Background: Colorectal cancer is the third most prevalent cancer, and the prognosis of patients with advanced metastatic (mCRC) is poor. The efficacy of standard of care (SOC) second-line chemotherapy combinations with anti-vascular endothelial growth factor (VEGF) therapies remains modest. Previously treated advanced mCRC that is microsatellite stable (MSS/pMMR) represents nearly 95% of the metastatic population and remains a high unmet medical need. DKN-01 is a humanized IgG4 monoclonal antibody (mAb) targeted against Dickkopf-related protein 1 (DKK1), a regulator of the Wnt signaling pathway. DKK1 has been identified as a potential oncogenic driver in CRC and has been correlated with 5FU resistance. Therefore, DKK1 expression is a potential predictive biomarker for chemotherapeutic resistance in CRC. Methods: This is a phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate safety and efficacy of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus SOC [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced mCRC patients. In Parts A and B, approximately 150 advanced MSS, BRAF Wild Type mCRC patients with radiographic progression during or following 1 prior line of systemic treatment will be enrolled in the study. Part A is a safety run-in with DKN-01 plus FOLFIRI/FOLFOX and bevacizumab in at least 20 safety evaluable patients. In Part B, approximately 130 patients will be randomized 1:1 to either the experimental (DKN-01 plus FOLFIRI/FOLFOX and bevacizumab) or control arm (FOLFIRI/FOLFOX and bevacizumab), using a central stratified block randomization scheme and stratified based on DKK1 RNAscope tumor percentage score (TPS) (≥1% vs <1%). Primary endpoint is progression free survival and secondary endpoints include overall response rate, duration of response, overall survival and incidence of ≥Grade 3 related treatment-related adverse events (TRAEs). Exploratory endpoints will include evaluation of efficacy outcomes based upon tumoral DKK1 expression. Recruitment is ongoing. Clinical trial information: NCT05480306.