A Randomized, Double-Blind, Phase (PH) III Study of Folfiri Plus Ramucirumab (RAM) or Placebo (PL) in Patients (Patients) with Metastatic Colorectal Carcinoma (MCRC) Progressed During or Following 1st-Line Therapy with Bevacizumab (BEV), Oxaliplatin (OXALI), and a Fluoropyrimidine (FP) (RAISE) (NCT01183780).

ABSTRACT Background Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In a preclinical study, antiangiogenic and antitumor effects were observed when DC101, an antibody that targets murine VEGFR-2, was administered to mice bearing human colon cancer xenografts. Antitumor activity for RAM has been demonstrated in a Ph I study in patients with solid tumors over a wide range of RAM dose levels and in a Ph II study with RAM + mFOLFOX-6 as 1st-line therapy in patients with mCRC. Methods This ongoing, randomized, double-blind, placebo-controlled Ph III study includes mCRC patients with measurable or nonmeasurable disease and ECOG performance status of 0-1 who have experienced disease progression during or within 6 months after completion of 1st-line therapy with BEV, OXALI, and any FP. Randomization is stratified by geographic region, KRAS status, and time to progression after initiation of 1st-line therapy. patients are randomized 1:1 to either RAM 8 mg/kg or PL every 14 days. patients in both arms receive FOLFIRI (irinotecan: 180 mg/m2, folinic acid: 400 mg/m2, 5-fluorouracil: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hours). The primary end point is overall survival (OS). The sample-size estimate assumes 85% power to detect at least a 2.5-month median OS difference (HR = 0.8) between treatment arms with a 1-sided alpha of 0.025. Secondary end points include progression-free survival, tumor response, safety, pharmacokinetics, immunogenicity, and correlations between biomarkers and clinical outcome. CRC tissue and blood collection is mandatory for biomarker analyses. As of 30 April 2012, 412 of 1050 planned patients have been enrolled from 141 sites in US, South America, Europe, Australia, and Asia including 30 patients from Japan.