FOLFERA: A randomized phase II study of irinotecan, 5-fluorouracil (5-FU), and folinic acid (FOLFIRI) with or without addition of the endothelin receptor antagonist (ETAR) zibotentan in patients with metastatic colorectal cancer after failure of oxaliplatin-containing chemotherapy.
406 Background: Zibotentan (Z) is an oral specific ETAR antagonist. The ETAR is over expressed in colorectal cancer, and pre-clinically, antagonism of the ETAR has been shown to enhance cytotoxicity when combined with cytotoxics such as 5-FU. This multi-center, randomized, double-blind, placebo-controlled phase II study evaluated the safety and anti-tumor activity of irinotecan and 5-FU (as the FOLFIRI regimen) in combination with Z in advanced colorectal cancer. Methods: Patients (pts) with advanced colorectal cancer who had progressed after oxaliplatin-containing chemotherapy (FOLFOX) were randomized (1:1) to receive 10 mg O.D Z/placebo (continuous dosing) with standard dose FOLFIRI for a maximum of 12 cycles. Z /placebo could be continued until progression or unacceptable toxicity in those patients with a documented response. The primary objective was progression–free survival (PFS) with secondary endpoints of safety and blood and archival tumor samples collected for translational work including circulating tumour cell (CTC) analysis. This study was run as part of the AZ/NCRN alliance, endorsed by Cancer Research UK (CRUKE/09/023) and coordinated by the Wales Cancer Trials Unit, Cardiff University. Results: A total of 111 patients were recruited: 61% men, median age of 62 years. Z was well tolerated with G3/4 toxicity balanced between both groups (34/55 patients in Z and 38/56 in placebo group). The study was terminated before the planned number of pts (122) were recruited due to lack of efficacy of the drug in two other tumour types. Median PFS was 4.0 months in the Z group and 7.4 months in the placebo group (HR=1.86, 95% CI 1.20 to 2.87, p=0.005). The CTC analysis in relation to outcome in the placebo group will be presented. Conclusions: Zibotentan does not have anti-cancer activity in combination with FOLFIRI in patients with colorectal cancer treated with previous FOLFOX. Taken in consideration with the other trial data we do not recommend the further development of zibotentan in oncology. Clinical trial information: 73199181.