Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have poor outcomes following standard treatment. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an antibody–drug conjugate (ADC) comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin, received accelerated (US) and conditional (EU) approval for R/R DLBCL after ≥2 lines of systemic therapy based on data from the phase 2 LOTIS-2 trial (Caimi PF et al. Lancet Oncol. 2021;22[6]:790). Rituximab (R), an anti-CD20 monoclonal antibody, is part of standard frontline and subsequent DLBCL immunotherapy. Preclinical evidence suggests that R + anti-CD19 ADC therapy may result in prolonged tumor control (Ryan MC et al. Blood. 2017;130[18]:2018). LOTIS-5 will evaluate Lonca-R vs standard immunochemotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in R/R DLBCL. Methods: This phase 3, randomized, open-label, 2-part, multicenter study of Lonca-R in patients with R/R DLBCL (NCT04384484) consists of part 1 (a nonrandomized safety run-in with Lonca-R) and part 2 (a randomized efficacy and safety evaluation of Lonca-R vs R-GemOx). Approximately 350 patients will be enrolled across both parts: part 1 is complete; part 2 will enroll approximately 330 patients (randomized 1:1) to achieve 262 events for the primary end point analysis of progression-free survival by independent central review. Secondary end points include overall survival, overall response rate (2014 Lugano classification), complete response rate, duration of response, frequency and severity of adverse events, change from baseline in safety assessments, concentration and pharmacokinetic parameters of Lonca (antibody [conjugated and total] and unconjugated PBD), antidrug antibody titers, and changes in patient-reported outcomes from baseline. The dosing regimen for Lonca-R is Lonca 150 μg/kg + rituximab 375 mg/m² every 3 weeks (Q3W) for 2 cycles, then Lonca 75 μg/kg + rituximab 375 mg/m² Q3W for up to 6 additional cycles. The dose regimen of R-GemOx is rituximab 375 mg/m², gemcitabine 1000 mg/m², and oxaliplatin 100 mg/m² every 2 weeks for up to 8 cycles. Key eligibility criteria include age ≥18 years, pathologic diagnosis of DLBCL (including patients with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, ≥1 line of prior systemic therapy, previous stem cell transplant >30 days (autologous) or >60 days (allogenic) before start of study drug or stem cell transplant ineligibility, and measurable disease (2014 Lugano classification). The randomized part of LOTIS-5 began in January 2022; the estimated primary completion date is September 2025. Enrollment continues; 254 patients are enrolled across sites in North America, South America, Europe, and Asia. Clinical trial information: NCT04384484.