Background: For advanced colorectal cancer (CRC), fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin) with VEGF inhibitors (bevacizumab) is standard first-line treatment. However, once this treatment had been used, the second line treatment is limited. Although continuation of bevacizumab after first progression can improve PFS and OS, the benefit of bevacizumab may be reduced compared with who never pre-treated with bevacizumab (the ML18147 study). Anlotinib is an oral small molecule tyrosine kinases inhibitor, targeting VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α/β and c-kit. mXELIRI is a chemotherapy regimen consisting of irinotecan and capecitabine. The trial is to investigate the efficacy and safety of anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pre-treated with bevacizumab plus standard chemotherapy. Methods: This is a multi-center, prospective, single-arm, 2-part, phase Ib/II study. Eligible pts are aged 18-75 years with histologically and radiographically confirmed mCRC who had progressed or intolerant with bevacizumab plus FOLFOX or CAPEOX regimen chemotherapy treatment. ECOG performance status 0 - 1, and adequate organ function. Treatment: anlotinib (8mg, 10mg or 12mg), po, qd, on days 1-14 every 3 weeks; irinotecan 180-200 mg/m², iv, on day 1 every 3 weeks; capecitabine, 800 mg/m², po, bid, on days 1-14 every 3 weeks. For the phase 1b segment, a standard 3+3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of anlotinib. 3 patients are enrolled and treated per dose level (8mg,10mg,12mg). If no DLT, dose is escalated for the next cohort of 3 patients; If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs；If ≥ 2 DLTs, prior dose level is defined as MTD. MTD decided when 6 patients are treated at a dose level with < 2 DLTs. Primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and quality of life (QoL). Based on a one-sided one sample log-rank test with 2.5% Type I error, 80% power to detect an improvement in ORR from 5.4% to 15%, there will be 94 patients consider 20% of patients fall off. Research Sponsor: Guangdong Provincial Hospital of Chinese Medicine Clinical trial information: NCT05035914.