Background: The preferred first-line regimen for DLBCL is rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); but novel therapies are needed. A recent phase 3 study showed that replacing vincristine with an antibody-drug conjugate (ADC) is a viable approach (Tilly H et al. N Engl J Med. 2022;386:351-363). Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is an oncofetal protein that is minimally expressed in adult tissues and overexpressed in DLBCL. ZV is an ADC comprising a humanized IgG1 monoclonal anti-ROR1, a proteolytically cleavable linker, and the antimicrotubule agent, monomethyl auristatin E. The single-arm, open-label, phase 2 waveLINE-007 study (NCT05406401) will investigate ZV combined with R-CHP in patients with previously untreated DLBCL. Part 1 is being conducted to determine safety and tolerability and recommended phase 2 dose (RP2D) of ZV in combination with R-CHP. Part 2 will be conducted to investigate efficacy of ZV at the RP2D with R-CHP. Methods: Eligible patients will be ≥18 years of age and have previously untreated histologically confirmed DLBCL, positron emission tomography (PET)–positive disease verified by blinded independent central review (BICR), an ECOG PS of 0 or 1, and adequate organ function. Patients diagnosed with primary mediastinal B-cell lymphoma, with a history of transformation of indolent disease to DLBCL, or active central nervous system lymphoma will be excluded. Approximately 60 patients will be enrolled (part 1, n = 45; part 2, n = 15). Part 1 will use a modified toxicity probability interval design to establish the RP2D of ZV when administered with R-CHP. The starting dose of ZV will be 1.75 mg/kg (modified to 1.5, 2.0, 2.25, or 2.5 mg/kg) administered as an intravenous infusion every 3 weeks (Q3W) in combination with R-CHP. In part 2, an additional 15 patients will receive ZV at RP2D plus R-CHP Q3W for up to 6 cycles until disease progression per Lugano 2014 criteria, unacceptable toxicity, or withdrawal. Disease response assessment, computed tomography, and PET will occur at baseline and cycles 3 and 6. Adverse events (AEs) will be monitored up to 30 days after cessation of treatment (90 days for serious AEs, or 30 days if new anticancer therapy is initiated). AEs will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Primary end points are safety and tolerability and RP2D for ZV in combination with R-CHP, and complete response rate per Lugano 2014 criteria as assessed by the investigator. Secondary end points are objective response rate and duration of response per Lugano 2014 criteria by investigator review. Exploratory end points include progression-free survival per Lugano 2014 criteria by BICR and overall survival. Recruitment is currently underway. Clinical trial information: NCT05406401.