Background: Despite the utilization of systemic targeted agents with chemotherapy for mCRC, long-term survival remains poor. Disease progression in mCRC is common, and SOC options are associated with reduced quality of life (QoL) that has been negatively associated with survival. Here, we present daNIS-3, a Phase II, randomized, open-label platform study (NCT04952753) of NIS793 and other investigational drug combinations in pts with second-line mCRC, with an emphasis on the exploratory PROs and biomarker assessments. Methods: Eligible pts are adults with microsatellite-stable mCRC who have progressed on or within 6 months of one prior line of systemic therapy for mCRC and are not amenable to potentially curative surgery. Pts are treated with NIS793 (Day [D]1 ± D15; 2100 mg) + SOC (D1 + D15; bevacizumab [5 mg/kg] + FOLFIRI/mFOLFOX6) +/- tislelizumab (D1; 300 mg), or SOC alone. All drugs are administered intravenously on 28-day cycles. Each investigational arm begins with a safety run-in involving ≥6 eligible pts; safety run-in of the tislelizumab arm follows completion of the NIS793 + SOC safety run-in. Following confirmation of the recommended dose, pts are randomized (2:1) in the expansion part to receive investigational drug(s) + SOC (n≈75) or SOC alone (n≈38). Exploratory objectives include PROs (expansion part only) and biomarker assessments. PRO measures (EORTC-QLQ-C30, QLQ-CR29, PRO-CTCAE, and FACT-GP5) will be collected electronically throughout the study and used to explore pt-reported disease symptoms, health-related QoL, functioning, and treatment-related side effects. Potential biomarkers of response and mechanisms of resistance will be assessed in tumor and blood samples. Baseline archival/tumor biopsies will be collected to assess the correlations between clinical response and molecular subtype, tumor mutational burden, TGF-β gene signatures, and immune-related biomarkers. Optional biopsies during Cycle 3 and at the end of treatment will be used to assess pharmacodynamic effects of NIS793 on the tumor microenvironment and resistance mechanisms, respectively. Circulating tumor DNA and cytokine and TGF-β levels will be continuously monitored through serial blood samples to evaluate treatment benefit, correlate alterations with response, and assess the effect(s) of NIS793. An additional blood sample for nucleic acid analysis will evaluate the effect(s) of TGF-β blockade. The daNIS-3 study started on November 15, 2021, and plans to recruit approximately 266 pts from 77 sites across 19 countries. Clinical trial information: NCT04952753.