Background: The first-line FOLFOXIRI with Bevacizumab (BEV) is highly effective and regarded as one of standard-of-care treatments in patients (pts) with metastatic colorectal cancer (mCRC) despite a high incidence of adverse events (AEs) such as neutropenia and diarrhea. The AXEPT, Asian Phase III study showed CAPIRI+BEV [Capecitabine (CAP: 1600 mg/m²), Irinotecan (IRI: 200 mg/m²) and BEV (7.5 mg/m²)] q3wk was non-inferior to FOLFIRI+BEV in pts with the second-line mCRC, with a lower incidence hematologic toxicity favoring CAPIRI+BEV over FOLFIRI+BEV. Based on these, a reduced dose of CAP and IRI regimen in combination with Oxaliplatin (OX) and BEV, CAPOXIRI+BEV may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: QUATTRO-II is an open-label, multicenter, randomized phase II study. Key eligibility criteria are as follows; age ≥20 years, ECOG performance status (PS) 0-1 (≥71 years age: PS 0), adequate organ function, and UGT1A1 single-heterozygous (UGT1A1*1/*6 or *1/*28) or wild-type (*1/*1) genotype. Pts are randomized to either the recommended dose of CAPOXIRI+BEV or FOLFOXIRI+BEV (OX: 85 mg/m², IRI: 165 mg/m², l-leucovorin: 200 mg/m², 5-FU: 3200 mg/m²), with the strata of RAS/BRAF status, previous adjuvant OX, tumor sidedness, and UGT1A1 status. Induction triplet chemotherapy plus BEV treatments are administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The recommended dose of CAPOXIRI+BEV will be determined as a safety-lead-in before moving forward to the phase II main part. The primary endpoint is progression-free survival (PFS). The similarity of PFS between the two arms is evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls in between 0.80 and 1.25. Ensuring 70% probability that the observed HR will be “0.8<HR<1.25” under the assumption of the true HR of 1.0, a total of 100 patients will be needed with 3-year study period. Secondary endpoints included overall survival, overall response rate, safety, and patient-reported outcome (FACT/GOG-Ntx4). The enrollment started in October 2019. Clinical trial information: NCT04097444