Background: Consensus treatment guidelines are unavailable for patients with diffuse large B-cell lymphoma (DLBCL) whose disease progresses after first-line therapy. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including hematological malignancies. Zilovertamab vedotin (ZV; MK-2140, previously known as VLS-101), an antibody-drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E, targets ROR1 and has shown promising efficacy and tolerability in hematological malignancies, including DLBCL. This 2-part (part 1, dose confirmation; part 2, dose expansion), open-label, randomized, active-control, phase 2/3 study (NCT05139017) will assess safety and efficacy of ZV + standard of care in patients with relapsed/refractory (R/R) DLBCL. Methods: Eligible adult patients must have histologically confirmed DLBCL per WHO classification, ineligible for or have failed autologous stem cell transplantation and chimeric antigen receptor T cell therapy, R/R DLBCL after ≥1 line of prior therapy (cohort A) or ≥2 lines of prior therapy (cohort B), measurable disease per Lugano 2014 criteria, and Eastern Cooperative Oncology Group performance status ≤2. Approximately 420 patients will be enrolled in the study (cohort A, n = 230; cohort B, n = 190). In the part 1 dose confirmation phase, 30 patients from cohort A will receive ZV (at increasing doses: 1.5, 1.75, 2.0, 2.25, and 2.5 mg/kg; starting at 1.75 mg/kg) plus gemcitabine-oxaliplatin + rituximab (R-GemOx) to establish the recommended phase 2 dose using the mTPI design. A safety run-in phase of part 2 will include 30 patients from cohort B and will receive ZV + bendamustine and rituximab (BR). Approximately 360 patients will be included in the part 2 dose expansion phase (cohort A, n = 200; cohort B, n = 160). Patients from cohort A will be randomly assigned 1:1 to 6 cycles of either ZV + R-GemOx or R-GemOx. Patients from cohort B will be randomly assigned 1:1 to 6 cycles of either ZV + BR or BR. Disease response assessments by CT and PET scans will occur every 12 weeks until disease progression or study discontinuation. Adverse events (AEs) will be monitored throughout the study and graded per NCI CTCAE version 5.0. In part 1, the primary end point is safety, including DLTs, AEs, and discontinuation due to AEs. The primary end point for cohorts A and B in the dose expansion phase of part 2 will be progression-free survival by blinded independent central review per Lugano 2014 criteria. Key secondary end points in the dose expansion phase of part 2 for both cohorts include objective response rate (including complete response and partial response) and duration of response, both per Lugano 2014 criteria and overall survival. Clinical trial information: NCT05139017.