Background: FTD/TPI has been widely used as one of the standard therapies in the late-line treatment for patients with mCRC, and the efficacy of FTD/TPI plus BEV combination was also recently reported in the SUNLIGHT trial. However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. On the other hand, several phase II studies suggested that modifying the FTD/TPI schedule in combination with BEV from 4-week intervals (2 weeks-on, 2 weeks-off) to bi-weekly dosing (1 week-on, 1 week-off) reduced hematologic toxicities without reducing efficacy. Therefore, we commenced a phase III study to confirm the superiority of bi-weekly FTD/TPI plus BEV to 4-week intervals FTD/TPI monotherapy. Methods: This study is an open-label, multicenter, phase III trial conducted in Colorectal Cancer Study Group of Japan Clinical Oncology Group. We randomly assigned, in a 1:1 ratio, patients who were refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, angiogenesis inhibitor, anti-EGFR antibody (if RAS-wild type), BRAF inhibitor and anti-EGFR antibody (if BRAF^V600E-mutant), and immune check point inhibitor (if dMMR/MSI-H) to the treatment of mCRC to receive 4-week intervals FTD/TPI 70mg/m²/day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5mg/kg (arm B). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. Results: In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). Patient backgrounds between the two arms were well balanced. At the data cut-off date, all enrolled patients discontinued protocol treatment due to disease progression (69.3% vs. 59.7%) and treatment-related adverse events (6.7% vs. 2.6%). With a median follow-up of 8.3 months for surviving patients (OS events, 45% vs. 40%), the median OS was 12.2 vs. 11.8 months (hazard ratio [HR], 0.905; 95% confidence interval [CI], 0.556 to 1.473) and the median PFS was 2.4 vs. 4.0 months (HR, 0.607; 95% CI, 0.426 to 0.865). RR was 1.3% vs. 5.3% and DCR was 45.3% vs. 53.3%. The most common Grade 3 or higher adverse events in each group were neutropenia (46.6% vs. 24.0%), anemia (15.1% vs. 4.0%), fatigue (2.7% vs. 8.0%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%) and febrile neutropenia (4.1% vs. 0%). Conclusions: Although this study was terminated early, the bi-weekly FTD/TPI plus BEV combination in late-line chemotherapy for patients with mCRC resulted in prolonged PFS and reduced hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy. Long-term results including OS are currently under follow-up. Clinical trial information: jRCTs031210544.