Background: ME-344 is a synthetic small molecule that inhibits oxidative phosphorylation, resulting in energy starvation and cell death via caspase-dependent and -independent mechanisms. The activity of mitochondrial inhibitors is enhanced when mitochondrial respiration is upregulated, a situation achieved in solid tumors by inducing vascular normalization and hypoxia correction with antiangiogenics. In a CT26 colon carcinoma syngeneic murine model, ME-344 in combination with regorafenib showed significantly reduced tumor growth compared to regorafenib alone (Navarro et al. Cell Reports. 2016;15:2705). A randomized phase 0/1 window of opportunity study in HER2-negative breast cancer showed significant decrease in the proliferation marker Ki67 in patients administered ME-344 plus bevacizumab vs. bevacizumab alone (Quintela-Fandino et al, Clin Cancer Res. 2020;26:35). The current study evaluates the safety and efficacy of ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer, a clinical setting where continued antiangiogenic inhibition has established benefit. Prior phase 1-1b studies of ME-344 as a single agent and in combination have established the RP2D at 10 mg/kg when administered intravenously weekly. Methods: This is an open-label phase 1b study in patients ≥18 years old with metastatic colorectal cancer after failure of standard therapies, including fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens, anti-EGFR if RAS wild-type, PD/L-1-blocking antibody if MSI-H/dMMR, and BRAF-targeted therapy if BRAF V600E mutated. Other key eligibility criteria include measurable disease, ECOG performance status 0-1, adequate bone marrow, liver and renal function, no uncontrolled brain metastatic disease, no peripheral neuropathy grade ≥2, no uncontrolled hypertension or diabetes, and no increased hemorrhagic risk. Enrollment will proceed in 2 cohorts of 20 patients each. Cohort 1 will be administered ME-344 at 10 mg/kg on days 1, 8, and 15 of a 28-day cycle and bevacizumab 5 mg/kg on days 1 and 15. Cohort 2 will be administered ME-344 at 10 mg/kg and bevacizumab 5 mg/kg both on days 1 and 15 of a 28-day cycle. Treatment will continue until disease progression or intolerance. Tumor assessment is performed every 8 weeks for 6 months and then every 3 months using RECIST-1 criteria. The primary endpoint is 16-week PFS. Secondary endpoints are PFS, response rate, and safety. Correlative analysis will evaluate treatment-related metabolic response. The study is actively enrolling, funded by MEI Pharma, and registered under NCT02100007. Clinical trial information: NCT02100007.