Background: Anti-angiogenic therapy for CRC has been accepted as standard therapy with approval of bevacizumab (bev) in both first-line and second-line settings. At the time this study was started, the benefit of continuing an anti-angiogenic in second line therapy was unproven. Ramucirumab (RAM, IMC 1121b) is a humanized antibody directed against the VEGF-R2 receptor, which may prove to have different activity compared to anti-VEGF antibody (bev). Additionally, while combining the anti-EGFR antibody, cetuximab (CMAB), with bev in first-line unselected patients was not effective, it is unknown whether the same may be true with RAM plus CMAB in a second-line setting for KRAS-selected patients. Methods: The study was designed as a randomized phase II trial with 147 patients assigned to IC = Irinotecan (I) 180 mg/m2 IV plus CMAB 500 mg/m2 IV q2w versus ICR = IC plus RAM 8 mg/kg IV q2w. Eligibility included prior treatment on one prior oxaliplatin and bev-containing regimen and progression within 42 days of last bev, PS 0-1, KRAS codon 12,13 wild-type and standard other chemo and bev criteria. Doses were modified for neutropenia, diarrhea, mucositis, rash and grade 3 other toxicities. The study was activated 10/8/10. After the first 35 patients were enrolled, accrual was held 6/24/12 for toxicity analysis per protocol. More grade 3 events of mucositis, diarrhea, neutropenia and perforation events (including peri-rectal abscesses) were seen in the ICR arm. The study has been modified to reflect the actual doses received, and will reopen with modified ICR (mICR) = I 150 mg/m2, CMAB 400 mg/m2 and RAM 6 mg/kg IV q2w. An additional 100 pts will be accrued to the revised study, giving 85% power to detect improved median PFS from 4.5 to 7.65 months. New eligibility criteria include any progression from 1^st line chemo (on or off), normal albumin, no bowel perforation or obstruction in last 6 months. The revision was approved by CTEP in December 2013 and will re-open to accrual in March 2014, with SWOG participation. Clinical trial information: NCT01079780.