Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST.

4000 Background: Inhibition of aberrant kinase signalling through the KIT or PDGFRα receptors with imatinib therapy has improved survival for pts with metastatic GIST, but over time, clonal evolution leads to imatinib-resistant disease. Imatinib resistance may be due to several mechanisms, including complex patterns of secondary kinase mutations. SU11248, an oral multitargeted tyrosine kinase inhibitor, has antiangiogenic and antitumor activity due to inhibition of signalling by VEGFR, PDGFRα and KIT. Prior studies have demonstrated clinically relevant activity in pts with imatinib-resistant GIST, including those associated with acquired secondary kinase mutations (Demetri et al. Proc ASCO 2004; 22: abstr 3001).,A double-blind, phase 3 trial is being conducted to evaluate the efficacy and safety of single-agent SU11248 (50 mg once daily for 4 wks followed by a 2-wk break in each 6-wk cycle) compared with placebo in pts with GIST following documented failure of imatinib (due to objective progression or intolerable adverse effect of prior imatinib). Pts are initially randomized 2:1 to SU11248 or placebo. Treatment of pts who exhibit RECIST-defined progression of GIST is unblinded, and these pts are crossed over to unblinded SU11248 therapy. The primary study endpoint is TTP. Secondary endpoints include OS, ORR, time to tumor response, duration of response, duration of performance status maintenance and clinical benefit-related parameters (McGill Pain Questionnaire, investigator-rated changes in severity of signs and symptoms and other pt-reported outcomes). Based on a planned sample size of 357 pts (238 SU11248, 119 placebo), the trial was designed to have a 90% power to detect a 50% improvement in median TTP from 4 to 6 mos (2-sided unstratified log-rank test; significance level 0.05). A prospectively planned interim analysis will be performed after the first 141 events (objective progression of GIST).,Results of the interim analysis will be submitted by the late-breaking abstract deadline.,Conclusions will be submitted. [Table: see text].