Background: Recent randomized trials investigating 5-fluorouracil [5-FU]/leucovorin [LV]/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab (BEV) for the first-line (1L) treatment (tx) of metastatic colorectal cancer (mCRC) patients (pts) showed improved progression-free survival (PFS) and overall response rate (ORR) vs. 5-FU/LV/irinotecan (FOLFIRI) with BEV (Falcone et al, ASCO 2013) and improved PFS, ORR, and resection rate of metastases vs. 5-FU/LV/oxaliplatin (FOLFOX) with BEV (Bridgewater et al, ESMO 2013). Toxicity may be a limitation of the regimen; alternating tx with FOLFOX and FOLFIRI (sequential FOLFOXIRI) may improve the tolerability of treating 1L pts with all three agents. The efficacy and safety of FOLFOXIRI-BEV have yet to be investigated in the US, and the impact of maintenance and of BEV tx beyond disease progression (PD) following FOLFOXIRI-BEV is unknown. Methods: The STEAM study (NCT01765582) is a randomized, open-label, US-based, phase 2 trial investigating sequential or concurrent FOLFOXIRI-BEV vs. FOLFOX-BEV and maintenance tx in pts with previously untreated mCRC. Key eligibility criteria include unresectable mCRC and age 18–75 years. Pts are randomized 1:1:1 to concurrent FOLFOXIRI-BEV, sequential FOLFOXIRI-BEV (alternating FOLFOX and FOLFIRI q4w), or FOLFOX-BEV q2w during a four to six month induction phase (BEV 5 mg/kg in each arm). After induction, pts receive 5-FU/LV + BEV (5 mg/kg) q2w or capecitabine + BEV (7.5 mg/kg) q3w as maintenance tx until PD. After PD, pts receive second-line (2L) 5-FU–based chemotherapy (physician’s choice) with BEV (dose equivalent of 2.5 mg/kg/week) until 2L PD. Pts are stratified by extent of metastatic disease (liver-limited vs non–liver-limited), primary tumor location (right- vs left-sided), and study center. Primary objectives are to evaluate 1L ORR (concurrent FOLFOXIRI-BEV vs FOLFOX-BEV), 1L PFS (concurrent and sequential FOLFOXIRI-BEV vs FOLFOX-BEV), and safety. Secondary objectives include resection rate, rate of conversion to resectable disease, time to 2L PFS, and overall survival (concurrent and sequential FOLFOXIRI-BEV vs FOLFOX-BEV). The study has enrolled 109 of a planned 280 pts to date. Clinical trial information: NCT01765582.