Background: Induction chemotherapy (CT) before CRT and surgery is now considered a new treatment alternative for patients with locally advanced rectal (LAR) cancer. Willet et al. (Nat Rev 2004) demonstrated that Induction treatment with anti VEGF therapy bevacizumab (BEV) before CRT, decreased tumor interstitial fluid pressure and blood flow, suggesting normalization of the tumor vasculature. The AVCROSS phase II trial (Nogue, The Oncologist 2011) showed that BEV combined with induction CT followed by BEV combined with CRT and surgery produced high pCR rates (36%) but with an unacceptable rate of surgical reoperations. Aflibercept (Afli) (ziv-aflibercept in the US) is a novel anti-angiogenic agent that acts as a soluble receptor that binds to human VEGF-A, VEGF-B, PlGF. We hypothesized that administering induction Afli/FOLFOX followed by CRT will improve pCR rate without compromise wound healing. Methods: We will conduct a multicenter phase II randomized trial, stratified by mrT stage and institution, with 2:1 allocation, comparing preoperative induction mFOLFOX6 with or without Afli prior to standard CRT (capecitabine with 50.4 Gy) and surgery. Primary endpoint: pathological complete response (pCR). 180 patients (p) will be recruited (120 p for mFOLFOX6 + Aflibercept group and 60 p for mFOLFOX6). Assumptions: 10% of dropouts, 0.10% one-sided type-I error, 80% power to detect a 15% difference in pCR. 2 interim analyses for safety, efficacy/futility (Lan de Mets, O’brien-Fleming). Major eligibility criteria: High-risk rectal cancer with 1 of the following criteria on high resolution MRI: Extramural vascular invasion or extramural extension > 5 mms into perirectal fat or mesorectal fascia threatened or involved in middle T3 tumors. mrT3 distal and mrT4 or N2 middle or distal tumors. Enrollment began in January 2015. ClinicalTrials.gov Identifier: NCT02340949 Clinical trial information: 02340949.