A randomized phase II study of irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) with or without the addition of an endothelin receptor antagonist in patients with metastatic colorectal cancer after failure of oxaliplatin-containing chemotherapy.
Thomas AL., Wilson RH., Steward WP., Adams RA., Bridges SE., Casbard AC., Maughan T., Griffiths G., NCRI Colorectal Clinical Studies Group None.
TPS161 Background: Plasma endothelin-1 levels are elevated in CRC patients and are prognostic for worse outcome. Endothelin-A receptor (ETAR) expression is increased in CRC samples compared with normal tissue. Antagonism of ETAR enhances cytotoxicity when combined pre-clinically with chemotherapeutics (Growcott JW, 2009. Anticancer Drugs 20: 83-88). We hypothesize that the anti-tumour activity of irinotecan and 5-FU (FOLFIRI regimen) can be increased by simultaneously blocking cell survival signalling through ETAR. METHODS: This trial is exploring the specific ETAR antagonist zibotentan or placebo combined with FOLFIRI administered for 24 weeks in second-line treatment of metastatic CRC. Patients are >18 years with RECIST measurable disease, ECOG PS0-1, good end-organ function, and no previous Irinotecan use. After chemotherapy, patients may continue zibotentan or placebo monotherapy. This is a double blind (1:1) randomised phase II trial. The dose of zibotentan is 10mg orally once daily. 56 of 122 planned patients have been enrolled to date. The control arm will enable direct comparison of toxicity and will provide an estimate of PFS to support the design of a future phase III trial. The primary objective is to establish the anti-tumour activity of zibotentan with FOLFIRI as measured by PFS (time-to-event). Secondary objectives are to determine the toxicity and feasibility of the combination, and to collect tumour and blood samples for future translational work. The predicted median PFS for patients on FOLFIRI chemotherapy is 16 weeks. 122 participants are required to demonstrate a statistically significant difference between arms. This is an academically led collaborative trial between the UK National Cancer Research Network and AstraZeneca, which is endorsed by Cancer Research UK (CRUKE/09/023) and coordinated by the CR UK Wales Cancer Trials Unit in Cardiff University, UK. The ISRCTN number is 73199181.