Background: Colorectal cancer (CRC) is the third most common cancer. In the metastatic (m) setting, the 5-year relative overall survival is approximately 15%. Conventional treatment comprises fluorouracil (5-FU)–based chemotherapy. Recently, targeted therapies have been studied for specific molecular subtypes. c-Met overexpression frequently occurs in a variety of tumors, including CRC. ABBV-400 is a c-Met–directed antibody-drug conjugate composed of the monoclonal antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Preliminary data from the first-in-human study of ABBV-400 in patients with advanced solid tumors indicate encouraging efficacy of ABBV-400 monotherapy in patients with third-line or later mCRC. This phase 2 randomized study evaluates the safety, efficacy, and optimal dose of ABBV-400 in combination with 5-FU, folinic acid (FA), and bevacizumab (bev) in patients with mCRC with progression after first line (1L) treatment. Methods: Global, open-label, phase 2 randomized controlled study (NCT06107413). Eligible patients (≥18 years) have confirmed unresectable mCRC and measurable disease per RECIST v1.1, are microsatellite stable or mismatch repair proficient, BRAF V600E wild type, and have progression after 1L combination chemotherapy ± an anti-vascular endothelial growth factor or anti-epidermal growth factor receptor antibody. Primary objectives are (a) optimize ABBV-400 dose in combination with 5-FU, FA, and bev; (b) evaluate the efficacy of the combination, using objective response and progression-free survival as dual primary endpoints; (c) evaluate the safety and tolerability of the combination. Approximately 206 patients planned for enrollment in 2 stages: safety lead-in dose escalation (stage 1; n=30) and dose optimization (stage 2; n=176). In stage 1, patients receive escalating doses of ABBV-400 either every 2 weeks (Q2W; 0.8–2.4 mg/kg) or every 4 weeks (Q4W; 1.6–3.0 mg/kg) in combination with Q2W 5-FU (2400 mg/m² infusion), FA (200 mg/m²), and bev (5 mg/kg) in 28-day cycles. Dose escalation of ABBV-400 uses a Bayesian optimal interval design, with target toxicity rate of 30%. Dose-limiting toxicities (DLT) are assessed during cycle 1, with ≥6 DLT evaluable patients required to declare a dose safe for the dose-optimization stage. In stage 2, patients are randomized to up to 4 ABBV-400 dose cohorts (2 with Q2W and 2 with Q4W ABBV-400 schedule; all in combination with Q2W 5-FU, FA, and bev) and a comparator cohort (irinotecan [180 mg/m²] + 5-FU [400 mg/m² bolus and 2400 mg/m² infusion] + FA [200 mg/m²] + bev [5 mg/kg]; all Q2W). Patients are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment was initiated in November 2023, with 3 patients enrolled as of January 4, 2024. Clinical trial information: NCT06107413.