical Center, Durham, NC
Background: Cures are rare in advanced UC. The EGF pathway is involved in proliferation, survival, angiogenesis, and metastasis of cancers including UC. EGFR is overexpressed in 50% of UC. Its expression correlates with higher tumor grade, stage, disease progression, and is an independent adverse prognostic factor for overall survival (OS) and disease-specific survival. The majority of UC metastases over-express EGFR. Resistance to chemotherapy in bladder cancer lines involves EGFR up-regulation and can be overcome by EGFR inhibition. Cetuximab (Ctx) is a humanized chimeric antibody against the extracellular domain of EGFR. In UC cell lines Ctx is cytostatic and downregulates angiogenic factors including VEGF and bFGF. In in-vivo UC tumors it results in tumor regression and growth and metastasis inhibition. Ctx is FDA approved in head and neck and colon cancer based on improvements in OS and/or progression-free survival (PFS).This study is designed to determine if Ctx + GC results in higher response rate in UC.
Methods: Eligible pts have locally advanced or metastatic UC, adequate organ function, ECOG performance status 0-2, no prior chemo or anti-EGFR therapy for current stage of disease. Pts are randomized to receive C 70 mg/m2 on day (D)1 and G 1000 mg/m2 on D1,8,15 in 28 D cycles (Arm A) or same chemotherapy + Ctx 500 mg/m2 D 1 and 15 (Arm B- Recent data suggest q 2 week dosing may be equivalent with q week schedule). Response is assessed q 2 cycles. GC therapy continues till progression or completion of 6 cycles. Arm A pts progressing after 2 cycles will receive GC + Ctx. Pts on GC+Ctx who do not progress after 6 cycles will continue on Ctx. Objectives:Assess the overall response rate (ORR) of GC ± Ctx, safety, response duration, PFS, OS and if Ctx sensitizes nonresponding pts to GC. Blood and tissue samples are collected for correlative studies. Design: Phase II, with a 2:1 experimental to control randomization. Accrual target is 27 pts to Arm A (expected ORR 50%) and 54 pts to Arm B (expected ORR 65%). To date 56/81 pts are enrolled.